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Abstract: Mouse islets are widely used in diabetes research. Thus an adequate quality, quantity, and purity of islets are needed for high-quality investigations. We performed a combination of filtration and [...]

Serine protease inhibitor Kazal type I (SPINK1) is highly expressed and promotes tumor progress in different cancers. This study aimed to evaluate SPINK1's prognostic value and its role in hepatocellular carcinoma (HCC) progress. We use tissue micro-arrays containing 273 tumor and paired para-tumor tissues to evaluate SPINK1's prognostic value in HCC. CCK8 cell proliferation assay, wound healing assays, transwell migration and invasion assays were performed to explore the effect of SPINIK1 on HCC cells. The Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) were used to verify the prognosis value of SPINK1 in HCC and explore the underlying mechanisms. SPINK1 expression was significantly higher in tumor tissues than paired para-tumor tissues (P < 0.001). Higher SPINK1 expression in tumor was significantly associated with portal vein tumor thrombus formation (P = 0.019) and shorter overall survival (P = 0.029). SPINK1 expression in tumor tissue was an independent predictor for overall survival. SPINK1 increased proliferation (P < 0.001), enhanced migration and invasion ability of HCC cell lines (P < 0.001). GSEA revealed that glycine, serine, threonine and bile acid metabolism may be the underlying mechanism of SPINK1 in HCC. In conclusion, high SPINK1 expression is associated with poor prognosis of HCC. SPINK1 promotes proliferation, migration and invasion ability of HCC cells. [ABSTRACT FROM AUTHOR]

Background and Aim: The evidences for use of postoperative antibiotics (POA) in hepatocellular carcinoma (HCC) patients who underwent hepatectomy are controversial. We aimed to explore the relationship between POA and hepatectomy‐related infection in a hepatitis B virus (HBV)‐related HCC population. Methods: We retrospectively collected 934 HCC patients who underwent hepatectomy for curative intent from three tertiary hospitals in China. The incidences of postoperative infection including surgical site infection and remote site infection were recorded and calculated. Univariable and multivariable logistic regression analyses were performed to explore related factors of postoperative infection and POA. And the relationship between infection rates with different durations of POA was investigated. Results: The overall infection rate was 8.2% (77/934), including 6.5% (61/934) of surgical site infection and 2.0% (19/934) of remote site infection. Multivariable analysis revealed that the administration of POA was negatively related with the incidence of postoperative infection significantly (odds ratio = 0.50, 95% confidence interval = 0.30 to 0.83; P = 0.008). Albumin‐bilirubin score, Barcelona Clinic Liver Cancer (BCLC) stage and extent of hepatectomy were independently related to the POA. And 3‐day regimen seemed to be the shortest duration of POA to gain the lowest incidence of postoperative infection. Conclusions: Postoperative antibiotic is necessary for HBV‐related HCC patients to prevent postoperative infection, especially for those with higher albumin‐bilirubin score, at BCLC stage B–C, or who underwent major hepatectomy. For HBV‐related HCC patients, postoperative second‐generation cephalosporins, or ceftriaxone for 3 days after surgery might be proper. [ABSTRACT FROM AUTHOR]

Background and Aim: Prognosis of infiltrative hepatocellular carcinoma (iHCC) is poor, and the treatments selection based on efficacy is unclear. We performed this multicenter study to compare the efficacy of hepatic resection and transarterial chemoembolization (TACE) in treating patients with iHCC. Methods: We retrospectively analyzed the overall survivals (OS) in 319 patients with iHCC who were initially treated by hepatic resection (n = 133) or TACE (n = 186) at four tertiary centers. Fifty‐eight patients in the TACE group were assessed as resectable and compared with the hepatic resection group in subgroup analysis. A propensity score matched (PSM) analysis was performed to reduce selection bias. Cox regression was performed to identify significant factors associated with OS. Results: The median OS time was significantly longer in the hepatic resection group than that in the TACE group, before and after PSM (before PSM, 17.5 vs 7.3 months, P < 0.0001; after PSM, 14.0 vs 7.3 months, P < 0.0001). The multivariable analysis indicated TACE as a risk factor of OS (hazard ratio = 2.233, 95% confidence interval = 1.492 to 3.341, P < 0.0001), as well as portal venous tumor thrombosis grades 3–4 and alpha fetal protein (AFP) > 400 ng/mL. In the subgroup analysis, the better efficacy of hepatic resection over TACE persisted regardless of the grade of portal venous tumor thrombosis and the level of AFP. As for resectable patients, hepatic resection still showed significant survival benefit (before PSM, 17.5 vs 11.2 months, P = 0.0013; after PSM, 14.0 vs 10.9 months, P = 0.0304). Conclusion: Hepatic resection might be the better choice for patients with iHCC due to its better survival benefit than TACE. [ABSTRACT FROM AUTHOR]

Overexpression of Golgi phosphoprotein 3 (GOLPH3) predicts poor prognosis and is a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC). However, its role and underlying molecular mechanisms in the progression of PDAC remain unknown. In the present study, using high-throughput bimolecular fluorescence complementation (BiFC) analysis, we identified that stress-inducible protein-1 (STIP1) interacts with GOLPH3 and confirmed the interaction using co-localization and co-immunoprecipitation. The levels of GOLPH3 and STIP1 in PDAC tissues and adjacent non-cancerous pancreatic tissues were determined using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR. Real-time Quantitative-telomere repeat amplification (Q-TRAP) was applied to detect relative telomerase activity, and cell proliferation was measured when small interfering RNAs targeting GOLPH3 or STIP1 were transfected into PDAC cell lines. BALB/c nude mice were used to assess tumor growth inhibition of BXPC3 cells stably transfected with GOLPH3 short hairpin RNA. In summary, GOLPH3 was found to interact with STIP1 and both proteins were overexpressed and co-localized in PDAC tissues and cell lines. Moreover, suppression of GOLPH3 expression using shRNAs in PANC1 and BXPC3 cells inhibited tumor cell proliferation both in vitro and in vivo. Mechanistically, GOLPH3 interacts with STIP1 to activate telomerase reverse transcriptase (hTERT) and telomerase activity by c-Myc, and then upregulates cell cycle-related signaling proteins, including cyclin D1, to promote tumor cell growth, suggesting that disrupting the interaction between STIP1 and GOLPH3 would be a promising new strategy to treat PDAC. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate the performance of a deep learning (DL)-based Radiomics strategy designed for analyzing contrast-enhanced ultrasound (CEUS) to not only predict the progression-free survival (PFS) of radiofrequency ablation (RFA) and surgical resection (SR) but also optimize the treatment selection between them for patients with very-early or early-stage hepatocellular carcinoma (HCC). Methods: We retrospectively enrolled 419 patients examined by CEUS within 1 week before receiving RFA or SR (RFA: 214, SR: 205) from January 2008 to 2016. Two Radiomics signatures were constructed by the Radiomics model R-RFA and R-SR to stratify PFS of different treatment groups. Then, RFA and SR nomograms were built by incorporating Radiomics signatures and significant clinical variables to achieve individualized 2-year PFS prediction. Finally, we applied both Radiomics models and both nomograms to each enrolled patient to investigate whether there were space for treatment optimization and how much prognostic improvement could be expected. Results: R-RFA and R-SR showed remarkable discrimination (C-index: 0.726 for RFA, 0.741 for SR). RFA and SR nomograms provided good 2-year PFS prediction accuracy and good calibrations. We identified 17.3% RFA patients and 27.3% SR patients should swap their treatment, so their average probability of 2-year PFS would increase 12 and 15%, respectively. Conclusions: The proposed Radiomics models and nomograms achieved accurate preoperative prediction of PFS for RFA and SR, and they could facilitate the optimized treatment selection between them for patients with very-early or early-stage HCC. [ABSTRACT FROM AUTHOR]

Gut microbiota dysbiosis is closely associated with primary hepatocellular carcinoma (HCC). Recent studies have evaluated the early diagnosis of primary HCC through analysis of gut microbiota dysbiosis. However, the relationship between the degree of dysbiosis and the prognosis of primary HCC remains unclear. Because primary HCC is accompanied by dysbiosis and dysbiosis usually increases the circulatory concentrations of endotoxin and other harmful bacterial substances, which further increases liver damage, we hypothesized that level of dysbiosis associated with primary HCC increases with the stage of cancer progression. To test this hypothesis, we introduced a more integrated index referred to as the degree of dysbiosis (Ddys); and we investigated Ddys of the gut microbiota with the development of primary HCC through high-throughput sequencing of 16S rRNA gene amplicons. Our results showed that compared with healthy individuals, patients with primary HCC showed increased pro-inflammatory bacteria in their fecal microbiota. The Ddys increased significantly in patients with primary HCC compared with that in healthy controls. Moreover, there was a tendency for the Ddys to increase with the development of primary HCC, although no significant difference was detected between different stages of primary HCC. Our findings provide important insights into the use of gut microbiota analysis during the treatment of primary HCC. [ABSTRACT FROM AUTHOR]

Background: The role of transarterial chemoembolization (TACE) as the standard treatment for intermediate‐stage hepatocellular carcinoma (HCC) is being challenged by increasing studies supporting liver resection (LR); but evidence of survival benefits of LR is lacking. We aimed to compare the overall survival (OS) of LR with that of TACE for the treatment of intermediate‐stage HCC in cirrhotic patients. Methods: A Markov model, comparing LR with TACE over 15 years, was developed based on the data from 31 literatures. Additionally, external validation of the model was performed using a data set (n = 1735; LR: 701; TACE: 1034) from a tertiary center with propensity score matching method. We conducted one‐way and two‐way sensitivity analyses, in addition to a Monte Carlo analysis with 10 000 patients allocated into each arm. Results: The mean expected survival times and survival rates at 5 years were 77.8 months and 47.1% in LR group, and 48.6 months and 25.7% in TACE group, respectively. Sensitivity analyses found that initial LR was the most favorable treatment. The 95% CI for the difference in OS was 2.42‐2.46 years between the two groups (P < 0.001). In the validation set, the 5‐year survival rates after LR were significantly better than those after TACE before (40.2% vs. 25.9%, P < 0.001) and after matching (43.2% vs 30.9%, P < 0.001), which was comparable to the model results. Conclusions: For cirrhotic patients with resectable intermediate‐stage HCC, LR may provide survival benefit over TACE, but large‐scale studies are required to further stratify patients at this stage for different optimal treatments. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively compare the efficacy and safety of combined radiofrequency ablation and percutaneous ethanol injection (RFA-PEI) with repeat hepatectomy for elderly patients with initial recurrent hepatocellular carcinoma (HCC) after hepatic surgery. Methods: From January 2009 to June 2015, 105 elderly patients (≥70 years) who underwent RFA-PEI (n = 57) or repeated hepatectomy (n = 48) for recurrent HCC ≤ 5.0 cm were included in the study. The overall survival (OS) and recurrence-free survival (RFS) were analysed with the Kaplan-Meier method and compared by the log-rank test. Non-tumour-related death, complications and hospital stays were assessed. Univariate and multivariate analyses were performed to identify the prognostic significance of the variables in predicting the OS and RFS. Results: OS rates were 78.2%, 40.8% and 36.7% at 1, 3 and 5 years after RFA-PEI and 76.3%, 52.5% and 42.6% after repeat hepatectomy, respectively (p = 0.413). Correspondingly, the 1-, 3- and 5-year RFS rates after RFA-PEI and repeat hepatectomy were 69.5%, 37.8%, 33.1% and 73.1%, 49.7%, 40.7%, respectively (p = 0.465). Non-tumour-related deaths in the RFA-PEI group (2/57) were significantly fewer than those in the repeat hepatectomy group (10/48) (p = 0.016). RFA-PEI was superior to repeat hepatectomy regarding the major complication rates and length of in-hospital stay (both p < 0.001). Multivariate analysis showed that the tumour number was the significant prognostic factor for the OS (hazard ratio (HR) = 1.961, 95% CI = 1.043-3.686, p = 0.037) and RFS (HR = 1.866, 95% CI = 1.064-3.274, p = 0.030). Conclusion: RFA-PEI provides comparable OS and RFS to repeat hepatectomy for elderly patients with small recurrent HCC after hepatectomy but with fewer non-tumour-related deaths, major complications and shorter hospital stays. [ABSTRACT FROM AUTHOR]

Hepatectomy is currently routinely performed in most hospitals in China. China owns the largest population of liver diseases and the biggest number of liver resection cases. A nationwide multicenter retrospective investigation involving 112 hospitals was performed, and focused on liver resection for patients with hepatocellular carcinoma (HCC). 42,573 cases of hepatectomy were enrolled, and 18,275 valid cases of liver resection for HCC patients were selected for statistical analysis. The epidemiology of HCC, distribution of hepatectomy, postoperative complications and prognosis were finally analyzed. In the 18,275 HCC patients, 81% had hepatitis B virus infection and 10% had hepatitis C virus infection. 38% of the HCC patients had normal Alphafetoprotein (AFP) level, and other 35% had an AFP level lower than 400 ng mL−1. In the study period, 97% of the hepatectomy for HCC were treated with open surgery, and 23.81% had vascular exclusion techniques. The operation time was (191.7±105.6) min, the blood loss was (546.0±562.8) mL, and blood transfusion was (543.0±1,035.2) mL. The median survival for HCC patients was 631 days, with 1-, 3-, and 5-year overall survival of 73.2%, 28.8% and 19.6%, respectively. Liver cirrhosis, multiple nodules, tumor thrombosis and high AFP level were risk factors that affect postoperative survival. [ABSTRACT FROM AUTHOR]

This study investigated the effects of intratumoral injection of immunoactivator after microwave ablation on antitumor immunity in a mouse model of hepatocellular carcinoma. Hepatocellular carcinoma cell line Hepa1-6 was subcutaneously injected into C57/B6 mice to establish a mouse model of hepatocellular carcinoma. When tumor diameter reached 8 mm, microwave ablation was performed for 3 min with temperature controlled at 55°C. Cytokine sustained-release microspheres (CytoMPS) containing human interleukin-2 (hIL-2) and mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) were injected into the tumor of mice in the experimental group (n=5) at 3, 7 and 14 days after ablation, while sustained-release microspheres containing no cytokine were used in the control group (n=5). Mice were sacrificed on the 17th day after ablation, and CD4+ and CD8+ T cells in peripheral blood were counted by flow cytometry. Spleen was collected from the mice to isolate lymphocytes. Lactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of spleen cells to Hepal-6 cells. Injection of CytoMPS after ablation increased the percentage of CD4+ and CD8+ T cells in peripheral blood. Cytotoxicity of CD8+ CTL to Hepal-6 is significantly higher in experimental group than in control group (P<0.01). The results showed that intratumoral injection of CytoMPS containing hIL-2 and mGM-CSF can significantly increase the proportion of CD4+ and CD8+ T cells in blood and increase the cytotoxicity of CTL cells to tumor cells in mice with hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency ablation (RFA) can not only effectively kill hepatocellular carcinoma (HCC) tumour cells but also release tumour antigens that can provoke an immune response. However, there is no consensus regarding which antigens could constitutively be generated after RFA and could potentiate the immune response. The aim of this study was to identify these immune-potentiating antigens.Methods: We performed two-dimensional electrophoresis (2-DE) and MALDI-TOF-MS/MS analyses on serum obtained before and after RFA from 5 HCC patients. Further validation for selected proteins was performed utilizing ELISA analysis on another 52 HCC patients. Disease-free survival (DFS) analysis according to the differential expression of the interested protein before and after RFA was performed.Results: Twelve decreased and 6 increased proteins after RFA were identified by MS. Three proteins, including clusterin, Ficolin-3, and serum retinol binding protein-4, were further verified by ELISA on the 52 HCC patients. Only Ficolin-3 proved to be significantly changed after RFA. The 52 patients were divided into two groups according to the expression of Ficolin-3 before and after RFA. The 1-, 2- and 3-year DFS rates were 59.1%, 31.8%, and 22.7%, respectively, for patients in the low Ficolin-3 group (22 patients) and 73.3%, 60.0%, and 50.0%, respectively, for patients in the high Ficolin-3 group (30 patients) (P = 0.038).Conclusions: In conclusion, Ficolin-3 was overexpressed in the serum of most HCC patients after RFA. Ficolin-3 might be a biomarker for RFA treatment efficacy and a potential target for HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Objective. To investigate the imaging features observed in preoperative Gd-EOB-DTPA-dynamic enhanced MRI and correlated with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. Methods. 66 HCCs in 60 patients with preoperative Gd-EOB-DTPA-dynamic enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, peritumor enhancement during mid-arterial phase, peritumor hypointensity during hepatobiliary phase, signal intensity ratio on DWI and apparent diffusion coefficients (ADC), T1 relaxation times, and the reduction rate between pre- and postcontrast enhancement images were assessed. Correlation between these features and histopathological presence of MVI was analyzed to establish a prediction model. Results. Histopathology confirmed that MVI were observed in 17 of 66 HCCs. Univariate analysis showed tumor size (p=0.003), margin (p=0.013), peritumor enhancement (p=0.001), and hypointensity during hepatobiliary phase (p=0.004) were associated with MVI. A multiple logistic regression model was established, which showed tumor size, margin, and peritumor enhancement were combined predictors for the presence of MVI (α=0.1). R2 of this prediction model was 0.353, and the sensitivity and specificity were 52.9% and 93.0%, respectively. Conclusion. Large tumor size, irregular tumor margin, and peritumor enhancement in preoperative Gd-EOB-DTPA-dynamic enhanced MRI can predict the presence of MVI in HCC. [ABSTRACT FROM AUTHOR]

Introduction: To retrospectively evaluate the efficacy and safety of salvage resection(SR) for recurrence or metastasis of hepatocellular carcinoma (HCC) after initial percutaneous ablation therapy (PAT).Methods: From September 2006 to September 2013, 50 consecutive patients who received SR for recurrent or metastatic HCC undergone initial PAT were enrolled. Safety and efficacy of SR for these patients were analyzed.Results: No treatment-related death occurred. Curative outcome was achieved in all the patients. The median overall survival after SR was 40 months, and the 1-, 3-, 5-year overall survival rate after SR was 85.2%, 46.4% and 34.8%, respectively. The disease-free survival was 38.6% at 1 year and 12.1% at 3 years after SR.Conclusion: SR is an effective and safe method for patients with recurrent or metastatic HCC after initial PAT treatment. [ABSTRACT FROM AUTHOR]

Introduction. This study evaluated long-term outcomes of salvage surgery as additional therapy following downstaging of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) in patients with initially unresectable HCC. Methods. A retrospective analysis was performed of 831 consecutive patients with unresectable HCC who underwent TACE as initial treatment between June 2004 and December 2014. Of these, 82 patients with downstaged resectable HCC were enrolled in this study: 43 received salvage surgery (S group) and the remaining 39, who refused salvage resection, were the control group (T group). The primary endpoint was overall survival (OS). Results. The median OS in the S and T groups was 49 and 31 months, respectively (p = .027).The 2-, 4-, and 5-year survival rates were 93%, 47%, and 26% in the S group and 74%, 18%, and 10% in the T group, respectively (p = .019). Treatment modality (hazard ratio [HR], 0.337; 95% confidential interval [CI], 0.184-0.616; p < .001) and response to TACE (complete vs. partial; HR, 3.154; 95% CI, 1.709-5.822; p < .001) were independent prognostic factors for survival. The median OS for patients in the complete response and partial response (PR) subgroups was 50 and 49 months, respectively, in the S group and 54 and 24 months, respectively, in the T group (p = .699 and p < .001, respectively). The median OS for HCC patients with macroscopic vascular invasion (MVI) was 58 and 30 months in the S and T groups, respectively (p < .024). Conclusion. Salvage surgery after downstaging of unresectable HCC had a survival benefit only for patients with MVI or a PR to TACE. [ABSTRACT FROM AUTHOR]

Gamma-glutamyltranspeptidase (γ-GGT), an oxidative stress marker, is correlated with inflammation in the extracellular hepatic microenvironment. This study aimed to evaluate the prognostic value of serum γ-GGT levels in patients with hepatocellular carcinoma (HCC) after hepatectomy. Three hundred and eight patients who underwent hepatic resection for HCC were included in the study. Preoperative serum γ-GGT levels, as well as demographic, clinical, and pathologic data, were analyzed. The optimal cutoff value of γ-GGT was 88 U/L. All patients were divided into γ-GGT ≤ 88 U/L group ( n = 146) and γ-GGT > 88 U/L group ( n = 162). The disease-free survival (DFS) and overall survival (OS) rates of patients in the γ-GGT > 88 U/L group were poorer than those in γ-GGT ≤ 88 U/L group. Preoperative serum γ-GGT levels, associating with gender, HBsAg status, tumor size, capsulation, tumor number, and vascular invasion, was an independent prognostic predictor of disease-free survival [hazard ratio (HR) = 1.616; 95 % confidence interval (CI), 1.223-2.135; P = 0.001] and overall survival (HR = 2.043; 95 % CI, 1.509-2.766; P < 0.001). Furthermore, γ-GGT was also associated with DFS and OS in small HCC (tumor size ≤5 cm) and alpha-fetoprotein (AFP) ≤ 200 ng/mL subgroup. In conclusion, γ-GGT is a promising and reliable prognostic biomarker in HCC patients after hepatic resection, especially for patients with small HCC or AFP ≤ 200 ng/mL. [ABSTRACT FROM AUTHOR]

Background: Notch signaling, a critical pathway for tissue development, contributes to tumorigenesis in many tissues; however, the roles of Notch signaling in Intrahepatic Cholangiocarcinoma (ICC) remains unclear. In this study, we evaluated the expression and effects of Notch1 on cell migration in ICC.Methods: Multiple cellular and molecular approaches were performed including gene transfection, siRNA transfection, RT-PCR, Western blotting, Rac activation assays and immunofluorescence.Results: We found that Notch1 was up-regulated in ICC tissues and cell lines. The exogenous expression of Notch1 in glioma cells increased their migratory and invasive capacity. Similarly, the suppression of Notch1 expression inactivated Rac1 and inhibited ICC cell migration. Notch1 over expression induced an Epithelial-to-mesenchymal transition (EMT) phenotype that included enhanced expression of α-SMA and Vimentin, loss of E-cadherin expression, morphological changes and cytoskeletal reorganization in ICC cells.Conclusion: Notch1 may induce a migratory effect in ICC by causing an epithelial-mesenchymal transition and activating Rac1 and could serve as a novel diagnostic and therapeutic target in patients with ICC. [ABSTRACT FROM AUTHOR]

Abstract: We report on the two-wave mixing of light in photorefractive waveguides in H ion-implanted Fe-doped near-stoichiometric lithium niobate crystals. For pump light of 632.8nm wavelength a gain coefficient as high as 15cm−1 is found. A response time of the order of a few seconds is achieved for micro-watt input powers. [Copyright &y& Elsevier]

Purpose: We evaluated the effect of a new antitumour immunity regimen that included microwave ablation, intratumoural microspheres encapsulating granulocyte-macrophage colony stimulating factor (GM-CSF), and blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Materials and methods: C57BL6 mice with an established subcutaneous Hepa 1-6 hepatoma underwent microwave ablation, followed by intratumoural injection of GM-CSF microspheres, and intraperitoneal injection of anti-CTLA-4 antibodies. The therapeutic effects were evaluated by tumour growth, survival analysis, and cytotoxicity of T lymphocytes against Hepa 1-6. Results: The co-administration of microwave thermal ablation, GM-CSF microspheres, and anti-CTLA-4 rejected tumour rechallenge in 90% of treated mice in a subcutaneous murine Hepa 1-6 model, and cured established distant tumour in 50% of the treated mice. This antitumour immune response was tumour-specific and mediated by natural killer (NK), CD4+, and CD8+ T cells. Conclusions: Microwave ablation, followed by intratumoural GM-CSF microspheres, and anti-CTLA-4 antibodies results in the local eradication of tumours, rejection of tumours following rechallenge, and cures established distant tumours, suggesting that this is a promising regimen and one that is readily applicable in the clinic. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Sorafenib (SORA), as a first-line therapeutic drug, has been used to treat HCC, but resistance poses a major limitation on the efficacy of SORA chemotherapy. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells in vitro.Purpose: The aim of this study was to investigate whether PRIS can exert synergistic anti-tumor effects with the combination of SORA, and if so, through what mechanism.Methods: Conditionally reprogrammed patient derived-primary hepatocellular carcinoma cells (CRHCs) were isolated from human liver cancer tissues and treated with SORA and PRIS. Cell proliferation, apoptosis, migration and tube formation ability were detected by DNA content quantification, flow cytometry, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively.Results: Initially, we observed that the combination of the two drugs had a much stronger inhibitory effect on CRHCs growth than either drug alone. Moreover, the combination of 2 µM SORA and 1 µM PRIS exhibited a significant anti‑migrative and anti-invaded effect on CRHCs, and remarkably inhibited capillary structure formation of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, the combined treatment with SORA and PRIS synergistically induced intrinsic apoptosis in CRHCs, involving a caspase-4-dependent mechanism paralleled by an increased Bax/Bcl-xL ratio. These activities were mediated through ROS generation and the induction of endoplasmic reticulum (ER) stress and mitochondrial dysfunction. GRP78 silencing or ER stress inhibitor 4-phenylbutyric acid administration was revealed to abolish the anticancer effects of PRIS, indicating the critical role of GRP78 in mediating the bioactivity of PRIS. The present study also provides mechanistic evidence that PRIS modulated the Akt/FoxO1/p27kip1 signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and, consequently resulting in suppressed cell viability, migration and angiogenesis co-treated with SORA in CRHCs.Conclusion: Our results suggest the use of PRIS as sensitizers of chemotherapy paving the way for innovative and promising targeted chemotherapy-based therapeutic strategies in human HCC. [ABSTRACT FROM AUTHOR]

Guanine nucleotide binding protein alpha 13 (GNA13) has been found to play critical roles in the development of several human cancers. However, little is known about GNA13 expression and its clinical significance in hepatocellular carcinoma (HCC). In our study, GNA13 was reported to be significantly up-regulated in HCC tissues, and this was correlated with several clinicopathological parameters, including tumor multiplicity (P = 0.004), TNM stage (P = 0.002), and BCLC stage (P = 0.010). Further Cox regression analysis suggested that GNA13 expression was an independent prognostic factor for overall survival (P = 0.014) and disease-free survival (P = 0.005). Moreover, we found that overexpression of GNA13 couldn't promote cell proliferation in vitro, but could significantly increase the invasion ability of HCC cells. Together, our study demonstrates GNA13 may be served as a prognostic biomarker for HCC patients after curative hepatectomy, in which high expression of GNA13 suggests poor prognosis of HCC patients. [ABSTRACT FROM AUTHOR]

Background Recently, increasing studies have revealed the association of inflammatory parameters, such as preoperative platelet count, and the prognosis of hepatocellular carcinoma (HCC). However, the link between the platelet count and the prognosis of patients with HCC after hepatic resection is still controversial. Methods We searched PubMed, Web of Science, EMBASE, and CBM for relevant trials and analyzed outcomes with random-effects model. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated. Results In total, 31 studies, including a total of 10,730 patients, met our criteria. The results showed that thrombocytopenia in HCC patients was associated with poor overall survival (HR = 1.47, 95% CI: 1.21-1.78), disease-free survival (HR = 1.36, 95% CI: 1.08-1.72), and a high risk of cancer recurrence (HR = 1.41, 95% CI: 1.22-1.62), but a low risk of extrahepatic metastasis (HR = 0.55, 95% CI: 0.47-0.63). Conclusions The meta-analysis revealed that preoperative platelet count could act as a significant biomarker in the prognosis of HCC, especially a platelet count of <100 × 10 3 /mm 3 . Additional high-quality trials are needed, considering the low-quality studies analyzed. [ABSTRACT FROM AUTHOR]

Rapid progress and metastasis remain the major treatment failure modes of hepatocarcinoma (HCC). Unfortunately, the underlying molecular mechanisms of hepatoma cell proliferation and migration are poorly understood. Metabolic abnormalities play critical roles in tumorigenesis and progression. Hexokinase domain containing 1 (HKDC1) catalyzes the phosphorylation of glucose. However, the functions and mechanisms of HKDC1 in cancer remain unknown. In this study, real-time RT-PCR and Western blotting assays were used to detect the HKDC1 expression levels in HCC tissues and cell lines. The Oncomine™ Cancer Microarray Database was applied to analysis the correlations between HKDC1 expression and HCC clinical characteristics. MTT and Transwell migration assays were performed to determine the functions of HKDC1 in HCC cells. The effect of HKDC1 on Wnt/β-catenin signaling pathway was assessed using Western blotting assay. In this study, we found that HKDC1 expression levels were elevated in HCC tissues compared with the adjacent tissues. HCC patients with high expression levels of HKDC1 had poor overall survival (OS). Furthermore, higher HKDC1 levels also predicted a worse OS of patients within solitary, elevated pre-operated serum alpha fetoprotein (AFP) level and higher tumor diameter. Moreover, silencing HKDC1 suppressed HCC cells proliferation and migration in vitro . Downregulated HKDC1 expression repressed β-Catenin and c-Myc expression, which indicates that silencing HKDC1 may reduce proliferation and migration via inhibiting the Wnt/β-catenin signaling pathway in HCC. In summary, HKDC1 provides further insight into HCC tumor progression and may provide a novel prognostic biomarker and therapeutic target for HCC treatment. [ABSTRACT FROM AUTHOR]

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression. [Display omitted] • METTL1-mediated m7G tRNA modification promotes ICC cancer progression • METTL1-mediated m7G tRNA modification regulates tRNA expression and mRNA translation • m7G tRNA selectively modulates translation in a codon-dependent manner • Oncogenic function of m7G tRNA modification is verified in multiple ICC mouse models Dai et al. show that METTL1-mediated m7G tRNA modification selectively regulates the translation of certain oncogenic transcripts and promotes intrahepatic cholangiocarcinoma progression in vitro and in vivo. The selective translation mechanism is regulated at the tRNA-mRNA codon recognition step in a codon-frequency-dependent manner. [ABSTRACT FROM AUTHOR]

Background/aim: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has a poor prognosis. Periodontitis, or tooth loss, is considered to be related to hepatocarcinogenesis and its poor prognosis. This study aimed to explore potential associations and cross-talk mechanisms between periodontitis and HCC., Materials and Methods: Periodontitis and HCC microarray datasets were acquired from the Gene Expression Omnibus (GEO) database and were analyzed to obtain differentially expressed (DE) lncRNAs, miRNAs and mRNAs. Functional enrichment analysis was used to detect the functions of these mRNAs. Then, a ceRNA network of periodontitis-related HCC was constructed. Least absolute shrinkage and selection operator (LASSO) regression, random forest algorithm, and support vector machine-recursive feature elimination (SVM-RFE) were performed to explore the diagnostic significance of mRNAs in periodontitis-related HCC. Cox regression analyses were conducted to screen mRNAs with prognostic significance in HCC. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were conducted to validate the expression of these mRNAs in HCC tissues., Results: A ceRNA network was constructed. Functional enrichment analysis indicated that the network is associated with immune and inflammatory responses, the cell cycle and liver metabolic function. LASSO, random forest algorithm and SVM-RFE showed the diagnostic significance of DE mRNAs in HCC. Cox regression analyses revealed that MSH2, GRAMD1C and CTHRC1 have prognostic significance for HCC, and qRT-PCR and IHC validated this finding., Conclusion: Periodontitis may affect the occurrence of HCC by changing the immune and inflammatory response, the cell cycle and liver metabolic function. MSH2, GRAMD1C and CTHRC1 are potential prognostic biomarkers for HCC., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To clarify the underlying regulatory mechanisms of progression from liver cirrhosis to hepatocellular carcinoma (HCC), we analyzed the microbiomics, metabolomics, and proteomics in plasma and tissues from patients with HCC or decompensated liver cirrhosis (DC)., Patients and Methods: Tissues and plasma from 44 HCC patients and 28 patients with DC were collected for metabolomic analysis. 16S rRNA sequencing was performed in nine HCC tissues (HCCT), four distal noncancerous tissues (HCCN), and 11 DC tissues (DCT). Five HCC tissues had liver cirrhosis (HCCT-LC). Five hepatocellular carcinoma tissues without liver cirrhosis (HCCT-NLC) and five DCT were selected for proteomic sequencing. After combining proteomic and metabolomic analysis, we constructed a mouse model of chronic liver injury using carbon tetrachloride (CCl4) and treated them with vitamin B6 (VB6)., Results: 16s rRNA sequence results showed that HCC tissues had higher alpha diversity. The highest LDA scores were detected for Elizabethkingia in HCCT, Subsaxibacter in DCT, and Stenotrophomon in HCCN. Metabolomics results demonstrated some metabolites, including capric acid, L-threonate, choline, alpha-D-Glucose, D-ribose, betaine, 2E-eicosenoic acid, linoleic acid, L-palmitoylcarnitine, taurodeoxycholic acid, L-pyroglutamic acid, androsterone sulfate, and phthalic acid mono-2-ethylhexyl ester (MEHP), had better diagnostic efficacy than AFP (AUC: 0.852; 95% CI: 0.749, 0.954). In a combined analysis of metabolomics and proteomics, we found that HCCT-LC had more obvious disorders of VB6 metabolism and pentose and glucuronate interconversions than DCT, and kynurenine metabolism disorder was more significant in HCCT-LC than in HCCT-NLC. In the CCl4-induced chronic liver injury model, after VB6 supplementation, inflammatory cell infiltration, hepatocyte edema, and degeneration were significantly improved., Conclusion: We found significant differences in the flora distribution between HCCT and DC; MEHP was a new diagnostic biomarker of HCC, and VB6 ameliorated the inflammatory cell infiltration, hepatocyte edema, and degeneration in chronic liver injury., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Mei et al.)