Circ_0007386 Promotes the Progression of Hepatocellular Carcinoma Through the miR-507/ CCNT2 Axis.

Background: Circular RNAs (circRNAs) have been shown to play a crucial role in the initiation and development of Hepatocellular carcinoma (HCC). However, the mechanism and function of circ_0007386 in HCC are still unknown. Methods: Circ_0007386 expression level in HCC tissues, and HCC cell lines was further analyzed by qRT-PCR. Agarose gel electrophoresis and Sanger sequencing were used to figure out the structure of circ_0007386. The involvement of circ_0007386 in HCC development was evaluated by experimental investigations conducted in both laboratory settings (in vitro) and living organisms (in vivo). RNA immunoprecipitation, Western blotting, luciferase reporter assay and fluorescence in situ hybridization (FISH) were applied for finding out the interaction among circ_0007386, miR-507 and CCNT2. To assess the connection between circ_0007386 and lenvatinib resistance, lenvatinib-resistant HCC cell lines were employed. Results: The expression of circ_0007386 was found to increase in HCC tissues, and it was observed to be associated with a worse prognosis. Overexpression of circ_0007386 stimulated HCC cells proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) while silencing of circ_0007386 resulted in the opposite effect. Mechanistic investigations revealed that circ_0007386 acted as a competing endogenous RNA of miR-507 to prevent CCNT2 downregulation. Downregulating miR-507 or overexpressing CCNT2 could reverse phenotypic alterations that originated from inhibiting of circ_0007386. Importantly, circ_0007386 determines the resistance of hepatoma cells to lenvatinib treatment. Conclusion: Circ_0007386 advanced HCC progression and lenvatinib resistance through the miR-507/ CCNT2 axis. Meanwhile, circ_0007386 served as a potential biomarker and therapeutic target in HCC patients.

Exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of hepatocellular carcinoma by inhibiting HIPK3.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with rich blood supply. HCC-derived exosomes containing hereditary substances including microRNAs (miRNAs) were involved in regulating tumor angiogenesis and metastasis. Subsequently, series experiments were performed to evaluate the effect of exosomal miR-3174 on HCC angiogenesis and metastasis. HCC-derived exosomal miR-3174 was ingested by human umbilical vein endothelial cells (HUVECs) in which HIPK3 was targeted and silenced, causing subsequent inhibition of Fas and p53 signaling pathways. Furthermore, exosomal miR-3174 induced permeability and angiogenesis of HUVECs to enhance HCC progression and metastasis. Under hypoxia, upregulated HIF-1α further promoted the transcription of miR-3174. Moreover, HNRNPA1 augmented the package of miR-3174 into exosomes. Clinical data analysis confirmed that HCC patients with high-level miR-3174 were correlated with worse prognosis. Thus, exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of HCC by inhibiting HIPK3/p53 and HIPK3/Fas signaling pathways. Our findings might provide potential targets for anti-tumor therapy.

Exosome-transported circHDAC1_004 Promotes Proliferation, Migration, and Angiogenesis of Hepatocellular Carcinoma by the miR-361-3p/NACC1 Axis.

Background and Aims: Hepatocellular carcinoma (HCC) is among the most common malignant tumors globally. Circular RNAs (circRNAs), as a type of noncoding RNAs, reportedly participate in various tumor biological processes. However, the role of circHDAC1_004 in HCC remains unclear. Thus, we aimed to explore the role and the underlying mechanisms of circHDAC1_004 in the development and progression of HCC. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect circHDAC1_004 expression (circ_0005339) in HCC. Sanger sequencing and agarose gel electrophoresis were used to determine the structure of circHDAC1_004. In vitro and in vivo experiments were used to determine the biological function of circHDAC1_004 in HCC. Herein, qRT-PCR, RNA immunoprecipitation, western blotting, and a luciferase reporter assay were used to explore the relationships among circHDAC1_004, miR-361-3p, and NACC1. Results: circHDAC1_004 was upregulated in HCC and significantly associated with poor overall survival. circHDAC1_004 promoted HCC cell proliferation, stemness, migration, and invasion. In addition, circHDAC1_004 upregulated human umbilical vein endothelial cells (HUVECs) and promoted angiogenesis through exosomes. circHDAC1_004 promoted NACC1 expression and stimulated the epithelial-mesenchymal transition pathway by sponging miR-361-3p. Conclusions: We found that circHDAC1_004 overexpression enhanced the proliferation, stemness, and metastasis of HCC via the miR-361-3p/NACC1 axis and promoted HCC angiogenesis through exosomes. Our findings may help develop a possible therapeutic strategy for HCC.

Efficacy and safety of regorafenib in combination with immune checkpoint inhibitor therapy as second-line and third-line regimen for patients with advanced hepatocellular carcinoma: a retrospective study.

Background: Despite the emergence of immune checkpoint inhibitors (ICIs) as first-line treatment for advanced hepatocellular carcinoma (HCC), there is an unmet need regarding subsequent treatments in patients that fail ICI. Regorafenib is a vascular endothelial growth factor receptor (VEGFR) inhibitor, which could increase programmed death-ligand 1 (PD-L1) expression in tumors and increase intra-tumoral CD8+ T-cell infiltration by normalizing the cancer vasculature and improving the efficacy of the programmed cell death protein 1 (PD-1) antibody. Thus, we evaluated the combination of regorafenib and a PD-1 inhibitor for advanced HCC patients that had failed combined tyrosine kinase inhibitors (TKIs) plus ICI. Methods: Data of patients with advanced HCC who had failed combined TKIs plus ICI treatment and were afterwards treated with combined regorafenib plus a PD-1 inhibitor were reviewed. All patients had received PD-1 inhibitors as part of the first-line treatment and regorafenib every 4 weeks until disease progression, intolerable toxicities, or physician/patient withdrawal. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events (AEs) during follow-ups were recorded. Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 was used to evaluate AEs and Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 was used to evaluate response. The primary endpoint was safety, and the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and duration of response (DOR). Results: From November 15, 2020, to January 31, 2022, data of 17 patients with advanced HCC that met the criteria were reviewed. The cohort included 16 men and 1 woman with a median age of 54 years (interquartile range, 46 to 63 years). Sixteen patients had Child-Pugh class A (n=16, 94.12%) and one with class B (n=1, 15.9%) liver disease. Thirteen patients received second-line treatment, and the remaining patients received third-line treatment. All patients received at least 1 dose of PD-1 inhibitors. The median follow-up duration was 7.62 months. Twelve recipients experienced treatment-related AEs. The most frequent AE (≥5%) included fatigue (17.64%), diarrhea (17.65%), proteinuria (5.88%), bleeding gums (11.76%), and hypertension (11.76%). No grade-4 AE or new safety signals were identified. The ORR and DCR were 41.2% and 64.7%, respectively, and the median PFS was 5.09 months. Conclusions: Regorafenib combined with PD-1 inhibitor is a promising regimen in treating patients with advanced HCC owing to its safety and effectiveness as well as low incidence of serious AEs with its use.

Metformin Suppresses Hepatocellular Carcinoma through Regulating Alternative Splicing of LGR4.

Methods: First, the expression of LGR4 in HCC tumor tissues and cell lines was detected by western blotting and immunofluorescence. The ability of cell proliferation, migration, and invasion was detected with CCK8, wound-healing, and transwell assays when overexpressing LGR4 or treating with metformin. The ß-catenin expression was detected by immunofluorescence. In order to investigate novel AS-associated LGR4, we discarded LGR4 isoforms from GSO databases. We used siRNA to knock down the specific isoform to check the cell proliferation, migration, and invasion when treated with metformin. Results: The level of LGR4 expression was higher in HCC cell lines and tumor tissues. The HCC cell proliferation, migration, and invasion were increased when overexpressing LGR4, which could be reduced by metformin treatment. The GEO database (GSE190076) showed that LGR4 had switching properties in HCC cell lines treated with metformin. We used siRNA to knock down the specific isoform, and the result showed that the specific isoform siRNA could promote the inhibition of cell invasion caused by metformin treatment. Conclusions: LGR4 could promote the ability of cell proliferation, migration, and invasion in HCC, which could be reduced by metformin through alternative splicing.

CircMYH9 increases KPNA2 mRNA stability to promote hepatocellular carcinoma progression in an EIF4A3-dependent manner.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed cancer worldwide with a high incidence of recurrence and metastasis; however, the molecular mechanisms underlying HCC development remain to be fully understood. In this study, we identified circMYH9 as an important regulator of HCC. Overexpression of circMYH9 induced, while knockdown of circMYH9 inhibited, the proliferation, migration, and invasion of HCC cells. Mechanistically, circMYH9 bound to eukaryotic translation initiation factor 4A3 (EIF4A3) and increased karyopherin subunit alpha 2 (KPNA2) mRNA stability. circMYH9 knockdown in HCC cells reduced the stability of KPNA2 mRNA. Importantly, circMYH9 regulation of HCC required the activity of KPNA2. In support with this, circMYH9 level was positively correlated with the expression of KPNA2 in HCC patient samples. Taken together, our study was the first to uncover the oncogenic role of circMYH9 in HCC and further elucidated the functional mechanism of circMYH9 by interacting with EIF4A3 to increase KPNA2 mRNA stability. Our findings might provide a novel potential target for the diagnose and treatment of HCC.

Genistein Restricts the Epithelial Mesenchymal Transformation (EMT) and Stemness of Hepatocellular Carcinoma via Upregulating miR-1275 to Inhibit the EIF5A2/PI3K/Akt Pathway.

Purpose: Genistein is a natural phytoestrogen with various antitumor effects. In recent years, some microRNAs (miRNA) in cancer cells have been reported to be regulated by genistein. Our study focused on exploring the mechanisms of miRNA upregulation to inhibit the epithelial mesenchymal transformation (EMT) and stemness of hepatocellular carcinoma (HCC). Patients and Methods: MiR-1275 was discovered by the transcriptome sequencing of miRNA expression profiles in HepG2 cells treated with genistein or DMSO as a control. Then, we performed series functional experiments in vitro and vivo to explore the relationship between genistein and miR-1275 in HCC. The target gene (Eukaryotic initiation factor 5A2, EIF5A2) of miR-1275 was predicted by databases and finally determined by a dual luciferase reporter assay. The downstream signaling pathway of EIF5A2 was assessed by bioinformatics analysis and Western blot. Results: the inhibition of genistein on the viability of HCC cells was enhanced by the increase in treatment time and dose, but it had no obvious inhibitory effect on normal hepatocytes (QSG-7701). Through qRT-PCR and transcriptome sequencing, we discovered that miR-1275 was lowly expressed in HCC, and it can be raised by genistein. The overall survival (OS) and recurrence-free survival (RFS) of HCC patients with lowly expressed miR-1275 were lower than those of those with high expression levels. In vitro and vivo experiments exhibited that genistein and the overexpression of miR-1275 can both significantly suppress the proliferation, migration, invasion, metastasis, EMT and stemness of HCC. Moreover, the inhibition can be further enhanced when miR-1275 mimic and genistein exist together. Finally, we demonstrated that miR-1275 can inhibit the epithelial mesenchymal transformation (EMT) and stemness of HCC via inhibiting the EIF5A2/PI3K/Akt pathway. Conclusion: Our findings proved that genistein can inhibit the EIF5A2/PI3K/Akt pathway by upregulating miR-1275 so as to attenuate the EMT and stemness of HCC cells to restrict their progression and metastasis.

CircASPH Promotes Hepatocellular Carcinoma Progression Through Methylation and Expression of HAO2.

CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and para-tumor normal samples in HCC patients. We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival of HCC patients. Mechanistically, circASPH could regulate the methylation of the promoter and expression of hydrocyanic oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370-3p, and miR-370-3p could target DNMT3b and increase the 5mC level. In summary, our study determined that circASPH could regulate the methylation and expression of HAO2 and it could be considered an important epigenetic regulator in HCC progression.

Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/ nuclear factor -kappa B (NF-κB) pathway.

Chemoresistance in hepatocellular carcinoma (HCC) has been found to be influenced by exosomal transport of circRNAs. However, the role of circZFR in HCC chemoresistance still remains unclear. In the present study, circZFR was highly expressed in cisplatin (DDP)-resistant HCC cell lines and could regulate DDP resistance of the HCC cells. Also, circZFR was highly expressed in cancer-associated fibroblast (CAFs) and the exosome of CAFs. In addition, supplementation of CAFs in culture medium could promote DDP resistance of HCC cells. In vivo tumor xenograft experiments showed that knockdown of circZFR inhibited tumor growth and weakened DDP resistance, while CAFs-derived exosomes incubation increased the expression of circZFR, inhibited the STAT3/NF-κB pathway, promoted tumor growth, and enhanced DDP resistance. In general, CAFs-derived exosomes deliver circZFR to HCC cells, inhibit the STAT3/NF-κB pathway, and promote HCC development and chemoresistance. The results provided a new sight for the prevention and treatment of chemoresistance in HCC.

MiR-3174 promotes proliferation and inhibits apoptosis by targeting FOXO1 in hepatocellular carcinoma.

INTRODUCTION: MicroRNAs (miRNAs) have been confirmed to play a crucial part in oncogenesis. Several studies suggested that MiR-3174 act as a tumor promoter in various Malignant neoplasm. However, the biological function of miR-3174 in hepatocellular carcinoma (HCC) still highly unexplored. METHODS: We screened differentially over-expressed miRNAs by The Cancer Genome Atlas (TCGA) and the GEO databases. The expression of miR-3174 in HCC cells and tissues was detected by qRT-PCR. The cellular behaviors of transfected cells were respectively examined by colony formation assays, EdU Assays and flow cytometry. Forkhead box O1 transcription factor (FOXO1) was predicted and confirmed as a direct target of miR-3174 by bioinformatics analysis and dual-luciferase reporter gene assay. RESULTS: MiR-3174 was up-regulated in HCC tissues and cells, and the expression level of it was highly associated with tumor size and Edmondson grade. Our study pioneering validates that upregulated miR-3174 promote cell proliferation and inhibit cell apoptosis in vitro and in vivo. Meanwhile, our study verified that miR-3174 regulate Bim, P21, cyclin D1 and c-MYC expression by directly targeting FOXO1. CONCLUSION: The upregulated miR-3174 promote cell proliferation and inhibit cell apoptosis by downregulating FOXO1 expression in HCC. MiR-3174 may be a novel candidate for targeted delivery of miRNA therapeutics for HCC patients.

Roquin-1 Regulates Macrophage Immune Response and Participates in Hepatic Ischemia-Reperfusion Injury.

With the development of liver surgery, ischemia-reperfusion (IR) injury has received increasing attention. Roquin-1 has been shown to play an important role in innate immune and immune balance. We demonstrate that Roquin-1 expression increased at 1 h after IR and then decreased in C57B/L mice. The immunofluorescence double-label showed that Roquin-1 was mainly expressed in macrophages (mø). Furthermore, we used clodronate liposomes to remove mø, and injected the bone marrow-derived mø (BMDM) through the tail vein in 1 h before IR. We found that liver IR injury was aggravated by Roquin-1 interference. The results of PCR and ELISA suggested that after interference with Roquin-1, mø increased toward M1 and decreased toward M2. Then, interference with Roquin-1 promoted the polarization of mø to M1 and inhibited the polarization of M2. By Western blot technology and AMPKα and mTOR inhibitors, we found that Roquin-1 promotes the phosphorylation of mTOR and STAT3 by inhibiting the phosphorylation of AMPKα. We used AICAR to activate AMPKα in mø and found that the level of ubiquitination of AMPKα was decreased after activation of AMPKα. Furthermore, by bioinformatics methods, we identified potential ubiquitination sites on AMPKα. By the point mutation experiments in vitro, we confirmed that the ubiquitination of these sites is regulated by Roquin-1. Meanwhile, Roquin-1 interference inhibited the activation and function of AMPKα. This topic describes the protection of liver IR injury by Roquin-1 and discusses its main mechanism for regulating AMPKα activity through ubiquitination and affecting the polarization of mø.

Kinesin family member 15 promotes cancer stem cell phenotype and malignancy via reactive oxygen species imbalance in hepatocellular carcinoma.

The development and progression of hepatocellular carcinoma (HCC) is associated with the presence of cancer stem cells (CSCs). In the present study, kinesin family member 15 (KIF15) expression was shown to be overexpressed in HCC tissues, cell lines, and CSCs. Patients with HCC with high KIF15 expression had shortened overall survival (OS) and high recurrence probability. Downregulation of KIF15 in vitro as well as in HCC organoids resulted in a significant reduction in sphere formation and expression of stemness-related genes. KIF15 downregulation in human HCC xenograft models delayed tumor initiation, growth, and metastasis. KIF15 was also demonstrated to interact with phosphoglycerate dehydrogenase (PHGDH) and inhibit proteasomal degradation of PHGDH, thus promoting CSC phenotype and malignancy via PHGDH-mediated intracellular reactive oxygen species (ROS) imbalance in HCC. Moreover, AAA nuclear coregulator cancer-associated protein (ANCCA) upregulation acts as a key mediator in KIF15 expression upregulation in HCC. Conclusion: In this study, we found that KIF15 promotes the CSC phenotype and malignancy via PHGDH-mediated ROS imbalance in HCC. These findings highlight potential therapeutic targets for HCC.

Circular RNA MAT2B Promotes Glycolysis and Malignancy of Hepatocellular Carcinoma Through the miR-338-3p/PKM2 Axis Under Hypoxic Stress.

Glucose metabolism reprogramming, which is a well-established characteristic of multiple cancers, demands a higher rate of glycolysis to meet the increasing demands for macromolecular synthesis and to maintain rapid proliferation in a hypoxic environment. However, the mechanism underlying this switch remains to be elucidated. In this study, we investigated the function of circular RNA MAT2B (circMAT2B) in hepatocellular carcinoma (HCC) glucose metabolism reprogramming and malignancy. CircMAT2B was identified by bioinformatics analysis of Gene Expression Omnibus data sets. CircMAT2B expression was up-regulated in HCC tissues and cell lines. HCC patients with high circMAT2B expression had shortened overall survival. We analyzed the positive correlation between glycolysis and circMAT2B expression in HCC using a maximum standardized uptake value determined by preoperative positron emission tomography/computed tomography scanning combined with high-performance liquid chromatography assessment of the metabolites of glycolysis and the citric acid cycle. The effect of circMAT2B on glycolysis was validated in vitro and in vivo under hypoxic (1% O2 ) conditions. Functional assays were performed in HCC cells, HCC organoids, and nude mice to explore the tumor-promoting roles of circMAT2B in HCC. Biotin-coupled probe pull-down assays, biotin-coupled microRNA capture, luciferase reporter assays, fluorescence in situ hybridization, and RNA immunoprecipitation assays were performed to confirm the interaction among different RNAs. Mechanistically, we demonstrated that circMAT2B up-regulated expression levels of the microRNA (miR)-338-3p target gene PKM2, which encodes a key enzyme in the process of glycolysis, through "sponging" miR-338-3p; thus, glycolysis and HCC progression are promoted through this mechanism. Conclusion: CircMAT2B promoted HCC progression by enhanced glycolysis by activating the circMAT2B/miR-338-3p/PKM2 axis under hypoxia, which may provide a therapeutic target for HCC.

Precoagulation with microwave ablation for hepatic parenchymal transection during liver partial resection.

PURPOSE: To evaluate the feasibility of precoagulation with microwave ablation (MWA) for hepatic parenchymal transection during liver partial resection. METHODS: A total of 66 eligible patients were enrolled in this double-blind, randomized, controlled study. Patients were randomized to receive either the traditional clamp-crushing method (Control group) or the MWA precoagulation method (MWA group) for hepatic parenchymal transection during liver partial resection. The operative time, hepatic portal occlusion time, intraoperative blood loss and transfusion, postoperative complications and recovery outcomes were compared. RESULTS: Compared to the Control group, the MWA group had significantly less intraoperative blood loss. Fewer red blood cell transfusions were observed in the MWA group but without statistical significance. The MWA group showed significantly higher serum alanine aminotransferase and aspartate aminotransferase levels at day 1 postoperatively, but no differences between the MWA and Control groups were found at days 3 and 7. There were no significant differences in terms of operative time, hepatic portal occlusion time, postoperative total bilirubin levels, human albumin solution consumption or length of hospital stay. Postoperative complications such as impaired renal function, pyrexia, admission to ICU, abscess, biliary leakage, intrahepatic and distant tumor recurrence and in-hospital mortality were comparable between the two groups. CONCLUSION: Precoagulation with MWA reduced intraoperative blood loss with similar postoperative complications, providing a safe, effective, novel alternative for hepatic parenchymal transection during liver partial resection. Additional results from larger series are recommended to confirm these findings.

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion.

BACKGROUND/AIMS: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). METHODS: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co-cultured BMDCs/DEXs and naïve T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naïve T cells by WB and FCM. RESULTS: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-ß, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naïve T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naïve T cells. CONCLUSION: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naïve T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury.

Application of microwave ablation in the emergent control of intraoperative life-threatening tumor hemorrhage during hepatic surgeries.

PURPOSE: This study was designed to evaluate the efficacy and safety of microwave ablation (MWA) in the treatment of intraoperative life-threatening tumour haemorrhage during hepatic surgeries. METHODS: Three cases of MWA application in the emergent control of life-threatening hepatic tumour haemorrhage were analysed and reported. RESULTS: Satisfactory hemostasis for hepatic tumour rupture was achieved by MWA in all three cases. No major complications, such as post-operative haemorrhage, bile duct injury, liver abscess, colon perforation, skin burns, tumour seeding or renal dysfunction, were identified. CONCLUSIONS: MWA may be a feasible, effective and simple strategy for the emergent control of intraoperative hepatic tumour bleeding. To the best of our knowledge, this study represents the first reported cases of this novel application of MWA.

Mir-24 regulates hepatocyte apoptosis via BIM during acute liver failure.

Acuteliver failure (ALF) has a high mortality rate and is characterized by massive hepatocyte destruction. Although microRNAs (miRNAs) play an important role in manyliver diseases, the role of miRNAs in ALF development is unknown. In this study, the murine ALF model was induced by intraperitoneal injection of D-galactosamine/lipopolysaccharide (D-GalN/LPS). Compared with saline-treated mice, miR-24 was distinctly down-regulated post D-GalN/LPS challenge in vivo and D-galactosamine/tumor necrosis factor (D-GalN/TNF) challenge in vitro, which was confirmed by quantitative real-time polymerase chain reaction. Meanwhile, the mRNA and protein levels of the BH3-only-domain-containing protein BIM were upregulated after challenge both in vivo and in vitro. Previous studies have demonstrated that hepatocyte apoptosis is a distinguishing feature of D-GalN/LPS-associated liver failure. In this study, D-GalN/LPS-challenged mice showed higher alanine aminotransferase and aspartate aminotransferase levels, more severe liver damage, increased numbers of apoptotic hepatocytes and higher levels of caspase-3 compared with saline-treated mice. In D-GalN/TNF-treated BNLCL2 cells, miR-24 overexpression attenuated apoptosis.Furthermore, miR-24 overexpression reduced BIM mRNA and protein levels in vitro. Taken together, these findings demonstrate that miR-24 regulates hepatocyte apoptosis via BIM during ALF development, suggesting that miR-24 is a novel onco-miRNA that may provide potential therapeutic targets for ALF.

Systemic haemodynamics and regional tissue oxygen saturation after bidirectional cavopulmonary shunt: positive pressure ventilation versus spontaneous breathing.

OBJECTIVES: Spontaneous breathing has been shown to improve global haemodynamics in patients with bidirectional cavopulmonary shunt. What has not been evaluated, however, is the effect of spontaneous breathing on the distribution of cardiac output after bidirectional cavopulmonary shunt. We investigated the effects of extubation on systemic haemodynamics and regional tissue oxygen saturation, and determined whether redistribution of cardiac output is present after extubation in these patients. METHODS: In 24 patients undergoing bidirectional cavopulmonary shunt, standard haemodynamic variables including heart rate, arterial blood pressure and central venous pressure were monitored continuously. Near-infrared spectroscopy of the brain and mesenteric circulation was monitored and recorded every hour. Cardiac index, derived from ascending aorta flow, was measured by ultrasound at three time points: 30 min before, 30 min after and 12 h after extubation. RESULTS: The central venous pressure decreased significantly from 19.50 ± 3.65 mmHg before extubation to 16.17 ± 3.41 mmHg 30 min after extubation (P = 0.006) and 13.96 ± 2.49 mmHg 12 h after extubation (P = 0.001). Cardiac index increased significantly from 3.32 ± 0.43 l/min/m(2) before extubation to 3.73 ± 0.51 l/min/m(2) 30 min after extubation (P = 0.012) and 3.98 ± 0.54 l/min/m(2) 12 h after extubation (P = 0.001). Cerebral oxygen saturation increased from 50.83 ± 5.84% before extubation to 56.79 ± 8.64% 30 min after extubation (P = 0.023), then remained unchanged for the following 12 h. Mesenteric oxygen saturation remained unchanged during the early period of extubation, but increased significantly 12 h after extubation (P = 0.002). CONCLUSIONS: The lower values of cerebral oxygen saturation before extubation indicated that the cerebral blood flow was less satisfactory. During the early period of extubation, despite the increase in cardiac index, the mesenteric oxygen saturation is lower than that at 12 h after extubation, suggesting that the obligatory increase in respiratory muscle perfusion and the increase in cerebral oxygen saturation have utilized most of the flow from the increased cardiac index. The increase in mesenteric oxygen saturation 12 h after extubation suggests a gradual improvement in microcirculation and macrocirculation.

Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children.

To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64±15.81 (7-63) minutes and mean RCP time was 36.18±12.86 (10-82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time-consuming corrected procedures for complex congenital cardiac defect repair procedures.

Stable periodic oscillations in a two-stage cancer model of tumor and immune system interactions.

This paper presents qualitative and bifurcation analysis near the degenerate equilibrium in a two-stage cancer model of interactions between lymphocyte cells and solid tumor and contributes to a better understanding of the dynamics of tumor and immune system interactions. We first establish the existence of Hopf bifurcation in the 3-dimensional cancer model and rule out the occurrence of the degenerate Hopf bifurcation. Then a general Hopf bifurcation formula is applied to determine the stability of the limit cycle bifurcated from the interior equilibrium. Sufficient conditions on the existence of stable periodic oscillations of tumor levels are obtained for the two-stage cancer model. Numerical simulations are presented to illustrate the existence of stable periodic oscillations with reasonable parameters and demonstrate the phenomenon of long-term tumor relapse in the model.