Chitosan oligosaccharide attenuates acute kidney injury and renal interstitial fibrosis induced by ischemia-reperfusion.

Acute kidney injury (AKI) and renal interstitial fibrosis are global clinical syndromes associated with high morbidity and mortality. Renal ischemia-reperfusion (I/R) injury, which commonly occurs during surgery, is one of the major causes of AKI. Nevertheless, an efficient therapeutic approach for AKI and the development of renal interstitial fibrosis is still lacking due to its elusive pathogenetic mechanism. Here, we showed that chitosan oligosaccharide (COS), a natural oligomer polysaccharide degraded from chitosan, significantly attenuates I/R-induced AKI and maintains glomerular filtration function by inhibiting oxidative stress, mitochondrial damage, and excessive endoplasmic reticulum stress both in vitro and in vivo. In addition, long-term administration of COS can also attenuate the proliferation of myofibroblasts, mitigate extra cellular matrix deposition, and thus inhibit the transition of AKI to chronic kidney disease through participating in metabolic and redox biological processes. Our findings provide novel insights into the protective role of COS against acute kidney injury.

Cell membrane-coated human hair nanoparticles for precise disease therapies.

Precision medicine is the ultimate goal for current disease therapies, including tumor and infection. The lack of specific targeted drugs for liver cancer and the lack of specific anti-infective drugs in the treatment of diabetic foot ulcer with infection (DFI) are the representative obstacles in those 2 major diseases currently plaguing human beings. Inventing natural biocompatible polymers derived from natural materials is one of the main development directions of current bio-medical materials. Though previous studies have demonstrated the potential application values of human black hair-derived nanoparticles (HNP) in cancer, methicillin-resistant Staphylococcus aureus (MRSA) infection, and thrombosis scenarios treatments, it still has not solved the problem of low local therapeutic concentration and general targeting ability. Here, we firstly modified the HNP with membrane encapsulations, which endowed these dual-pure natural bio-fabricated materials with better targeting ability at the disease sites with no reduction in photothermal therapy (PTT) effect. HNP coated by red blood cell membrane loaded with DSPE-PEG-cRGD peptide for the therapeutic application of liver cancer greatly prolonged in vivo circulation time and enhanced local targeting efficacy as well as low toxicity; HNP coated by the murine macrophage cell membrane (RAWM) for the DFIs treatment greatly promoted the adhesive ability of HNP on the bacteria and thereby improved the killing effect. Briefly, the appropriate cell membranes camouflaged HNP nanomedicine has the characteristics of excellent photothermal effect, an all-natural source with excellent biocompatibility and easy access, which is expected to have huge potential in both benign and malignant diseases.

Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA.

Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Moyamoya disease with distal anterior choroidal artery aneurysm resected via transcallosal approach: A case report and review.

RATIONALE: Moyamoya disease (MMD) is a cerebrovascular structural disorder characterized by bilateral stenosis and obstruction of the internal carotid artery, anterior cerebral artery, and initial segment of a middle cerebral artery, as well as the aberrant formation of collateral arteries at the base of the brain. Moyamoya disease with distal anterior choroidal artery (AChA) aneurysm is extremely uncommon. At present, the treatment of Moyamoya disease with aneurysm mainly includes conservative treatment and surgical treatment, including revascularization, endovascular therapy and microsurgical clipping or resection. Interventional therapy is the first treatment of choice. For those whose paths are tortuous and inaccessible and intervention fails, I successfully excised them through craniotomy. PATIENT CONCERNS: The 38-year-old male patient, diagnosed with Moyamoya disease 11 years ago and was hospitalized for multiple intraventricular hemorrhages throughout that time. During the 11 years, the patient was hospitalized for intra ventricular hemorrhage for several times. The patient was diagnosed as moyamoya disease for many times by digital subtraction angiography, but he was recommended to come to our hospital for cerebrovascular bypass surgery 3 months after each hemorrhage, but he did not come to our hospital until the next intraventricular hemorrhages. DIAGNOSES: This recurrent intraventricular bleeding was suspected to be caused by MMD, and a digital subtraction angiography of the brain revealed an aneurysm of the distal AChA. INTERVENTIONS: Interventional therapy was the first choice. During the operation, transcatheter aneurysm embolization was tried. Finally, interventional therapy was abandoned because the vessels were too thin and tortuous and the guide wire could not pass through. After detecting the aneurysm using computerized tomography angiography, the distal AChA aneurysm was resected through the lateral interventricular foramen of the corpus callosum, and the corpus callosum was parted along the interhemispheric fissure to access the third ventricle. OUTCOMES: On the 21st postoperative day, the patient improved, recovered to a Glasgow Coma Scale score of 15. LESSONS: We conclude that craniotomy is a satisfying alternative in patients with MMD complicated by perforated distal AChA aneurysm hemorrhage if the vascular prerequisites for endovascular treatment are not accessible and the patient has a favorable prognosis.

Aberrant DNA Methylation Patterns of Deleted in Liver Cancer 1 Isoforms in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), a common primary liver cancer, is the third leading cause of death worldwide. DNA methylation changes are common in HCC and have been studied to be associated with hepatocarcinogenesis. In our study, we used the MassARRAY® EpiTYPER technology to investigate the methylation differences of deleted in liver cancer 1 (DLC1) (isoform 1 and 3) promoter between HCC tissues and corresponding adjacent noncancerous tissues and the association between methylation levels and clinicopathological features. In addition, the modified CRISPR-Cas9 system and the DNA methyltransferase inhibitor (DNMTi) were utilized to explore the functional correlation of epigenetic modifications and DLC1 gene regulation. The methylation levels of the DLC1 isoforms in HCC samples were found significantly lower than those in the adjacent noncancerous tissues (all p < 0.0001). Also, we found that the expression of DLC1 could be bidirectionally regulated by the modified CRISPR-Cas9 system and the DNMTi. Moreover, the hypomethylation of DLC1 in HCC samples was connected with the presence of satellite lesions (p = 0.0305) and incomplete tumor capsule (p = 0.0204). Receiver operator characteristic curve analysis demonstrated that the methylation levels of DLC1 could be applied to discriminate HCC patients (area under the curve = 0.728, p < 0.0001). The hypomethylation status was a key regulatory mechanism of DLC1 expression and might serve as a potential biomarker for HCC.

Identification and development of a novel risk model based on cuproptosis-associated RNA methylation regulators for predicting prognosis and characterizing immune status in hepatocellular carcinoma.

BACKGROUND: Cuproptosis, a novel cell death caused by excess copper, is quite obscure in hepatocellular carcinoma (HCC) and needs more investigation. METHODS: RNA-seq and clinical data of HCC patients TCGA database were analyzed to establish a predictive model through LASSO Cox regression analysis. External dataset ICGC was used for the verification. GSEA and CIBERSORT were applied to investigate the molecular mechanisms and immune microenvironment of HCC. Cuproptosis induced by elesclomol was confirmed via various in vitro experiments. The expression of prognostic genes was verified in HCC tissues using qRT-PCR analysis. RESULTS: Initially, 18 cuproptosis-associated RNA methylation regulators (CARMRs) were selected for prognostic analysis. A nine-gene signature was created by applying the LASSO Cox regression method. Survival and ROC assays were carried out to validate the model using TCGA and ICGC database. Moreover, there exhibited obvious differences in drug sensitivity in terms of common drugs. A higher tumor mutation burden was shown in the high-risk group. Additionally, significant discrepancies were found between the two groups in metabolic pathways and RNA processing via GSEA analysis. Meanwhile, CIBERSORT analysis indicated different infiltrating levels of various immune cells between the two groups. Elesclomol treatment caused a unique form of programmed cell death accompanied by loss of lipoylated mitochondrial proteins and Fe-S cluster protein. The results of qRT-PCR indicated that most prognostic genes were differentially expressed in the HCC tissues. CONCLUSION: Overall, our predictive signature displayed potential value in the prediction of overall survival of HCC patients and might provide valuable clues for personalized therapies.

Insight into the history and trends of surgical simulation training in education: a bibliometric analysis.

BACKGROUND: Surgical simulation training enables surgeons to acquire clinical experience or skills from the operating room to the simulation environment. Historically, it has changed with advances in science and technology. Moreover, no previous study has analyzed this field from the bibliometric analysis dimension. The study aimed to review changes in surgical simulation training worldwide using bibliometric software. MATERIALS AND METHODS: Two searches were performed on the core collection database, Web of Science, regarding data from 1991 to the end of 2020 using three topic words (surgery, training, and simulation). From 1 January 2000, to 15 May 2022, the keyword 'robotic' was added for the hotspot exploration. The data were chiefly analyzed by publication date, country, author(s), and keywords using bibliometric software. RESULTS: A total of 5285 articles were initially analyzed, from which it was clear that laparoscopic skill, three-dimensional printing, and virtual reality were the main focuses during those study periods. Subsequently, 348 publications on robotic surgery training were identified. CONCLUSION: This study systematically summarizes the current status in the field of surgical simulation training and provides insights into the research focuses and future hotspot in a global context.

A Machine-Learning-Based Bibliometric Analysis of Cell Membrane-Coated Nanoparticles in Biomedical Applications over the Past Eleven Years.

Cell membrane encapsulation is a growing concept in nanomedicine, for it achieves the purpose of camouflage nanoparticles, realizing the convenience for drug delivery, bio-imaging, and detoxification. Cell membranes are constructed by bilayer lipid phospholipid layers, which have unique properties in cellular uptake mechanism, targeting ability, immunomodulation, and regeneration. Current medical applications of cell membranes include cancers, inflammations, regenerations, and so on. In this article, a general bibliometric overview is conducted of cell membrane-coated nanoparticles covering 11 years of evolution in order to provide researchers in the field with a comprehensive view of the relevant achievements and trends. The authors analyze the data from Web of Science Core Collection database, and extract the annual publications and citations, most productive countries/regions, most influential scholars, the collaborations of journals and institutions. The authors also divided cell membranes into several subgroups to further understand the application of different cell membranes in medical scenarios. This study summarizes the current research overview in cell membrane-coated nanoparticles and intuitively provides a direction for future research.

N-Acetylglucosamine mitigates lung injury and pulmonary fibrosis induced by bleomycin.

Lung injury and pulmonary fibrosis contribute to morbidity and mortality, and, in particular, are characterized as leading cause on confirmed COVID-19 death. To date, efficient therapeutic approach for such lung diseases is lacking. N-Acetylglucosamine (NAG), an acetylated derivative of glucosamine, has been proposed as a potential protector of lung function in several types of lung diseases. The mechanism by which NAG protects against lung injury, however, remains unclear. Here, we show that NAG treatment improves pulmonary function in bleomycin (BLM)-induced lung injury model measured by flexiVent system. At early phase of lung injury, NAG treatment results in silenced immune response by targeting ARG1+ macrophages activation, and, consequently, blocks KRT8+ transitional stem cell in the alveolar region to stimulate PDGF Rß+ fibroblasts hyperproliferation, thereby attenuating the pulmonary fibrosis. This combinational depression of immune response and extracellular matrix deposition within the lung mitigates lung injury and pulmonary fibrosis induced by BLM. Our findings provide novel insight into the protective role of NAG in lung injury.

TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression.

Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.

Abnormal hubs in global network as neuroimaging biomarker in right temporal lobe epilepsy at rest.

While abnormal neuroimaging features have been reported in patients suffering from right temporal lobe epilepsy (rTLE), the value of altered degree centrality (DC) as a diagnostic biomarker for rTLE has yet to be established. As such, the present study was designed to examine DC abnormalities in rTLE patients in order to gauge the diagnostic utility of these neuroimaging features. In total, 68 patients with rTLE and 73 healthy controls (HCs) participated in this study. Imaging data were analyzed using DC and receiver operating characteristic (ROC) methods. Ultimately, rTLE patients were found to exhibit reduced right caudate DC and increased left middle temporal gyrus, superior parietal gyrus, superior frontal gyrus, right precuneus, frontal gyrus Inferior gyrus, middle-superior frontal gyrus, and inferior parietal gyrus DC relative to HC. ROC analyses indicated that DC values in the right caudate nucleus could be used to differentiate between rTLE patients and HCs with a high degree of sensitivity and specificity. Together, these results thus suggest that rTLE is associated with abnormal DC values in the right caudate nucleus, underscoring the relevance of further studies of the underlying pathophysiology of this debilitating condition.

Comprehensive analysis of cuproptosis-related lncRNAs for prognostic significance and immune microenvironment characterization in hepatocellular carcinoma.

Cuproptosis was characterized as a novel type of programmed cell death. Recently, however, the role of cuproptosis-related long noncoding RNAs (CRLs) in tumors has not yet been studied. Identifying a predictive CRL signature in hepatocellular carcinoma (HCC) and investigating its putative molecular function were the goals of this work. Initially, Pearson's test was used to assess the relationship between lncRNAs and cuproptosis-associated genes obtained from HCC data of The Cancer Genome Atlas (TCGA). By implementing differential expression and univariate Cox analysis, 61 prognostic CRLs were subsequent to the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. A prognostic risk score model was then constructed to evaluate its ability to predict patients' survival when combined with clinicopathological parameters in HCC. The five-lncRNA prognostic signature categorized the HCC patients into high- and low-risk groups. The low-risk group exhibited more sensitivity to elesclomol than the high-risk one. Surprisingly, distinct mitochondrial metabolism pathways connected to cuproptosis and pivotal immune-related pathways were observed between the two groups via gene set enrichment analysis (GSEA). Meanwhile, there were substantial differences between the high-risk group and the low-risk group in terms of tumor-infiltrating immune cells (TIICs). Furthermore, a positive relationship was shown between the risk score and the expression of immune checkpoints. Additionally, differential expression of the five lncRNAs was confirmed in our own HCC samples and cell lines via RT-qPCR. Finally, in vitro assays confirmed that WARS2-AS1 and MKLN1-AS knockdown could sensitize HCC cells to elesclomol-induced cuproptosis. Overall, our predictive signature may predict the prognosis of HCC patients in an independent manner, give a better understanding of how CRLs work in HCC, and offer therapeutic reference for patients with HCC.

C8orf76 Modulates Ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. Chromosome 8 open reading frame 76 (C8orf76), a novel gene located in the nucleus, is highly expressed in many tumor types. However, the specific mechanisms and functions of C8orf76 in HCC remain unclear. Here, we reported for the first time that C8orf76 gene expression levels were frequently upregulated in liver cancer and significantly correlated with HCC development. C8orf76 downregulation induced G1-S arrest and inhibited cell proliferation. Intriguingly, C8orf76 deficiency could accelerate erastin or sorafenib-induced ferroptosis through increasing lipid reactive oxygen species (ROS) levels. Moreover, although C8orf76 overexpression did not affect tumorigenesis under normal conditions, it increased resistance to lipid disturbance and ferroptosis triggered by erastin or sorafenib, which further facilitated HCC cell growth and tumor progression. Mechanistically, C8orf76 bound to the promoter region of the solute carrier family 7 member 11 (SLC7A11) gene and upregulated SLC7A11 transcriptionally. SLC7A11-dependent cystine import led to sufficient GSH synthesis and lipid peroxidation inhibition, thus accelerating tumor growth. Our study indicated that C8orf76 could be a novel marker for HCC diagnosis. In addition, a better comprehensive understanding of the potential role of C8orf76 in HCC helped us develop novel therapeutic strategies for this intractable cancer.

Global Trends in Research of Lipid Metabolism in T lymphocytes From 1985 to 2022: A Bibliometric Analysis.

Lipids are involved in both energy metabolism and signaling transduction. Abnormal lipid metabolism in T cells is associated with the differentiation, longevity and activity of T cells, which has received increasing concern since its firstly reported in 1985. To evaluate the trends of lipid metabolism in T cells and map knowledge structure, we employed bibliometric analysis. A total of 286 related publications obtained from the Web of Science Core Collection published between 1985 and 2022 were analyzed using indicators of publication and citation metrics, countries, institutes, authors, cited references and key words. The present research status, the global trends and the future development directions in lipid metabolism and T cells were visualized and discussed. In summary, this study provides a comprehensive display on the field of lipid metabolism in T cells, which will help researchers explore lipid metabolism in T cells more effectively and intuitively.

Translating Metaphtonymy: Exploring Trainee Translators' Translation Approaches and Underlying Factors.

Metaphtonymy is identified as a special rhetoric figure that specifies the interaction between metaphor and metonymy and which is pervasive in literary works. How and why do trainee translators translate metaphtonymy? Using task analysis, semi-structured discourse-based interviews, and a questionnaire survey among 30 master of translation and interpreting (MTI) trainee translators, this study investigates their translation approaches adopted when translating the metaphtonymies in Chinese extracted prose and explores the effects of their choices. It is found that they mainly employed three approaches: omission, modification, and retainment, with omission being the most, and retainment the least frequent. The main factors attributing to each approach range from the prominence degrees and cross-cultural adaptation abilities of the metaphtonymies, rhetorical awareness of translators, and transference competence to their translation knowledge sub-competence. This study suggests that trainee translators should be instructed to systematically construct rhetoric knowledge, and the teaching design should emphasize the competence of trainees of identifying rhetorical devices and their competence of shifting rhetoric between languages.

Immunotherapy for Hepatocellular Carcinoma: Current Limits and Prospects.

Although many approaches have been used to treat hepatocellular carcinoma (HCC), the clinical benefits remain limited, particularly for late stage HCC. In recent years, studies have focused on immunotherapy for HCC. Immunotherapies have shown promising clinical outcomes in several types of cancers and potential therapeutic effects for advanced HCC. In this review, we summarize the immune tolerance and immunotherapeutic strategies for HCC as well as the main challenges of current therapeutic approaches. We also present alternative strategies for overcoming these limitations.

Cancer and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization and Bioinformatic Analysis.

The clinical management of patients with COVID-19 and cancer is a Gordian knot that has been discussed widely but has not reached a consensus. We introduced two-sample Mendelian randomization to investigate the causal association between a genetic predisposition to cancers and COVID-19 susceptibility and severity. Moreover, we also explored the mutation landscape, expression pattern, and prognostic implications of genes involved with COVID-19 in distinct cancers. Among all of the cancer types we analyzed, only the genetic predisposition to lung adenocarcinoma was causally associated with increased COVID-19 severity (OR = 2.93, ß = 1.074, se = 0.411, p = 0.009) with no obvious heterogeneity (Q = 17.29, p = 0.24) or symmetry of the funnel plot. In addition, the results of the pleiotropy test demonstrated that instrument SNPs were less likely to affect COVID-19 severity via approaches other than lung adenocarcinoma cancer susceptibility (p = 0.96). Leave-one-out analysis showed no outliers in instrument SNPs, whose elimination rendered alterations in statistical significance, which further supported the reliability of the MR results. Broad mutation and differential expression of these genes were also found in cancers, which may provide valuable information for developing new treatment modalities for patients with both cancer and COVID-19. For example, ERAP2, a risk factor for COVID-19-associated death, is upregulated in lung squamous cancer and negatively associated with patient prognosis. Hence, ERAP2-targeted treatment may simultaneously reduce COVID-19 disease severity and restrain cancer progression. Our results highlighted the importance of strengthening medical surveillance for COVID-19 deterioration in patients with lung adenocarcinoma by showing their causal genetic association. For these patients, a delay in anticancer treatment, such as chemotherapy and surgery, should be considered.

Implementation of artificial intelligence in the histological assessment of pulmonary subsolid nodules.

BACKGROUND: Clinical management of subsolid nodules (SSNs) is defined by the suspicion of tumor invasiveness. We sought to develop an artificial intelligent (AI) algorithm for invasiveness assessment of lung adenocarcinoma manifesting as radiological SSNs. We investigated the performance of this algorithm in classification of SSNs related to invasiveness. METHODS: A retrospective chest computed tomography (CT) dataset of 1,589 SSNs was constructed to develop (85%) and internally test (15%) the proposed AI diagnostic tool, SSNet. Diagnostic performance was evaluated in the hold-out test set and was further tested in an external cohort of 102 SSNs. Three thoracic surgeons and three radiologists were required to evaluate the invasiveness of SSNs on both test datasets to investigate the clinical utility of the proposed SSNet. RESULTS: In the differentiation of invasive adenocarcinoma (IA), SSNet achieved a similar area under the curve [AUC; 0.914, 95% confidence interval (CI): 0.813-0.987] with that of the 6 doctors (0.900, 95% CI: 0.867-0.922). When interpreting with the assistance of SSNet, the sensitivity of junior doctors, specificity of senior doctor, and their accuracy were significantly improved. In the external test, SSNet (AUC: 0.949, 95% CI: 0.884-1.000) achieved a better AUC than doctors (AUC: 0.883, 95% CI: 0.826-0.939) whose AUC increased (AUC: 0.908, 95% CI: 0.847-0.982) with SSNet assistance. In the histological subtype classifications, SSNet achieved better performance than practicing doctors. The AUCs of doctors were significantly improved with the assistance of SSNet in both 4-category and 3-category classifications to 0.836 (95% CI: 0.811-0.862) and 0.852 (95% CI: 0.825-0.882), respectively. CONCLUSIONS: The AI diagnostic system achieved non-inferior performance to doctors, and will potentially improve diagnostic performance and efficiency in SSN evaluation.

Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients.

Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs (P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway (P = 4.48E-5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort (n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.

Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma.

E-cadherin is well known as a growth and invasion suppressor and belongs to the large cadherin family. Loss of E-cadherin is widely known as the hallmark of epithelial-to-mesenchymal transition (EMT) with the involvement of transcription factors such as Snail, Slug, Twist and Zeb1/2. Tumor cells undergoing EMT could migrate to distant sites and become metastases. Recently, numerous studies have revealed how the expression of E-cadherin is regulated by different kinds of genetic and epigenetic alteration, which are implicated in several crucial transcription factors and pathways. E-cadherin signaling plays an important role in hepatocellular carcinoma (HCC) initiation and progression considering the highly mutated frequency of CTNNB1 (27%). Combining the data from The Cancer Genome Atlas (TCGA) database and previous studies, we have summarized the roles of gene mutations, chromosome instability, DNA methylation, histone modifications and non-coding RNA in E-cadherin in HCC. In this review, we discuss the current understanding of the relationship between these modifications and HCC. Perspectives on E-cadherin-related research in HCC are provided.