Background & Aims The aim of this randomized comparative trial (RCT) is to compare partial hepatectomy (PH) with transcatheter arterial chemoembolization (TACE) to treat patients with resectable ...multiple hepatocellular carcinoma (RMHCC) outside of Milan Criteria. Methods This RCT was conducted on 173 patients with RMHCC outside of Milan Criteria (a solitary tumor up to 5 cm or multiple tumors up to 3 in number and up to 3 cm for each tumor) who were treated in our centre from November 2008 to September 2010. The patients were randomly assigned to the PH group or the TACE group. The primary outcome measure was overall survival (OS) from the date of treatment. A multivariate Cox proportional hazards regression analysis was performed to assess the prognostic risk factors associated with OS. Results The 1-, 2-, and 3-year OS rates were 76.1%, 63.5%, and 51.5%, respectively, for the PH group compared with 51.8%, 34.8%, and 18.1%, respectively, for the TACE group (Log-rank test, χ2 = 24.246, p <0.001). Multivariate Cox proportional hazards regression analysis revealed the type of treatment (hazard ratio, 0.434; 95% CI, 0.293 to 0.644, p <0.001), number of tumor (hazard ratio, 1.758; 95% CI, 1.213 to 2.548, p = 0.003) and gender (hazard ratio, 0.451; 95% CI, 0.236 to 0.862, p = 0.016) were significant independent risk factors associated with OS. Conclusions PH provided better OS for patients with RMHCC outside of Milan Criteria than conventional TACE. The number of tumor and gender were also independent risk factors associated with OS for RMHCC.
Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by ...modulating miR-541-initiated microRNA-autophagy axis.
Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality.
The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment.
Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.
Systemic analyses using large‐scale genomic profiles have successfully identified cancer‐driving somatic copy number variations (SCNVs) loci. However, functions of vast focal SCNVs in “protein‐coding ...gene desert” regions are largely unknown. The integrative analysis of long noncoding RNA (lncRNA) expression profiles with SCNVs in hepatocellular carcinoma (HCC) led us to identify the recurrent deletion of lncRNA‐PRAL (p53 regulation‐associated lncRNA) on chromosome 17p13.1, whose genomic alterations were significantly associated with reduced survival of HCC patients. We found that lncRNA‐PRAL could inhibit HCC growth and induce apoptosis in vivo and in vitro through p53. Subsequent investigations indicated that the three stem‐loop motifs at the 5′ end of lncRNA‐PRAL facilitated the combination of HSP90 and p53 and thus competitively inhibited MDM2‐dependent p53 ubiquitination, resulting in enhanced p53 stability. Additionally, in vivo lncRNA‐PRAL delivery efficiently reduced intrinsic tumors, indicating its potential therapeutic application. Conclusions: lncRNA‐PRAL, one of the key cancer‐driving SCNVs, is a crucial stimulus for HCC growth and may serve as a potential target for antitumor therapy. (Hepatology 2016;63:850‐863)
We report on the synthesis, characterization, and electrochemical performance of novel, ultrathin Pt monolayer shell–Pd nanowire core catalysts. Initially, ultrathin Pd nanowires with diameters of ...2.0 ± 0.5 nm were generated, and a method has been developed to achieve highly uniform distributions of these catalysts onto the Vulcan XC-72 carbon support. As-prepared wires are activated by the use of two distinctive treatment protocols followed by selective CO adsorption in order to selectively remove undesirable organic residues. Subsequently, the desired nanowire core–Pt monolayer shell motif was reliably achieved by Cu underpotential deposition followed by galvanic displacement of the Cu adatoms. The surface area and mass activity of the acid and ozone-treated nanowires were assessed, and the ozone-treated nanowires were found to maintain outstanding area and mass specific activities of 0.77 mA/cm2 and 1.83 A/mgPt, respectively, which were significantly enhanced as compared with conventional commercial Pt nanoparticles, core–shell nanoparticles, and acid-treated nanowires. The ozone-treated nanowires also maintained excellent electrochemical durability under accelerated half-cell testing, and it was found that the area-specific activity increased by ∼1.5 fold after a simulated catalyst lifetime.
Although numerous long non-coding RNAs (lncRNAs) have been identified in mammals, many of their biological roles remain to be characterized. Early reports suggest that H19 contributes to ...carcinogenesis, including hepatocellular carcinoma (HCC). Examination of the Oncomine resource showed that most HCC cases express H19 at a level that is comparable with the liver, with a tendency toward lower expression. This is consistent with our previous microarray data and indicates a more complicated role of H19 in HCC that needs to be characterized. In this study, the expression level of H19 was assessed in different regions of HCC patients' liver samples. Loss- and gain-of-function studies on this lncRNA in the HCC cell lines, SMMC7721 and HCCLM3, were used to characterize its effects on gene expression and to assess its effect on HCC metastasis both in vitro and in vivo. In this study, we show that H19 was underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L). Additionally, low T/L ratio of H19 predicted poor prognosis. H19 suppressed HCC progression metastasis and the expression of markers of epithelial-to-mesenchymal transition. Furthermore, H19 associated with the protein complex hnRNP U/PCAF/RNAPol II, activating miR-200 family by increasing histone acetylation. The results demonstrate that H19 can alter the miR-200 pathway, thus contributing to mesenchymal-to-epithelial transition and to the suppression of tumor metastasis. These data provide an explanation for the hitherto puzzling literature on the relationship between H19 and cancer, and could suggest the development of combination therapies that target H19 and the miR-200 family.
There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a ...multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of
Murr (Huaier granule) to address this unmet need.
A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI -12.59 to -2.50; p=0.0018), respectively.
This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.
NCT01770431; Post-results.
We report on the synthesis, characterization, and electrocatalytic performance of ultrathin Pt nanowires with a diameter of less than 2 nm. An acid-wash protocol was employed in order to yield highly ...exfoliated, crystalline nanowires with a diameter of 1.3 ± 0.4 nm. The electrocatalytic activity of these nanowires toward the oxygen reduction reaction was studied in relation to the activity of both supported and unsupported Pt nanoparticles as well as with previously synthesized Pt nanotubes. Our ultrathin, acid-treated, unsupported nanowires displayed an electrochemical surface area activity of 1.45 mA/cm2, which was nearly 4 times greater than that of analogous, unsupported platinum nanotubes and 7 times greater than that of commercial supported platinum nanoparticles.
As an important epigenetic mechanism, histone acetylation modulates the transcription of many genes and plays important roles in hepatocellular carcinoma (HCC). Aberrations in histone acetylation ...have been observed in HCC, but the factors that contribute to the aberrations have not been fully elucidated. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in important epigenetic mechanisms. In this study, we determined that miR‐200a and the level of histone H3 acetylation at its promoter were reduced in human HCC tissues in comparison with adjacent noncancerous hepatic tissues. Furthermore, our results suggested that the histone deacetylase 4 (HDAC4) inhibited the expression of miR‐200a and its promoter activity and reduced the histone H3 acetylation level at the mir‐200a promoter through a Sp1‐dependent pathway. Interestingly, we observed that the miR‐200a directly targeted the 3′‐untranslated region of the HDAC4 messenger RNA and repressed expression of HDAC4. Therefore, miR‐200a ultimately induced its own transcription and increased the histone H3 acetylation level at its own promoter. Through targeting HDAC4, miR‐200a also induced the up‐regulation of total acetyl‐histone H3 levels and increased the histone H3 acetylation level at the p21WAF/Cip1 promoter. Finally, we determined that miR‐200a inhibited the proliferation and migration of HCC cells in vivo and in vitro. Conclusion: Our findings suggest that the HDAC4/Sp1/miR‐200a regulatory network induces the down‐regulation of miR‐200a and the up‐regulation of HDAC4 in HCC. As a result, down‐regulation of miR‐200a enhances the proliferation and migration of HCC cells and induces aberrant histone acetylation in HCC. These findings highlight a potential therapeutic approach in targeting the HDAC4/Sp1/miR‐200a regulatory network for the treatment of HCC. (HEPATOLOGY 2011
Survival of patients with hepatocellular carcinoma (HCC) remains poor, which is largely attributed to active angiogenesis. However, the mechanisms underlying angiogenesis in HCC remain to be ...discovered. In this study, we found that long noncoding RNA associated with microvascular invasion in HCC (lncRNA MVIH) (lncRNA associated with microvascular invasion in HCC) was generally overexpressed in HCC. In a cohort of 215 HCC patients, the overexpression of MVIH was associated with frequent microvascular invasion (P = 0.016) and a higher tumor node metastasis stage (P = 0.009) as well as decreased recurrence‐free survival (RFS) (P < 0.001) and overall survival (P = 0.007). Moreover, the up‐regulation of MVIH served as an independent risk factor to predict poor RFS. We also found that MVIH could promote tumor growth and intrahepatic metastasis by activating angiogenesis in mouse models. Subsequent investigations indicated that MVIH could activate tumor‐inducing angiogenesis by inhibiting the secretion of phosphoglycerate kinase 1 (PGK1). Additionally, in 65 HCC samples, MVIH expression was inversely correlated with the serum level of PGK1 and positively correlated with the microvessel density. Conclusion: Deregulation of lncRNA MVIH is a predictor for poor RFS of HCC patients after hepatectomy and could be utilized as a potential target for new adjuvant therapies against active angiogenesis. (HEPATOLOGY 2012;56:2142–2153)
Bat flight poses intriguing questions about how flight independently developed in mammals. Flight is among the most energy-consuming activities. Thus, we deduced that changes in energy metabolism ...must be a primary factor in the origin of flight in bats. The respiratory chain of the mitochondrial produces 95% of the adenosine triphosphate (ATP) needed for locomotion. Because the respiratory chain has a dual genetic foundation, with genes encoded by both the mitochondrial and nuclear genomes, we examined both genomes to gain insights into the evolution of flight within mammals. Evidence for positive selection was detected in 23.08% of the mitochondrial-encoded and 4.90% of nuclear-encoded oxidative phosphorylation (OXPHOS) genes, but in only 2.25% of the nuclear-encoded nonrespiratory genes that function in mitochondria or 1.005% of other nuclear genes in bats. To address the caveat that the two available bat genomes are of only draft quality, we resequenced 77 OXPHOS genes from four species of bats. The analysis of the resequenced gene data are in agreement with our conclusion that a significantly higher proportion of genes involved in energy metabolism, compared with background genes, show evidence of adaptive evolution specific on the common ancestral bat lineage. Both mitochondrial and nuclear-encoded OXPHOS genes display evidence of adaptive evolution along the common ancestral branch of bats, supporting our hypothesis that genes involved in energy metabolism were targets of natural selection and allowed adaptation to the huge change in energy demand that were required during the origin of flight.
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