Electrospun medicated gelatin/polycaprolactone Janus fibers for photothermal-chem combined therapy of liver cancer.

Liver cancer is a common cancer in the world, and core-shell nanoparticles as a commonly used combination therapy for local tumor ablation, have many shortcomings. In this study, photothermal Janus nanofibers were prepared using a electrospinning technology for tumor treatment, and the products were characterized and in vitro photothermal performance investigated. The micromorphology analysis showed that the photothermic agent CuS and electrospun fibers (loaded with CuS and anticancer drug dihydromyricetin) were successfully prepared, with diameters of 11.58 ± 0.27 µm and 1.19 ± 0.01 µm, respectively. Water contact angle and tensile test indicated that the fiber membranes has a certain hydrophilic adhesion and excellent mechanical strength. The fiber membranes has 808 nm near-infrared laser photothermal heating performance and photothermal stability, and it also has a strong response to the laser that penetrates biological tissue. In addition, in vitro cell culture and in vivo implantation study showed that the fiber membranes could kill HepG2 hepatocellular carcinoma cells combined with photothermal-chem and could be enriched in the implantation area, respectively. Hence, the Janus membranes may be a potential cancer treatment material.

The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.

Expression pattern of PD-1/PD-L1 in primary liver cancer with clinical correlation.

Immunotherapy, including ICIs, has emerged as an invaluable treatment option for advanced PLC. Nevertheless, the expression patterns of PD-L1 and PD-1 in PLC remain incompletely understood. In this study, the expression pattern and clinical correlation of PD-L1 and PD-1 were analysed in 5245 PLC patients. The positivity rates of PD-L1 and PD-1 were very low in the patient PLCs, but the positivity rates of PD-L1 and PD-1 were higher in the ICC and cHCC-ICC than in HCC. The expression of PD-L1 and PD-1 correlated with the malignant phenotypes and clinicopathological characteristics of PLC. Interestingly, PD-1 positivity might serve as an independent prognostic factor. Based on a systematic analysis of a large amount of PLC tissues, we proposed a novel classification of PD-1/PD-L1 expression in HCC and ICC. In light of this stratification, we observed a close correlation between PD-L1 levels and PD-1 expression in HCC and ICC.

Fast and convenient delivery of fluidextracts liquorice through electrospun core-shell nanohybrids.

Introduction: As an interdisciplinary field, drug delivery relies on the developments of modern science and technology. Correspondingly, how to upgrade the traditional dosage forms for a more efficacious, safer, and convenient drug delivery poses a continuous challenge to researchers. Methods, results and discussion: In this study, a proof-of-concept demonstration was conducted to convert a popular traditional liquid dosage form (a commercial oral compound solution prepared from an intermediate licorice fluidextract) into a solid dosage form. The oral commercial solution was successfully encapsulated into the core-shell nanohybrids, and the ethanol in the oral solution was removed. The SEM and TEM evaluations showed that the prepared nanofibers had linear morphologies without any discerned spindles or beads and an obvious core-shell nanostructure. The FTIR and XRD results verified that the active ingredients in the commercial solution were compatible with the polymeric matrices and were presented in the core section in an amorphous state. Three different types of methods were developed, and the fast dissolution of the electrospun core-shell nanofibers was verified. Conclusion: Coaxial electrospinning can act as a nano pharmaceutical technique to upgrade the traditional oral solution into fast-dissolving solid drug delivery films to retain the advantages of the liquid dosage forms and the solid dosage forms.

Electrospun fibers with blank surface and inner drug gradient for improving sustained release.

New engineering methods and advanced strategies are highly desired for creating novel drug sustained release nanomaterials. In this study, a trilayer concentric spinneret was explored to implement several multifluid electrospinning processes. A trilayer core-shell nanofiber was successfully fabricated, which comprise a drug-free polymeric coating and an inner drug gradient distribution, and then compared with bilayer core-shell and monolithic medicated nanofibers. All the electrospun nanofibers similarly consisted of two components (guest drug acetaminophen and host polymer cellulose acetate) and presented a linear morphology. Due to the secondary interactions within nanofibers, loaded drug with amorphous state was detected, as demonstrated by SEM, DSC, XRD, and FTIR determinations. In vitro and in vivo gavage treatments to rats tests were carried out, the trilayer nanofiber with an elaborate structure design were demonstrated to provide better drug sustained release profile than the bilayer core-shell nanofibers in term of initial burst release, later tail-off release and long sustained release time period. The synergistic mechanism for improving the drug sustained release behaviors is disclosed. By breaking the traditional concepts about the implementation of multifluid electrospinning and the strategy of combining surface properties and inner structural characteristics, the present protocols open a new way for developing material processing methods and generating novel functional nanomaterials.

Electrospun self-emulsifying core-shell nanofibers for effective delivery of paclitaxel.

The poor solubility of numerous drugs pose a long-existing challenge to the researchers in the fields of pharmaceutics, bioengineering and biotechnology. Many "top-down" and "bottom-up" nano fabrication methods have been exploited to provide solutions for this issue. In this study, a combination strategy of top-down process (electrospinning) and bottom-up (self-emulsifying) was demonstrated to be useful for enhancing the dissolution of a typical poorly water-soluble anticancer model drug (paclitaxel, PTX). With polyvinylpyrrolidone (PVP K90) as the filament-forming matrix and drug carrier, polyoxyethylene castor oil (PCO) as emulsifier, and triglyceride (TG) as oil phase, Both a single-fluid blending process and a coaxial process were utilized to prepare medicated nanofibers. Scanning electron microscope and transmission electron microscope (TEM) results clearly demonstrated the morphology and inner structures of the nanofibers. The lipid nanoparticles of emulsions after self-emulsification were also assessed through TEM. The encapsulation efficiency (EE) and in vitro dissolution tests demonstrated that the cores-shell nanofibers could provide a better self-emulsifying process int terms of a higher EE and a better drug sustained release profile. Meanwhile, an increase of sheath fluid rate could benefit an even better results, suggesting a clear process-property-performance relationship. The protocols reported here pave anew way for effective oral delivery of poorly water-soluble drug.

Effects of exercise by type and duration on quality of life in patients with digestive system cancers: A systematic review and network meta-analysis.

BACKGROUND: There is scant evidence regarding the effects of exercise type and duration on quality of life (QoL) in digestive system cancer (DSC) survivors. We aim to investigate the optimal type and duration of exercise to improve QoL for DSC survivors through a systematic review and network meta-analysis. METHODS: A systematic literature search of PubMed, Embase, and Web of Science was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving all kinds of exercise in adult patients with DSCs, and the comparator was in standard care or other types of exercise. The primary outcome was QoL, including general health, physical health, mental health, and role function. Secondary outcomes included cancer-related symptoms such as fatigue, insomnia, depression, anxiety, and duration of hospital stay. The network meta-analyses were performed using a random-effect model. RESULTS: The analysis included 32 eligible articles and a total of 2558 participants. Our primary outcome indicated that short-term aerobic exercise significantly enhanced general health (standardized mean difference (SMD) = 0.66, 95% credible intervals (CrIs): 0.05 to 1.30), and also contributed to a better mental health (SMD = 0.38, 95%CrI: -0.05 to 0.81) and role function (SMD = 0.48, 95%CrI: -0.27 to 1.20). Although without significant changes, short-term resistance exercise tended to increase the physical health of patients with DSCs (SMD = 0.69, 95%CrI: -0.07 to 1.50) and effective in alleviating fatigue (SMD = -0.77, 95%CrI: -1.50 to 0.01). Short-term aerobic exercise was related to a lower score of insomnia (SMD = -1.20, 95%CrI: -2.40 to 0.06), depression (SMD = -0.51, 95%CrI: -1.50 to 0.45), and anxiety (SMD = -0.45, 95%CrI: -1.30 to 0.34). All types of exercise related to a trend of declined hospital stays (-0.87 to -5.00 day). Long-term resistance exercise, however, was negatively associated with general health (SMD = -0.33, 95%CrI: -1.70 to 1.00), physical health (SMD = -0.18, 95%CrI: -1.30 to 0.90), and role function (SMD = -1.20, 95%CrI: -2.50 to 0.11). CONCLUSION: This study suggests that short-term aerobic exercise, with or without resistance exercise programs, enhances QoL (especially for general health) as well as relieves cancer-related symptoms for DSC survivors, while long-term resistance exercise may have negative effects, and thus should be adopted cautiously. These results provide important evidence for the management of DSCs.

Electrospun nanofiber-based glucose sensors for glucose detection.

Diabetes is a chronic, systemic metabolic disease that leads to multiple complications, even death. Meanwhile, the number of people with diabetes worldwide is increasing year by year. Sensors play an important role in the development of biomedical devices. The development of efficient, stable, and inexpensive glucose sensors for the continuous monitoring of blood glucose levels has received widespread attention because they can provide reliable data for diabetes prevention and diagnosis. Electrospun nanofibers are new kinds of functional nanocomposites that show incredible capabilities for high-level biosensing. This article reviews glucose sensors based on electrospun nanofibers. The principles of the glucose sensor, the types of glucose measurement, and the glucose detection methods are briefly discussed. The principle of electrospinning and its applications and advantages in glucose sensors are then introduced. This article provides a comprehensive summary of the applications and advantages of polymers and nanomaterials in electrospun nanofiber-based glucose sensors. The relevant applications and comparisons of enzymatic and non-enzymatic nanofiber-based glucose sensors are discussed in detail. The main advantages and disadvantages of glucose sensors based on electrospun nanofibers are evaluated, and some solutions are proposed. Finally, potential commercial development and improved methods for glucose sensors based on electrospinning nanofibers are discussed.

Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study.

Background: There is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients. Methods: This study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared. Results: The incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1-30.9) vs. 29.7 (95% CI: 21.4-38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1-16.3) vs. 15.9 (95% CI: 8.3-23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9-9.2) vs. 8.0 (95% CI: 5.1-10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380). Conclusions: Regorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14-22% and 62-60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.

Microfluidic Production of Zwitterion Coating Microcapsules with Low Foreign Body Reactions for Improved Islet Transplantation.

Islet transplantation is a promising strategy for type 1 diabetes mellitus (T1DM) treatment, whereas implanted-associated foreign body reaction (FBR) usually induces the necrosis of transplanted islets and leads to the failure of glycemic control. Benefiting from the excellent anti-biofouling property of zwitterionic materials and their successful application in macroscopic implanted devices, microcapsules with zwitterionic coatings may be promising candidates for islet encapsulation. Herein, a series of zwitterion-coated core-shell microcapsules is fabricated (including carboxybetaine methacrylate [CBMA]-coated gelatin methacrylate [GelMA] [CBMA-GelMA], sulfobetaine methacrylate [SBMA]-coated GelMA [SBMA-GelMA], and phosphorylcholine methacrylate [MPC]-coated GelMA [MPC-GelMA]) by one-step photopolymerization of inner GelMA and outer zwitterionic monomers via a handmade two-fluid microfluidic device and it is demonstrated that they can effectively prevent protein adsorption, cell adhesion, and inflammation in vitro. Interestingly, the zwitterionic microcapsules successfully resist FBR in C57BL/6 mice after intraperitoneal implantation for up to 4 months. After successfully encapsulating xenogeneic rat islets in the SBMA-GelMA microcapsules, sustained normoglycemia is further validated in streptozotocin (STZ)-induced mice for up to 3 months. The zwitterion-modified microcapsule using a microfluidic device may represent a platform for cell encapsulation treatment for T1DM and other hormone-deficient diseases.

BAP31 Promotes Proliferation, Invasion, and Metastasis of Liver Cancer Cells via Activating PI3K/AKT Pathway.

Background: Many breakthroughs have been made in the clinical treatment of liver cancer, but there are still many liver cancer patients with limited treatment methods. Therefore, it is very important to find targets for early diagnosis and specific treatment of liver cancer. Methods: During the operation, 32 pairs of tumor tissues and corresponding normal liver tissues were acquired from patients. The mRNA expression was measured by qPCR. The protein expression was evaluated via Western blot. Flow cytometry assay was performed to measure the cells apoptosis. CCK-8 assay was performed to detect cell proliferation. Transwell chamber assay was applied to detect migration and invasion of SNU-449 cells. Results: BAP31 was upregulated in liver cancer tissues and cells. Knockdown of BAP31 repressed cell proliferation and enhanced cell apoptosis of liver cancer. Knockdown of BAP31 apparently upregulated apoptosis-related proteins (Bax and Caspase-3), while it downregulated antiapoptotic proteins (Bcl-2). Knockdown of BAP31 repressed migration and invasion of SNU-449 cells. In contrast with the control and si-NC group, protein expression of MMP-2 and MMP-9 was obviously lower after si-BAP31 transfection of cells. Knockdown of BAP31 repressed PI3K/AKT signaling pathways in liver cancer cells. Conclusion: Knockdown of BAP31 repressed cell proliferation, migration, and invasion in liver cancer by suppressing PI3K/AKT/mTOR signaling pathways.

Strategies for sustained drug release from electrospun multi-layer nanostructures.

Among different kinds of modified release profiles, sustained drug release (SDR) has received the most attention due to its capability to provide a "safe, efficacious, and convenient" drug delivery effect. Electrospun nanofibers have shown their popularity in this interdisciplinary field, as demonstrated by the first reports about SDRs on drug delivery applications of blended nanofibers and core-shell nanofibers. Along with the evolution of electrospinning from a single-fluid blending process to coaxial, tri-axial, side-by-side, and other multi-fluid processes, more multi-chamber nanostructures can be created through a single-step straight forward manner. These multi-chamber nanostructures can act as a powerful platform to support a wide variety of new strategies for the development of novel SDR nanomaterials. Thus, this review describes a combination history of electrospinning and SDR and its further development trend. After a summary of the presently popular multi-chamber core-shell nanostructures, 15 strategies for furnishing SDR profiles are categorized and exemplified. The perspectives of electrospun multi-chamber nanostructures for further promoting SDR are narrated. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Development and validation of a nomogram to predict overall survival in patients with incidental gallbladder cancer: A retrospective cohort study.

Objective: The aim of this study was to develop and validate a nomogram to predict the overall survival of incidental gallbladder cancer. Methods: A total of 383 eligible patients with incidental gallbladder cancer diagnosed in Shanghai Eastern Hepatobiliary Surgery Hospital from 2011 to 2021 were retrospectively included. They were randomly divided into a training cohort (70%) and a validation cohort (30%). Univariate and multivariate analyses and the Akaike information criterion were used to identify variables independently associated with overall survival. A Cox proportional hazards model was used to construct the nomogram. The C-index, area under time-dependent receiver operating characteristic curves and calibration curves were used to evaluate the discrimination and calibration of the nomogram. Results: T stage, N metastasis, peritoneal metastasis, reresection and histology were independent prognostic factors for overall survival. Based on these predictors, a nomogram was successfully established. The C-index of the nomogram in the training cohort and validation cohort was 0.76 and 0.814, respectively. The AUCs of the nomogram in the training cohort were 0.8, 0.819 and 0.815 for predicting OS at 1, 3 and 5 years, respectively, while the AUCs of the nomogram in the validation cohort were 0.846, 0.845 and 0.902 for predicting OS at 1, 3 and 5 years, respectively. Compared with the 8th AJCC staging system, the AUCs of the nomogram in the present study showed a better discriminative ability. Calibration curves for the training and validation cohorts showed excellent agreement between the predicted and observed outcomes at 1, 3 and 5 years. Conclusions: The nomogram in this study showed excellent discrimination and calibration in predicting overall survival in patients with incidental gallbladder cancer. It is useful for physicians to obtain accurate long-term survival information and to help them make optimal treatment and follow-up decisions.

The difference in prolonged continuous and intermittent Pringle maneuver during complex hepatectomy for hepatocellular carcinoma patients with chronic liver disease: A retrospective cohort study.

PURPOSE: To explore the differences between prolonged continuous Pringle maneuver (CPM) and prolonged intermittent Pringle maneuver (IPM) in patients with hepatocellular carcinoma (HCC), who underwent complex hepatectomy. METHODS: This retrospective cohort study performed between June 2014 and May 2016 included 142 patients who underwent complex hepatectomy for HCC and concomitant chronic liver disease but with good liver function. Patients were categorized into CPM (n = 69) and IPM groups (n = 73). The differences in these aspects were compared between the two groups which include operation time, intraoperative bleeding, perioperative transfusion, postoperative complications, liver function injury, postoperative overall survival (OS), and tumor recurrence. RESULTS: The cumulative clamping time, operation time, intraoperative bleeding, and perioperative transfusion rates were 38.0, 132 min, 300 ml, and 17.4% in CPM and 40.0, 145 min, 400 ml, and 32.9% in IPM, respectively. There were significant intergroup differences in operation time (p = 0.018), intraoperative bleeding (p < 0.001), and perioperative transfusion rates (p = 0.034). Besides, the postoperative complications and postoperative liver function injury of the CPM group were better than those of IPM. There was no significant intergroup difference in OS (p = 0.908) and tumor recurrence (p = 0.671) between two groups. CONCLUSION: Compared with IPM, CPM with a cumulative clamping time between 30 and 50 min can shorten operation time, reduce intraoperative bleeding and perioperative transfusion, and reduce postoperative complications and postoperative liver function injury in patients who underwent complex hepatectomy for HCC and concomitant liver disease but with good liver function. There was no significant difference in OS and tumor recurrence between two groups.

SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/ß-catenin/MYC/HMGCS2 axis.

BACKGROUND: Many molecular alterations are shared by embryonic liver development and hepatocellular carcinoma (HCC). Identifying the common molecular events would provide a novel prognostic biomarker and therapeutic target for HCC. METHODS: Expression levels and clinical relevancies of SLC38A4 and HMGCS2 were investigated by qRT-PCR, western blot, TCGA and GEO datasets. The biological roles of SLC38A4 were investigated by functional assays. The downstream signalling pathway of SLC38A4 was investigated by qRT-PCR, western blot, immunofluorescence, luciferase reporter assay, TCGA and GEO datasets. RESULTS: SLC38A4 silencing was identified as an oncofetal molecular event. DNA hypermethylation contributed to the downregulations of Slc38a4/SLC38A4 in the foetal liver and HCC. Low expression of SLC38A4 was associated with poor prognosis of HCC patients. Functional assays demonstrated that SLC38A4 depletion promoted HCC cellular proliferation, stemness and migration, and inhibited HCC cellular apoptosis in vitro, and further repressed HCC tumorigenesis in vivo. HMGCS2 was identified as a critical downstream target of SLC38A4. SLC38A4 increased HMGCS2 expression via upregulating AXIN1 and repressing Wnt/ß-catenin/MYC axis. Functional rescue assays showed that HMGCS2 overexpression reversed the oncogenic roles of SLC38A4 depletion in HCC. CONCLUSIONS: SLC38A4 downregulation was identified as a novel oncofetal event, and SLC38A4 was identified as a novel tumour suppressor in HCC.

CircularRNA-9119 protects hepatocellular carcinoma cells from apoptosis by intercepting miR-26a/JAK1/STAT3 signaling.

Hepatocellular carcinoma (HCC) is a more common malignancy than the majority of cancers and ranks second in the world's top causes of cancer-related mortality. The objective of the study was to investigate and explain how circularRNA-9119 (circ9119) regulated the properties of HCC cell lines. Cancer cells isolated from HCC patients and HCC cell lines showed clearly upregulated expression of circ9119 and Janus kinase 1 (JAK1) with decreased levels of miR-26a compared to healthy controls and normal hepatic cells. To determine the function of circ9119, circ9119 was silenced in HCC cells, resulting in significantly less proliferation of HCC cells and increasing apoptosis. Circ9119 silencing also resulted in the upregulation of miR-26a. Bioinformatics prediction and dual-luciferase reporter assays showed that circ9119 targeted miR-26a. Further studies revealed that miR-26a had the opposite effect on circ9119; the inhibition of miR-26a antagonized circ9119 silencing, leading to reduced cell proliferation and increased apoptosis, while the ectopic overexpression of miR-26a impaired cell growth. Additionally, we found that the JAK1 3'-UTR was targeted by miR-26a; a decrease in the levels of JAK1 protein and mRNA followed transfection of a miR-26a mimic. Administration of the JAK1 inhibitor, baricitinib, caused the activation of signal transducer and activator of transcription 3 (STAT3) and revealed an effect similar to that of circ9119 silencing on cell proliferation and apoptosis. These results showed that circ9119 could modulate apoptosis, and broadly, cell proliferation by competitively binding miR-26a, which targeted JAK1-STAT3, in HCC cell lines. This study is a novel description of circ9119 regulation of HCC.

Bioinformatics profiling identifies seven immune-related risk signatures for hepatocellular carcinoma.

BACKGROUND: Density of tumor infiltrating lymphocytes (TIL) and expressions of certain immune-related genes have prognostic and predictive values in hepatocellular carcinoma (HCC); however, factors determining the immunophenotype of HCC patients are still unclear. In the current study, the transcript sequencing data of liver cancer were systematically analyzed to determine an immune gene marker for the prediction of clinical outcome of HCC. METHODS: RNASeq data and clinical follow-up information were downloaded from The Cancer Genome Atlas (TCGA), and the samples were assigned into high-stage and low-stage groups. Immune pathway-related genes were screened from the Molecular Signatures Database v4.0 (MsigDB) database. LASSO regression analysis was performed to identify robust immune-related biomarkers in predicting HCC clinical outcomes. Moreover, an immune gene-related prognostic model was established and validated by test sets and Gene Expression Omnibus (GEO) external validation sets. RESULTS: We obtained 319 immune genes from MsigDB, and the genes have different expression profiles in high-stage and low-stage of HCC. Univariate survival analysis found that 17 genes had a significant effect on HCC prognosis, among them, 13 (76.5%) genes were prognostically protective factors. Further lasso regression analysis identified seven potential prognostic markers (IL27, CD1D, NCOA6, CTSE, FCGRT, CFHR1, and APOA2) of robustness, most of which are related to tumor development. Cox regression analysis was further performed to establish a seven immune gene signature, which could stratify the risk of samples in training set, test set and external verification set (p < 0.01), and the AUC in both training set and test set was greater than 0.85, which also greater compared with previous studies. CONCLUSION: This study constructed a 7-immunogenic marker as novel prognostic markers for predicting survival of HCC patients.

WITHDRAWN: Prognostic biomarker AASS suppresses proliferation, migration and predicts a good survival of hepatocellular carcinoma in vivo and in vitro.

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The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma.

Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.

Autophagy-deficiency in hepatic progenitor cells leads to the defects of stemness and enhances susceptibility to neoplastic transformation.

Autophagy is a highly conserved and lysosome-dependent degradation process which assists in cell survival and tissue homeostasis. Although previous reports have shown that deletion of the essential autophagy gene disturbs stem cell maintenance in some cell types such as hematopoietic and neural cells, it remains unclear how autophagy-deficiency influences hepatic progenitor cells (HPCs). Here we report that Atg5-deficiency in HPCs delays HPC-mediated rat liver regeneration in vivo. In vitro researches further demonstrate that loss of autophagy decreases the abilities of colony and spheroid formations, and disrupts the induction of hepatic differentiation in HPCs. Meanwhile, autophagy-deficiency increases the accumulations of damaged mitochondria and mitochondrial reactive oxygen species (mtROS) and suppresses homologous recombination (HR) pathway of DNA damage repair in HPCs. Moreover, in both diethylnitrosamine (DEN) and CCl4 models, autophagy-deficiency accelerates neoplastic transformation of HPCs. In conclusion, these findings demonstrate that autophagy contributes to stemness maintenance and reduces susceptibility to neoplastic transformation in HPCs.