Heparin is an effective treatment for preventing liver failure after hepatectomy.

BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the most important causes of death following liver resection. Heparin, an established anticoagulant, can protect liver function through a number of mechanisms, and thus, prevent liver failure. AIM: To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy. METHODS: The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) v1. 4 pinpointed patients who had undergone hepatectomy for liver cancer, subdividing them into two cohorts: Those who were injected with heparin and those who were not. The statistical evaluations used were unpaired t-tests, Mann-Whitney U tests, chi-square tests, and Fisher's exact tests to assess the effect of heparin administration on PHLF, duration of intensive care unit (ICU) stay, need for mechanical ventilation, use of continuous renal replacement therapy (CRRT), incidence of hypoxemia, development of acute kidney injury, and ICU mortality. Logistic regression was utilized to analyze the factors related to PHLF, with propensity score matching (PSM) aiming to balance the preoperative disparities between the two groups. RESULTS: In this study, 1388 patients who underwent liver cancer hepatectomy were analyzed. PSM yielded 213 matched pairs from the heparin-treated and control groups. Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples. Further analysis in the matched cohorts confirmed a significant association, with heparin reducing the risk of PHLF (odds ratio: 0.518; 95% confidence interval: 0.295-0.910; P = 0.022). Additionally, heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations, diminished requirements for respiratory support and CRRT, and lower incidences of hypoxemia and ICU mortality. CONCLUSION: Liver failure is an important hazard following hepatic surgery. During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure. This indicates that heparin may provide a hopeful option for controlling PHLF.

The role and mechanism of TCM in the prevention and treatment of infectious diseases.

The constant presence of infectious diseases poses an everlasting threat to the entire world. In recent years, there has been an increased attention toward the application of traditional Chinese medicine (TCM) in the treatment of emerging infectious diseases, as it has played a significant role. The aim of this article is to provide a concise overview of the roles and mechanisms of TCM in treating infectious diseases. TCM possesses the ability to modulate relevant factors, impede signaling pathways, and inhibit microbial growth, thereby exhibiting potent antiviral, antibacterial, and anti-inflammatory effects that demonstrate remarkable efficacy against viral and bacterial infections. This article concludes that the comprehensive regulatory features of Chinese herbal medicines, with their various components, targets, and pathways, result in synergistic effects. The significance of Chinese herbal medicines in the context of infectious diseases should not be underestimated; however, it is crucial to also acknowledge their underutilization. This paper presents constructive suggestions regarding the challenges and opportunities faced by Chinese medicines. Particularly, it emphasizes the effectiveness and characteristics of Chinese medicines in the treatment of infectious diseases, specifying how these medicines' active substances can be utilized to target infectious diseases. This perspective is advantageous in facilitating researchers' pharmacological studies on Chinese medicines, focusing on the specific points of action. The mechanism of action of Chinese herbal medicines in the treatment of infectious diseases is comprehensively elucidated in this paper, providing compelling evidence for the superior treatment of infectious diseases through Chinese medicine. This information is favorable for advancing the development of TCM and its potential applications in the field of infectious diseases.

KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation.

Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP-qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR-433, while dual luciferase assay was carried out to confirm the targeting relationship between miR-433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo-tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A-miR-433-FXYD3-PI3K-AKT axis in the progression of HCC after loss- and gain-function assays. KDM5A p-p85 and p-AKT were highly expressed but miR-433 was down-regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR-433 by demethylating H3K4me3 on its promoterregion. miR-433 negatively targeted FXYD3. Depleting miR-433 or re-expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down-regulated miR-433 and up-regulated FXYD3-PI3K-AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3-PI3K-AKT axis to enhance angiogenesis in HCC by suppressing miR-433.

Developing a Selection-aided Model to Screen Cirrhotic Intrahepatic Cholangiocarcinoma for Hepatectomy.

Background: This study aimed to establish a model predicting the prognosis of intrahepatic cholangiocarcinoma (ICC) patients with cirrhosis before liver resection (LR). Methods: An Eastern Hepatobiliary Surgery Hospital (EHBH) model using the preoperative factors was established in a training cohort (305 patients from 2006 to 2011) and validated in an internal validation cohort (113 patients from 2012 to 2014). Predictive performance and discrimination were evaluated and compared with other staging systems. Results: The EHBH model containing preoperative factors of carbohydrate antigen 19-9 (CA19-9), radiological tumor diameter, tumor number, and satellite nodules outperformed other staging systems in predicting the prognosis of ICC. A contour plot of 3-year survival probability and a nomogram to form two differentiated groups of patients (high-risk group and low-risk group) were constructed based on the EHBH model to help surgeons predicting the overall survival (OS) before LR. Patients from the high-risk group (>86.56 points) in the training cohort had worse OS rates compared with those from the low-risk group (≤86.56 points). The one-, three-, and five-year OS rates were 50.4%, 29.0%, and 21.0% for the high-risk group and 68.2%, 45.5%, and 39.7% for the low-risk group, respectively (P<0.001). The same results were obtained in the internal validation patients. Conclusion: The contour plot is an easy-to-use tool to individually show the 3-year prognosis of ICC patients with different preoperative CA19-9 values and radiological characteristics before surgery. The EHBH model was suitable for selecting cirrhotic patients for LR to acquire a better survival.

Inflammation Score System using Preoperative Inflammatory Markers to Predict Prognosis for Hepatocellular Carcinoma after Hepatectomy: A Cohort Study.

Background: This study developed a novel inflammation score system to predict survival outcomes using preoperational inflammatory markers in hepatocellular carcinoma (HCC) after surgery. Materials and Methods: An inflammation score system was developed using five preoperative inflammatory markers based on the clinical data of 455 HCC patients (training cohort) receiving radical resection in the Eastern Hepatobiliary Surgery Hospital. The system was validated using a cohort from a different hospital (external validation). Kaplan-Meier curves and log-rank test were used to compare the survival of patients with different inflammation scores. A nomogram including inflammation scores for survival prediction was created to exhibit the risk factors of overall survival (OS). Results: The patients in the low-score group showed better OS and recurrence-free survival (RFS) in the training and external validation cohorts than those from the high-score group. Subgroup analysis showed that compared with patients in the training cohort from the high-score group, stage I (eighth TNM stage) patients in the low-score group exhibited better prognosis results, whereas the findings for Stage II and III patients were different. Multivariate Cox analysis revealed that high inflammation score is an independent risk factor of OS and RFS. The nomogram established using the inflammation score with the C-index value of 0.661 (95% confidence interval=0.624-0.698) revealed a good three- and five-year calibration curves. Conclusions: The inflammation score system based on five preoperative inflammatory markers well predicted the survival of HCC patients after surgery, especially in those at the early stage (Stage I).

Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis Through Epithelial-to-Mesenchymal Transition Pathway.

Over-expression of aspartyl (asparagynal)-ß-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC.

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.

Antiviral Therapy Inhibits Viral Reactivation and Improves Survival after Repeat Hepatectomy for Hepatitis B Virus-Related Recurrent Hepatocellular Carcinoma.

BACKGROUND: The aim of this study was to explore the impact of antiviral therapy (AVT) on short- and long-term outcomes after rehepatectomy for patients with recurrent hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). STUDY DESIGN: We analyzed data from 583 consecutive patients who underwent rehepatectomy for intrahepatic recurrence of HBV-related HCC after initial hepatectomy, between 2006 and 2011 at the Eastern Hepatobiliary Surgery Hospital. Tumor re-recurrence, recurrence to death survival (RTDS), and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test. The independent risk factors of prognoses were analyzed using the Cox proportional hazards model. Postoperative viral reactivation, surgical morbidity, and mortality were also observed. RESULTS: Preoperative AVT reduced viral reactivation rate after rehepatectomy (5.8% for AVT patients, 16.3% and 16.6% for non-AVT patients with viral level ≤ or >2,000 IU/mL, respectively; p ≤ 0.028). Viral reactivation and non-AVT were independent risk factors of tumor re-recurrence (hazard ratios 1.446 and 1.778, respectively), RTDS (1.691 and 2.457, respectively), and OS (1.781 and 1.857, respectively). The AVT improved long-term outcomes as compared with non-AVT with a viral level of ≤ or >2,000 IU/mL (5-year re-recurrence rate: 69% vs 81% vs 96%, respectively; 5-year RTDS rate: 47% vs 27% vs 17%, respectively; all p ≤ 0.016). Pre- plus postoperative AVT achieved a better 5-year OS rate than postoperative AVT alone (83% vs 60%; p = 0.045); there were insignificant differences in 5-year re-recurrence and RTDS rates (61% vs 77%, p = 0.102; 50% vs 44%, p = 0.395). CONCLUSIONS: Preoperative AVT decreased viral reactivation rate, and AVT initiated either before or after rehepatectomy contributed to better long-term prognoses after rehepatectomy for recurrent HBV-related HCC.

Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies. DESIGN: The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy. RESULTS: We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219-2.441) and survival (1.847; 1.291-2.642). CONCLUSION: Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection.

Nomograms for Pre-operative and Post-operative Prediction of Long-Term Survival of Patients Who Underwent Repeat Hepatectomy for Recurrent Hepatocellular Carcinoma.

BACKGROUND: Repeat hepatectomy (re-hepatectomy) is an effective treatment for patients with intrahepatic recurrence following liver resection for hepatocellular carcinoma (HCC). OBJECTIVE: This study aimed to develop nomograms for predicting prognosis after re-hepatectomy. METHODS: The data of 635 patients who underwent re-hepatectomy for recurrent HCC at the Eastern Hepatobiliary Surgery Hospital between 2004 and 2010 were prospectively collected. Multivariable Cox regression analyses based on data obtained before and after re-hepatectomy were performed to select independent predictors of recurrence to death survival (RTDS) which were incorporated into the pre- or post-re-hepatectomy nomograms. Discrimination and calibration of the nomograms were measured using the concordance index (C-index), Kaplan-Meier curves, and calibration plots. RESULTS: The 1-, 3- and 5-year overall survival rates were 96.9, 74.8, and 47.8 %, respectively, and the corresponding RTDS rates were 75.8, 45.7, and 37.6 %, respectively. Tumor size and number at the initial and recurrent stages, time to recurrence from the initial hepatectomy, hepatitis B virus deoxyribonucleic acid level and microvascular invasion were selected into the two nomograms. The C-indexes for predicting RTDS were 0.72 [95 % confidence interval (CI) 0.70-0.74] and 0.77 (95 % CI 0.74-0.80) for the pre- or post-re-hepatectomy nomograms, respectively. The calibration curves for the probability of 5-year RTDS after re-hepatectomy showed optimal agreement between the prediction shown in the nomograms and the actual observations. Both nomograms were able to accurately stratify patients into four distinct incremental prognostic subgroups. CONCLUSION: The proposed nomograms have shown accurate RTDS prediction for patients with intrahepatic recurrent HCC.

Polarized regulation of glycogen synthase kinase-3ß is important for glioma cell invasion.

Glioma malignancy greatly depends on its aggressive invasion. The establishment of cell polarity is an important initial step for cell migration, which is essential for cell-directional translocation. However, our understanding of the molecular mechanisms underlying cell polarity formation in glioma cell invasion remains limited. Glycogen synthase kinase-3 (GSK-3) has a critical role in the formation of cell polarity. We therefore investigated whether localized GSK-3ß, a subtype of GSK-3, is important for glioma cell invasion. We reported here that the localized phosphorylation of GSK-3ß at the Ser9 (pSer9-GSK-3ß) was critical for glioma cell invasion. Scratching glioma cell monolayer up-regulated pSer9-GSK-3ß specifically at the wound edge. Inhibition of GSK-3 impaired the cell polarity and reduced the directional persistence of cell migration. Consistently, down-regulation of GSK-3α and 3ß by specific small interfering RNAs inhibited glioma cell invasion. Over-expressing wild-type or constitutively active forms of GSK-3ß also inhibited the cell invasion. These results indicated the polarized localization of GSK-3 regulation in cell migration might be also important for glioma cell migration. Further, EGF regulated both GSK-3α and 3ß, but only pSer9-GSK-3ß was enriched at the leading edge of scratched glioma cells. Up- or down-regulation of GSK-3ß inhibited EGF-stimulated cell invasion. Moreover, EGF specifically regulated GSK-3ß, but not GSK-3α, through atypical PKC pathways. Our results indicated that GSK-3 was important for glioma cell invasion and localized inhibition of GSK-3ß was critical for cell polarity formation.

Association of tumor-associated fibroblasts with progression of hepatocellular carcinoma.

Interaction between tumor and stromal cells plays an important role in cancer progression. The aim of this study was to explore the effects of tumor-associated fibroblasts on regulation of hepatocellular carcinoma (HCC) progression. Sixty-five cases of HCC and the corresponding normal liver tissues were recruited for immunohistochemical assessment of α-smooth muscle actin (α-SMA) expression, a biomarker for activated fibroblasts. Clinicopathological data were also collected from HCC patients for association with α-SMA expression. Primary cell culture of fibroblasts from HCC tissues was used to generate conditioned medium for testing the effect on regulation of HCC cell migration capacity in the transwell cell migration assay. α-SMA protein was expressed in 84.0 % (21 out 25 cases) of the fibroblasts from the metastatic HCCs, 45 % (18/40) from HCCs without metastasis, and 19.2 % (5/26) from normal liver tissues, difference of which was statistically significant (P < 0.01). The expression of α-SMA protein in HCC tissues was associated with tumor thrombosis, poor pathology grade, advanced clinical stages, and lymph node metastasis. The conditioned medium from the primary cultured fibroblasts with α-SMA expression significantly promoted the migration capacity of HCC Hep3B cells compared to the heat-inactivated conditioned medium. The data from the current study demonstrated that expression of α-SMA protein in HCC fibroblasts associated with tumor metastasis and advanced clinical stages and that the conditioned medium from α-SMA-positive fibroblasts enhanced HCC cell migration. This study indicates that α-SMA protein might serve as a biomarker to predict HCC progression.

The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers.

Metastatic hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. However, the cell population responsible for its metastasis remains largely unknown. Here, we reported that CD133(+)CD44(+/high) defined a subgroup of tumor cells that was responsible for hematogenous metastasis of liver cancers. Immunohistochemical investigation of human HCC specimens revealed that the number of CD133(+) and CD44(+) HCC cells was increased and was associated with portal vein invasion. Purified CD133(+) or CD44(high) HCC cells were superior in clonogenic growth and vascular invasion, respectively. Thus, the combination of CD133 and CD44 was used to define a novel HCC sub-population. CD133(+)CD44(high), but not CD133(+)CD44(low/-), CD133(-)CD44(high) or CD133(-)CD44(low/-) xenografts, produced intrahepatic or lung metastasis in nude mice. Further analysis of human HCC samples by flow cytometry showed that the number of CD133(+)CD44(+) tumor cells was associated with portal vein metastasis. The cDNA microarray analysis of CD133(+)CD44(+) and CD133(+)CD44(-) tumor cells isolated from metastatic HCC patients revealed that these cells comprised of two different populations possessing distinct gene expression profiles. Our results suggest that CD133(+)CD44(+) tumor cells are a particular population responsible for hematogenous metastasis in liver cancers and that these cells might be targets for treatment of HCC metastasis.

Overexpression of aspartyl-(asparaginyl)-beta-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome.

UNLABELLED: The association between the overexpression of aspartyl-(asparaginyl)-beta-hydroxylase (AAH) and the invasiveness of hepatocellular carcinoma (HCC) in vitro has been reported. However, the prognostic value of AAH expression in HCC remains unclear. The purpose of this study was to investigate the relationship between AAH expression, tumor recurrence, and patient survival. We identified AAH as the most overexpressed gene in HCC by way of complementary DNA microarray hybridization. A prospective study of 233 patients undergoing curative resection indicated that AAH expression was an independent factor affecting recurrence (hazard ratio [HR] 3.161, 95% confidence interval [CI] 2.115-4.724, P < 0.001) and survival (HR 2.712, 95% CI 1.734-4.241, P < 0.001). Patients with AAH overexpression had a poorer prognosis than those with AAH underexpression (P < 0.001 for both recurrence and survival). In Barcelona Clinic Liver Cancer stage A patients with AAH overexpression or underexpression, the tumor recurrence and survival rates were also statistically different (45% and 85% versus16% and 33% in 1- and 3-year cumulative recurrence rates, respectively; 73% and 37% versus 90% and 80% in 1- and 3-year survival rates, respectively; P < 0.001 for both). Furthermore, in stage A patients with tumors measuring < or =5 cm in diameter, the time to recurrence was 26.7 +/- 1.6 versus 51.9 +/- 2.8 months, and the 1- and 3- year survival rates were 97% and 52% versus 100% and 90% in AAH overexpression and underexpression patients, respectively (P < 0.001 for both). CONCLUSION: AAH overexpression in HCC is strongly correlated with worse surgical outcome, and this molecule likely provides a more precise prognostic predictor in early stage HCCs.

Critical role of TRPC6 channels in VEGF-mediated angiogenesis.

Intracellular Ca(2+) signaling plays critical roles in VEGF-mediated angiogenesis. Transient receptor potential canonical (TRPC) channel 6, a Ca(2+)-permeable non-selective cation channel, can be activated by VEGF. Here, we report that TRPC6 is important for VEGF-mediated angiogenesis. Inhibition of TRPC6 in human umbilical vein endothelial cells (HUVECs) by pharmacological or genetic approaches arrested HUVECs at G2/M phase and suppressed VEGF-induced HUVEC proliferation and tube formation. Furthermore, inhibition of TRPCs abolished VEGF-, but not FGF-induced angiogenesis in the chick embryo chorioallantoic membrane. These results suggest that TRPC6 plays an important role in VEGF-mediated angiogenesis.