Current understanding of the functional roles of aberrantlyexpressed microRNAs in esophageal cancer The incidence of esophageal cancer is rising, mostlybecause the increasing incidence of esophagealadenocarcinoma in Western countries. Despiteimprovements in diagnosis and treatment, the overall5-year survival rates remain low. MicroRNAs （miRNAs）are small non-coding RNA molecules that regulate theexpression of target genes. Recently, disease specificmiRNAs have been identified, which act as tumorsuppressors or oncogenes. In this review, we willsummarize the current knowledge about the functionof aberrantly expressed miRNAs in esophageal cancer.We selected 5 miRNAs （miRNA-21, -143, -145, -196aand let-7） based on the available literature, anddescribed their potential role in regulating pathwaysthat are deregulated in esophageal cancer. Finally wewill highlight the current achievements of using andtargeting miRNAs. Because these miRNAs likely haveimportant regulatory roles in cancer development,they open a therapeutic window for new treatmentmodalities.
Optimal management for alcoholic liver disease：Conventional medications, natural therapy or combination？ Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liverdisease （ALD） is defined by histological lesions on theliver that can range from simple hepatic steatosis tomore advanced stages such as alcoholic steatohepatitis,cirrhosis, hepatocellular carcinoma and liver failure. Asone of the oldest forms of liver injury known to humans,ALD is still a leading cause of liver-related morbidityand mortality and the burden is exerting on medicalsystems with hospitalization and management costsrising constantly worldwide. Although the biologicalmechanisms, including increasing of acetaldehyde,oxidative stress with induction of cytochrome p4502E1, inflammatory cytokine release, abnormal lipidmetabolism and induction of hepatocyte apoptosis,by which chronic alcohol consumption triggers seriouscomplex progression of ALD is well established, thereis no universally accepted therapy to prevent orreverse. In this article, we have briefly reviewed thepathogenesis of ALD and the molecular targets fordevelopment of novel therapies. This review is focusedon current therapeutic strategies for ALD, includinglifestyle modification with nutrition supplements,available pharmacological drugs and new agents thatare under development, liver transplantation, applicationof complementary medicines, and their combination.The relevant molecular mechanisms of each conventionalmedication and natural agent have beenreviewed according to current available knowledge inthe literature. We also summarized efficacy vs safety onconventional and herbal medicines which are specificallyused for the prevention and treatment of ALD. Througha system review, this article highlighted that thecombination of pharmaceutical drugs with naturallyoccurring agents may offer an optimal management forALD and its complications. It is worthwhile to conductlarge-scale, multiple centre clinical trials to further provethe safety and benefits for the integrative therapy onALD.
Multipotent mesenchymal stromal cells： A promisingstrategy to manage alcoholic liver disease Chronic alcohol consumption is a major cause of liver disease. The term alcoholic liver disease （ALD） refersto a spectrum of mild to severe disorders includingsteatosis, steatohepatitis, cirrhosis, and hepatocellularcarcinoma. With limited therapeutic options, stemcell therapy offers significant potential for thesepatients. In this article, we review the pathophysiologicfeatures of ALD and the therapeutic mechanisms ofmultipotent mesenchymal stromal cells, also referredto as mesenchymal stem cells （MSCs）, based ontheir potential to differentiate into hepatocytes, theirimmunomodulatory properties, their potential topromote residual hepatocyte regeneration, and theircapacity to inhibit hepatic stellate cells. The perfectmatch between ALD pathogenesis and MSC therapeuticmechanisms, together with encouraging, availablepreclinical data, allow us to support the notion thatMSC transplantation is a promising therapeutic strategyto manage ALD onset and progression.
Relationships among alcoholic liver disease, antioxidants,and antioxidant enzymes Excessive consumption of alcoholic beverages isa serious cause of liver disease worldwide. Themetabolismof ethanol generates reactive oxygenspecies, which play a significant role in the deteriorationof alcoholic liver disease （ALD）. Antioxidantphytochemicals, such as polyphenols, regulate theexpression of ALD-associated proteins and peptides,namely, catalase, superoxide dismutase, glutathione,glutathione peroxidase, and glutathione reductase.These plant antioxidants have electrophilic activityand may induce antioxidant enzymes via the KelchlikeECH-associated protein 1-NF-E2-related factor-2pathway and antioxidant responsive elements.Furthermore, these antioxidants are reported toalleviate cell injury caused by oxidants or inflammatorycytokines. These phenomena are likely induced viathe regulation of mitogen-activating protein kinase（MAPK） pathways by plant antioxidants, similar topreconditioning in ischemia-reperfusion models.Although the relationship between plant antioxidantsand ALD has not been adequately investigated, plantantioxidants may be preventive for ALD because oftheir electrophilic and regulatory activities in the MAPKpathway.
Metabolic derivatives of alcohol and the molecular culpritsof fibro-hepatocarcinogenesis： Allies or enemies？ Chronic intake of alcohol undoubtedly overwhelmsthe structural and functional capacity of the liver byinitiating complex pathological events characterizedby steatosis, steatohepatitis, hepatic fibrosis andcirrhosis. Subsequently, these initial pathological eventsare sustained and ushered into a more complex andprogressive liver disease, increasing the risk of fibrohepatocarcinogenesis.These coordinated pathologicalevents mainly result from buildup of toxic metabolicderivatives of alcohol including but not limited toacetaldehyde （AA）, malondialdehyde （MDA）, CYP2E1-generated reactive oxygen species, alcohol-inducedgut-derived lipopolysaccharide, AA/MDA protein andDNA adducts. The metabolic derivatives of alcoholtogether with other comorbidity factors, includinghepatitis B and C viral infections, dysregulated ironmetabolism, abuse of antibiotics, schistosomiasis,toxic drug metabolites, autoimmune disease and othernon-specific factors, have been shown to underlieliver diseases. In view of the multiple etiology ofliver diseases, attempts to delineate the mechanismby which each etiological factor causes liver diseasehas always proved cumbersome if not impossible. Inthe case of alcoholic liver disease （ALD）, it is evenmore cumbersome and complicated as a result of themany toxic metabolic derivatives of alcohol with theirvarying liver-specific toxicities. In spite of all thesehurdles, researchers and experts in hepatology havestrived to expand knowledge and scientific discourse,particularly on ALD and its associated complicationsthrough the medium of scientific research, reviewsand commentaries. Nonetheless, the molecular mechanisms underpinning ALD, particularly thoseunderlying toxic effects of metabolic derivatives ofalcohol on parenchymal and non-parenchymal hepaticcells leading to increased risk of alcohol-induced fibrohepatocarcinogenesis,are still incompletely elucidated.In this review, we examined published scientificfindings on how alcohol and its metabolic deriv...Molecular changes in hepatic metabolism and transport incirrhosis and their functional importance Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liverfailure and hepatocellular carcinoma. The progressof liver fibrosis and cirrhosis is accompanied bydeteriorating liver function. This review summarizesthe regulatory and functional changes in phase Ⅰ andphase Ⅱ metabolic enzymes as well as transportproteins and provides an overview regarding lipid andglucose metabolism in cirrhotic patients. Interestingly,phase Ⅰ enzymes are generally downregulatedtranscriptionally, while phase Ⅱ enzymes are mostlypreserved transcriptionally but are reduced in theirfunction. Transport proteins are regulated in a specificway that resembles the molecular changes observed inobstructive cholestasis. Lipid and glucose metabolismare characterized by insulin resistance and catabolism,leading to the disturbance of energy expenditureand wasting. Possible non-invasive tests, especiallybreath tests, for components of liver metabolismare discussed. The heterogeneity and complexityof changes in hepatic metabolism complicate theassessment of liver function in individual patients.Additionally, studies in humans are rare, and speciesdifferences preclude the transferability of datafrom rodents to humans. In clinical practice, someestablished global scores or criteria form the basis forthe functional evaluation of patients with liver cirrhosis,but difficult treatment decisions such as selection fortransplantation or resection require further researchregarding the application of existing non-invasive testsand the development of more specific tests.
Four-dimensional flow magnetic resonance imaging incirrhosis Since its introduction in the 1970＇s, magnetic resonanceimaging （MRI） has become a standard imagingmodality. With its broad and standardized application,it is firmly established in the clinical routine and anessential element in cardiovascular and abdominalimaging. In addition to sonography and computertomography, MRI is a valuable tool for diagnosingcardiovascular and abdominal diseases, for determiningdisease severity, and for assessing therapeutic success.MRI techniques have improved over the last fewdecades, revealing not just morphologic information,but functional information about perfusion, diffusionand hemodynamics as well. Four-dimensional （4D）flow MRI, a time-resolved phase contrast-MRI withthree-dimensional （3D） anatomic coverage and velocityencoding along all three flow directions has been usedto comprehensively assess complex cardiovascularhemodynamics in multiple regions of the body. Thetechnique enables visualization of 3D blood flowpatterns and retrospective quantification of blood flowparameters in a region of interest. Over the last fewyears, 4D flow MRI has been increasingly performed inthe abdominal region. By applying different accelerationtechniques, taking 4D flow MRI measurements hasdropped to a reasonable scanning time of 8 to 12 min.These new developments have encouraged a growingnumber of patient studies in the literature validatingthe technique＇s potential for enhanced evaluationof blood flow parameters within the liver＇s complexvascular system. The purpose of this review articleis to broaden our understanding of 4D flow MRI forthe assessment of liver hemodynamics by providinginsights into acquisition, data analysis, visualization andquantification. Furthermore, in this article we highlightits development, focussing on the clinical application ofthe technique.
Magnetic resonance imaging of the cirrhotic liver in the eraof gadoxetic acid Gadoxetic acid improves detection and characterizationof focal liver lesions in cirrhotic patients and canestimate liver function in patients undergoing liverresection. The purpose of this article is to describe theoptimal gadoxetic acid study protocol for the liver, theunique characteristics of gadoxetic acid, the differencesbetween gadoxetic acid and extra-cellular gadoliumchelates, and the differences in phases of enhancementbetween cirrhotic and normal liver using gadoxeticacid. We also discuss how to obtain and recognize anadequate hepatobiliary phase.
Left ventricular function assessment in cirrhosis： Currentmethods and future directions Cirrhotic cardiomyopathy has been defined as a chroniccardiac dysfunction in patients with cirrhosis characterizedby impaired contractile responsiveness to stress and/oraltered diastolic relaxation with electrophysiologicalabnormalities in the absence of other known cardiacdisease. Non-invasive cardiovascular imaging modalitiesplay a major role in unmasking systolic and diastolicdysfunction in patients with cirrhosis. Echocardiographyhas been the most commonly used modality for assessingmyocardial function in these patients. Conventionalechocardiographic indices rely on several assumptionsthat may limit their applicability in patients with ahyperdynamic circulation. Newer imaging modalities maycontribute to a more accurate diagnosis of cardiovascularabnormalities in cirrhotic patients, thereby influencingclinical management. We aimed to review the differentnon-invasive imaging technologies currently used forassessing left ventricular systolic and diastolic function incirrhosis, as well as to describe new imaging modalitieswith potential clinical applicability in the near future.
Genetic variation of hepatitis B virus and its significance forpathogenesis Hepatitis B virus （HBV） has a worldwide distribution andis endemic in many populations. Due to its unique lifecycle which requires an error-prone reverse transcriptasefor replication, it constantly evolves, resulting intremendous genetic variation in the form of genotypes,sub-genotypes, and mutations. In recent years, there hasbeen considerable research on the relationship betweenHBV genetic variation and HBV-related pathogenesis,which has profound implications in the natural history ofHBV infection, viral detection, immune prevention, drugtreatment and prognosis. In this review, we attempted toprovide a brief account of the influence of HBV genotypeon the pathogenesis of HBV infection and summarizeour current knowledge on the effects of HBV mutationsin different regions on HBV-associated pathogenesis,with an emphasis on mutations in the preS/S proteins inimmune evasion, occult HBV infection and hepatocellularcarcinoma （HCC）, mutations in polymerase in relationto drug resistance, mutations in HBV core and e antigenin immune evasion, chronicalization of infection andhepatitis B-related acute-on-chronic liver failure, andfinally mutations in HBV x proteins in HCC.
Overview of hepatitis B virus mutations and theirimplications in the management of infection Hepatitis B virus （HBV） affects approximately twobillion people worldwide and more than 240 millionpeople in the world are currently chronic carrier thatcould develop serious complications in the future, likeliver cirrhosis and hepatocellular carcinoma. Althoughan extended HBV immunization program is beingcarried out since the early ＇80s, representing effectivepreventive measure, leading to a dramatic reductionof HBV hepatitis incidence, globally HBV infection stillrepresents a major public health problem. The HBVvirus is a DNA virus belongs to the Hepadnaviridaefamily. The HBV-DNA is a circular, partial doublestrand genome. All coding information is on theminus DNA strand and it is organized into four openreading frames. Despite hepatitis B virus is a DNAvirus, it has a high mutation rate due to its replicativestrategy, that leads to the production of many nonidenticalvariants at each cycle of replication. In fact,it contains a polymerase without the proofreadingactivity, and uses an RNA intermediate （pgRNA） duringits replication, so error frequencies are comparableto those seen in retroviruses and other RNA virusesrather than in more stable DNA viruses. Due to thelow fidelity of the polymerase, the high replicationrate and the overlapping reading frames, mutationsoccur throughout the genome and they have beenidentified both in the structural and not structural gene.The arise of mutations being to develop of a whole ofviral variants called ＂quasi-species＂ and the prevalentpopulation, which favors virus replication, was selectedby viral fitness, host＇s immune pressure and externalpressure, i.e. , vaccination or antiviral therapy. Naturallyoccurring mutations were found both in acute andchronic subjects. In the present review we examineand discuss the most recent available data about HBVgenetic variability and its significance.
Association between hepatitis B and metabolic syndrome：Current state of the art Chronic hepatitis B （CHB） is a global health issue that increases the risk of liver cirrhosis and hepatocellularcarcinoma in infected patients. Metabolic syndrome（MetS） is a disease endemic mostly to the developedcountries. It is associated with high cardiovascularmortality and morbidity, diabetes mellitus as well ascancer. In this manuscript, we systematically review thepublished data on the relationship between MetS andCHB infection. Multiple studies have described highlyvariable correlations between CHB on one hand andMetS, non-alcoholic fatty liver disease and dyslipidemiaon the other. No association between CHB and diabetesmellitus or atherosclerosis has been described as ofnow. The presence of MetS in patients infected withhepatitis B virus increases the risk of fibrosis, cirrhosisand hepatocellular carcinoma. Appropriate lifestyle,but also pharmacological interventions are needed toprevent the development of these complications.
Prophylactic managements of hepatitis B viral infection inliver transplantation Liver transplantation （LT） is a considerably effectivetreatment for patients with end-stage hepatitis B virus（HBV）-related liver disease. However, HBV infectionoften recurs after LT without prophylaxis. Since the1990s, the treatment for preventing HBV reinfectionafter LT has greatly progressed with the introduction ofhepatitis B immunoglobulin （HBIG） and nucleos（t）ideanalogues （NAs）, resulting in improved patient survival.The combination therapy consisting of high-dose HBIGand lamivudine is highly efficacious for preventing therecurrence of HBV infection after LT and became thestandard prophylaxis for HBV recurrence. However,mainly due to the high cost of HBIG treatment, analternative protocol for reducing the dose and durationof HBIG has been evaluated. Currently, combinationtherapy using low-dose HBIG and NAs is considered asthe most efficacious and cost-effective prophylaxis forpost-LT HBV reinfection. Recently, NA monotherapyand withdrawal of HBIG from combination therapy,along with the development of new, potent high geneticbarrier NAs, have provided promising efficacy, especiallyfor low-risk recipients. This review summarizes theprophylactic protocol and their efficacy includingprophylaxis of de novo HBV infection from anti-HBcantibody-positive donors. In addition, challengingapproaches such as discontinuation of all prophylaxisand active immunity through hepatitis B vaccination arediscussed.
Autophagy and microRNA in hepatitis B virus-relatedhepatocellular carcinoma Approximately 350 million people worldwide arechronically infected by hepatitis B virus （HBV）. HBVcauses severe liver diseases including cirrhosis andhepatocellular carcinoma （HCC）. In about 25% ofaffected patients, HBV infection proceeds to HCC.Therefore, the mechanisms by which HBV affects thehost cell to promote viral replication and its pathogenesishave been the subject of intensive research efforts.Emerging evidence indicates that both autophagy andmicroRNAs （miRNAs） are involved in HBV replicationand HBV-related hepatocarcinogenesis. In this review,we summarize how HBV induces autophagy, therole of autophagy in HBV infection, and HBV-relatedtumorigenesis. We further discuss the emerging roles ofmiRNAs in HBV infection and how HBV affects miRNAsbiogenesis. The accumulating knowledge pertainingto autophagy and miRNAs in HBV replication and itspathogenesis may lead to the development of novelstrategies against HBV infection and HBV-related HCCtumorigenesis.
Naturally derived anti-hepatitis B virus agents and theirmechanism of action Despite that some approved drugs and geneticallyengineered vaccines against hepatitis B virus （HBV）are available for HBV patients, HBV infection is stilla severe public health problem in the world. All theapproved therapeutic drugs （including interferonalphaand nucleoside analogues） have their limitations.No drugs or therapeutic methods can cure hepatitisB so far. Therefore, it is urgently needed to discoverand develop new anti-HBV drugs, especially nonnucleosideagents. Naturally originated compoundswith enormous molecular complexity and diversityoffer a great opportunity to find novel anti-HBV leadcompounds with specific antiviral mechanisms. Inthis review, the natural products against HBV arediscussed according to their chemical classes suchas terpenes, lignans, phenolic acids, polyphenols,lactones, alkaloids and flavonoids. Furthermore, novelmode of action or new targets of some representativeanti-HBV natural products are also discussed. The aimof this review is to report new discoveries and updatespertaining to anti-HBV natural products in the last 20years, especially novel skeletons and mode of action.Although many natural products with various skeletonshave been reported to exhibit potent anti-HBV effectsto date, scarcely any of them are found in the list ofconventional anti-HBV drugs worldwide. Additionly, inanti-HBV mechanism of action, only a few referencesreported new targets or novel mode of action of anti-HBV natural products.
Advances in computed tomography and magnetic resonanceimaging of hepatocellular carcinoma Hepatocellular carcinoma （HCC） is the most commonprimary liver cancer. Imaging is important forestablishing a diagnosis of HCC and early diagnosis isimperative as several potentially curative treatmentsare available when HCC is small. Hepatocarcinogenesisoccurs in a stepwise manner on a background ofchronic liver disease or cirrhosis wherein multiplegenes are altered resulting in a range of cirrhosisassociatednodules. This progression is related toincreased cellularity, neovascularity and size of thenodule. An understanding of the stepwise progressionmay aid in early diagnosis. Dynamic and multiphasecontrast-enhanced computed tomography and magneticresonance imaging still form the cornerstone in thediagnosis of HCC. An overview of the current diagnosticstandards of HCC in accordance to the more commonpracticing guidelines and their differences will bereviewed. Ancillary features contribute to diagnosticconfidence and has been incorporated into the morerecent Liver Imaging Reporting and Data System. Theuse of hepatocyte-specific contrast agents is increasingand gradually changing the standard of diagnosis ofHCC; the most significant benefit being the lack ofuptake in the hepatocyte phase in the earlier stagesof HCC progression. An outline of supplementarytechniques in the imaging of HCC will also be reviewed.
Molecular imaging and therapy targeting coppermetabolism in hepatocellular carcinoma Hepatocellular carcinoma （HCC） is the fifth mostcommon cancer worldwide. Significant efforts havebeen devoted to identify new biomarkers for molecularimaging and targeted therapy of HCC. Copper is anutritional metal required for the function of numerousenzymatic molecules in the metabolic pathways ofhuman cells. Emerging evidence suggests that copperplays a role in cell proliferation and angiogenesis.Increased accumulation of copper ions was detectedin tissue samples of HCC and many other cancers inhumans. Altered copper metabolism is a new biomarkerfor molecular cancer imaging with position emissiontomography （PET） using radioactive copper as atracer. It has been reported that extrahepatic mousehepatoma or HCC xenografts can be localized with PETusing copper-64 chloride as a tracer, suggesting thatcopper metabolism is a new biomarker for the detectionof HCC metastasis in areas of low physiological copperuptake. In addition to copper modulation therapy withcopper chelators, short-interference RNA specific forhuman copper transporter 1 （hCtr1） may be used tosuppress growth of HCC by blocking increased copperuptake mediated by hCtr1. Furthermore, altered coppermetabolism is a promising target for radionuclidetherapy of HCC using therapeutic copper radionuclides.Copper metabolism has potential as a new theranosticbiomarker for molecular imaging as well as targetedtherapy of HCC.
Prediction of hepatocellular carcinoma biological behaviorin patient selection for liver transplantation Morphological criteria have always been considered thebenchmark for selecting hepatocellular carcinoma （HCC）patients for liver transplantation （LT）. These criteria, whichare often inappropriate to express the tumor＇s biologicalbehavior and aggressiveness, offer only a static viewof the disease burden and are frequently unable tocorrectly stratify the tumor recurrence risk after LT.Alpha-fetoprotein （AFP） and its progression as wellas AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin,inflammatory markers and other serological testsappear to be correlated with post-transplant outcomes.Several other markers for patient selection includingfunctional imaging studies such as 18F-FDG-PET imaging,histological evaluation of tumor grade, tissue-specificbiomarkers, and molecular signatures have beenoutlined in the literature. HCC growth rate and responseto pre-transplant therapies can further contribute tothe transplant evaluation process of HCC patients.While AFP, its progression, and HCC response to pretransplanttherapy have already been used as a part ofan integrated prognostic model for selecting patients,the utility of other markers in the transplant setting isstill under investigation. This article intends to review thedata in the literature concerning predictors that couldbe included in an integrated LT selection model and toevaluate the importance of biological aggressiveness inthe evaluation process of these patients.
Current status and perspectives of immune-based therapiesfor hepatocellular carcinoma Hepatocellular carcinoma （HCC） is a frequent cancerwith a high mortality. For early stage cancer thereare potentially curative treatments including localablation, resection and liver transplantation. However,for more advanced stage disease, there is no optimaltreatment available. Even in the case of a ＂curative＂treatment, recurrence or development of a new cancerin the precancerous liver is common. Thus, there isan urgent need for novel and effective （adjuvant）therapies to treat HCC and to prevent recurrenceafter local treatment in patients with HCC. Theunique immune response in the liver favors tolerance,which remains a genuine challenge for conventionalimmunotherapy in patients with HCC. However,even in this ＂immunotolerant＂ organ, spontaneousimmune responses against tumor antigens have beendetected, although they are insufficient to achievesignificant tumor death. Local ablation therapyleads to immunogenic tumor cell death by inducingthe release of massive amounts of antigens, whichenhances spontaneous immune response. Newimmune therapies such as dendritic cell vaccination andimmune checkpoint inhibition are under investigation.Immunotherapy for cancer has made huge progress inthe last few years and clinical trials examining the useof immunotherapy to treat hepatocellular carcinomahave shown some success. In this review, we discussthe current status of and offer some perspectives onimmunotherapy for hepatocellular carcinoma, whichcould change disease progression in the near future.
Controversies regarding and perspectives on clinical utilityof biomarkers in hepatocellular carcinoma The prevalence of hepatocellular carcinoma （HCC）worldwide parallels that of persistent infection with thehepatitis B virus （HBV） and/or hepatitis C virus （HCV）.According to recommendations by the World HealthOrganization guidelines for HBV/HCV, alpha-fetoprotein（AFP） testing and abdominal ultrasound should beperformed in routine surveillance of HCC every 6 mo forhigh-risk patients. These examinations have also beenrecommended worldwide by many other HCC guidelinesover the past few decades. In recent years, however,the role of AFP in HCC surveillance and diagnosis hasdiminished due to advances in imaging modalities. AFPwas excluded from the surveillance and/or diagnosticcriteria in the HCC guidelines published by theAmerican Association for the Study of Liver Diseasesin 2010, the European Association for the Study of theLiver in 2012, and the National Comprehensive CancerNetwork in 2014. Other biomarkers, including the Lensculinaris agglutinin-reactive fraction of AFP （AFP-L3）,des-γ-carboxyprothrombin, Dickkopf-1, midkine,and microRNA, are being studied in this regard.Furthermore, increasing attention has focused on theclinical utility of biomarkers as pre-treatment predictorsfor tumor recurrence and as post-treatment monitors.Serum and tissue-based biomarkers and genomics mayaid in the diagnosis of HCC, determination of patientprognosis, and selection of appropriate treatment.However, further studies are needed to better characterizethe accuracy and potential role of theseapproaches in clinical practice.
Glypican-3 is a prognostic factor and an immunotherapeutictarget in hepatocellular carcinoma Glypican-3 （GPC3） is a cell surface oncofetal proteoglycanthat is anchored by glycosylphosphatidylinositol.Whereas GPC3 is abundant in fetal liver, its expressionis hardly detectable in adult liver. Importantly, GPC3is overexpressed in hepatocellular carcinoma （HCC）,and several immunohistochemical studies reportedthat overexpression predicts a poorer prognosis forHCC patients. Therefore, GPC3 would serve as a usefulmolecular marker for HCC diagnosis and also as a targetfor therapeutic intervention in HCC. Indeed, someimmunotherapy protocols targeting GPC3 are underinvestigations; those include humanized anti-GPC3cytotoxic antibody, peptide vaccine and immunotoxintherapies. When considering the clinical requirementsfor GPC3-targeting therapy, companion diagnostics toselect the appropriate HCC patients are critical, and bothimmunohistochemical analysis of tissue sections andmeasurement of serum GPC3 level have been suggestedfor this purpose. This review summarizes currentknowledge regarding the clinical implication of GPC3detection and targeting in the management of patientswith HCC.
Differentiation of hepatocellular carcinoma from its variousmimickers in liver magnetic resonance imaging： What arethe tips when using hepatocyte-specific agents？ Hepatocellular carcinoma is the most common primaryhepatic malignant tumor. With widespread use of liverimaging, various cirrhosis-related nodules are frequentlydetected in patients with chronic liver disease, whilediverse hypervascular hepatic lesions are incidentallydetected but undiagnosed on dynamic computedtomography and magnetic resonance imaging （MRI）.However, use of hepatocyte-specific MR contrast agentswith combined perfusion and hepatocyte-selectiveproperties have improved diagnostic performance indetection and characterization of focal liver lesions.Meanwhile, the enhancement patterns observed duringdynamic phases using hepatocyte-specific agents maybe different from those observed during MRI usingconventional extracellular fluid agents, leading toconfusion in diagnosis. Therefore, we discuss usefultips for the differentiation of hepatocellular carcinomafrom similar lesions in patients with and without chronicliver disease using liver MRI with hepatocyte-specificagents.
Hepatocellular carcinoma mouse models： Hepatitis B virusassociatedhepatocarcinogenesis and haploinsufficienttumor suppressor genes The multifactorial and multistage pathogenesis ofhepatocellular carcinoma （HCC） has fascinated a widespectrum of scientists for decades. While a numberof major risk factors have been identified, theirmechanistic roles in hepatocarcinogenesis still need tobe elucidated. Many tumor suppressor genes （TSGs）have been identified as being involved in HCC. TheseTSGs can be classified into two groups dependingon the situation with respect to allelic mutation/lossin the tumors the recessive TSGs with two requiredmutated alleles and the haploinsufficient TSGs withone required mutated allele. Hepatitis B virus （HBV）is one of the most important risk factors associatedwith HCC. Although mice cannot be infected with HBVdue to the narrow host range of HBV and the lack ofa proper receptor, one advantage of mouse modelsfor HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypiceffects of viral proteins and allow the dissection ofthe dose-dependent action of TSGs. Here, we mainlyfocus on the application of mouse models in relation toHBV-associated HCC and on TSGs that act either in arecessive or in a haploinsufficient manner. Discoveriesobtained using mouse models will have a great impacton HCC translational medicine.
Targeting adeno-associated virus and adenoviral genetherapy for hepatocellular carcinoma Human hepatocellular carcinoma （HCC） heavily endangershuman heath worldwide. HCC is one of mostfrequent cancers in China because patients with liverdisease, such as chronic hepatitis, have the highestcancer susceptibility. Traditional therapeutic approacheshave limited efficacy in advanced liver cancer, and novelstrategies are urgently needed to improve the limitedtreatment options for HCC. This review summarizesthe basic knowledge, current advances, and futurechallenges and prospects of adeno-associated virus （AAV）and adenoviruses as vectors for gene therapy of HCC.This paper also reviews the clinical trials of gene therapyusing adenovirus vectors, immunotherapy, toxicity andimmunological barriers for AAV and adenoviruses, andproposes several alternative strategies to overcome thetherapeutic barriers to using AAV and adenoviruses asvectors.
Xenobiotics and loss of tolerance in primary biliarycholangitis Data from genome wide association studies andgeoepidemiological studies established that a combinationof genetic predisposition and environmentalstimulation is required for the loss of tolerance inprimary biliary cholangitis （PBC）. The serologic hallmarkof PBC are the presence of high titer anti-mitochondrialautoantibodies （AMA） that recognize the lipoyl domainof the mitochondrial pyruvate dehydrogenase E2（PDC-E2） subunit. Extensive efforts have been directedto investigate the molecular basis of AMA. Recently,experimental data has pointed to the thesis that thebreaking of tolerance to PDC-E2 is a pivotal event inthe initial etiology of PBC, including environmentalxenobiotics including those commonly found in cosmeticsand food additives, suggesting that chemicalmodification of the PDC-E2 epitope may render itsvulnerable to become a neo-antigen and trigger animmune response in genetically susceptible hosts.Here, we will discuss the natural history, genetics andimmunobiology of PBC and structural constraints ofPDC-E2 in AMA recognition which makes it vulnerable tochemical modification.
Combination antiretroviral studies for patients with primarybiliary cirrhosis Following the characterization of a human betaretrovirusin patients with primary biliary cirrhosis （PBC）,pilot studies using antiretroviral therapy have beenconducted as proof of principal to establish a link ofvirus with disease and with the eventual aim to findbetter adjunct therapies for patients unresponsive toursodeoxycholic acid. In the first open label pilot study,the reverse transcriptase inhibitor lamivudine hadlittle demonstrable biochemical or histological effectafter 1 year. Whereas, lamivudine in combination withzidovudine was associated with a significant reductionin alkaline phosphatase as well as improvement innecroinflammatory score, cholangitis and ductopeniaover a 12 mo period. A double blind, multi-centerrandomized controlled trial using lamivudine withzidovudine for 6 mo confirmed a significant reductionin alkaline phosphatase, ALT and AST in patientson antiviral therapy. However, none of the patientsachieved the stringent endpoint criteria for normalizationof alkaline phosphatase. Furthermore, some patientsdeveloped biochemical rebound consistent with drugresistance. A major fault of these studies has been theinability to measure the viral load in peripheral bloodand therefore, provide a direct correlation betweenimprovement of hepatic biochemistry and reduction inviral load. Nevertheless, viral mutants to lamivudinewith zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to testother antiretroviral regimens to betaretrovirus. Thecombination of tenofovir and emtricitabine reversetranscriptase inhibitors and the HIV protease inhibitor,lopinavir were found to abrogate cholangitis in theNOD.c3c4 mouse model and the same regimennormalized the liver tests in a PBC patient with HIVand human betaretrovirus infection. This combinationantiretroviral therapy has now been used in a doubleblind randomized controlled crossover study for patientswith PBC followed by an open label extension study.Only a third of the PB...Gut microbiota in autism and mood disorders The hypothesis of an important role of gut microbiotain the maintenance of physiological state into thegastrointestinal （GI） system is supported by severalstudies that have shown a qualitative and quantitativealteration of the intestinal flora in a number of gastrointestinaland extra-gastrointestinal diseases. Inthe last few years, the importance of gut microbiotaimpairment in the etiopathogenesis of pathology such asautism, dementia and mood disorder, has been raised.The evidence of the inflammatory state alteration,highlighted in disorders such as schizophrenia, majordepressive disorder and bipolar disorder, stronglyrecalls the microbiota alteration, highly suggestingan important role of the alteration of GI system alsoin neuropsychiatric disorders. Up to now, availableevidences display that the impairment of gut microbiotaplays a key role in the development of autism and mooddisorders. The application of therapeutic modulators ofgut microbiota to autism and mood disorders has beenexperienced only in experimental settings to date, withfew but promising results. A deeper assessment of therole of gut microbiota in the development of autismspectrum disorder （ASD）, as well as the advancementof the therapeutic armamentarium for the modulation ofgut microbiota is warranted for a better management ofASD and mood disorders.
Capsule endoscopy： the road ahead Since its introduction into clinical practice 15 yearsago, capsule endoscopy （CE） has become the first-lineinvestigation procedure in some small bowel pathologies,and more recently, dedicated esophageal and colonCE have expanded the fields of application to includethe upper and lower gastrointestinal disorders. Duringthis time, CE has become increasingly popular amonggastroenterologists, with more than 2 million capsuleexaminations performed worldwide, and nearly 3000PubMed-listed studies on its different aspects published.This huge interest in CE may be explained by its noninvasivenature, patient comfort, safety, and accessto anatomical regions unattainable via conventionalendoscopy. However, CE has several limitations whichimpede its wider clinical applications, including the lackof therapeutic capabilities, inability to obtain biopsiesand control its locomotion. Several research groups arecurrently working to overcome these limitations, whilenovel devices able to control capsule movement, obtainhigh quality images, insufflate the gut lumen, performchromoendoscopy, biopsy of suspect lesions, or evendeliver targeted drugs directly to specific sites are underdevelopment. Overlooking current limitations, especiallyas some of them have already been successfullysurmounted, and based on the tremendous progress intechnology, it is expected that, by the end of next 15years, CE able to perform both diagnostic and therapeuticprocedures will remain the major form of digestiveendoscopy. This review summarizes the literature thatprognosticates about the future developments of CE.
Proteoglycans in liver cancer Proteoglycans are a group of molecules that contain atleast one glycosaminoglycan chain, such as a heparan,dermatan, chondroitin, or keratan sulfate, covalentlyattached to the protein core. These molecules arecategorized based on their structure, localization,and function, and can be found in the extracellularmatrix, on the cell surface, and in the cytoplasm.Cell-surface heparan sulfate proteoglycans, such assyndecans, are the primary type present in healthyliver tissue. However, deterioration of the liver resultsin overproduction of other proteoglycan types. Thepurpose of this article is to provide a current summaryof the most relevant data implicating proteoglycansin the development and progression of human andexperimental liver cancer. A review of our work andother studies in the literature indicate that deteriorationof liver function is accompanied by an increase inthe amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interfereswith the physiologic function of the liver on severallevels. This article details and discusses the roles ofsyndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan,asporin, fibromodulin, lumican, and versican in liverfunction. Specifically, glypicans, agrin, and versicanplay significant roles in the development of liver cancer.Conversely, the presence of decorin could potentiallyprovide protective effects.
Chemoprevention of obesity-related liver carcinogenesis byusing pharmaceutical and nutraceutical agents Obesity and its related metabolic disorders are serioushealth problems worldwide, and lead to various healthrelatedcomplications, including cancer. Among humancancers, hepatocellular carcinoma （HCC） is one ofthe most common malignancies affected by obesity.Therefore, obesity and its related disorders might bea key target for the prevention of HCC. Recently, newresearch indicates that the molecular abnormalitiesassociated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokineimbalance, and oxidative stress, are possible molecularmechanisms underlying the pathogenesis of obesityrelatedhepatocarcinogenesis. Green tea catechinsand branched-chain amino acids, both of which areclassified as nutraceutical agents, have been reportedto prevent obesity-related HCC development byimproving metabolic abnormalities. The administrationof acyclic retinoid, a pharmaceutical agent, reduced theincidence of HCC in obese and diabetic mice, and wasalso associated with improvements in insulin resistanceand chronic inflammation. In this article, we reviewthe detailed molecular mechanisms that link obesityto the development of HCC in obese individuals. Wealso summarize recent evidence from experimentaland clinical studies using either nutraceutical orpharmaceutical agents, and suggest that nutraceuticaland pharmaceutical approaches targeting metabolicabnormalities might be a promising strategy to preventthe development of obesity-related HCC.
Treatment of hepatocellular carcinoma with portal venoustumor thrombosis： A comprehensive review The natural history of hepatocellular carcinoma （HCC）with portal vein tumor thrombosis （PVTT） is dismal（approximately 2-4 mo）, and PVTT is reportedlyfound in 10%-40% of HCC patients at diagnosis.According to the Barcelona Clinic Liver Cancer（BCLC） Staging System （which is the most widelyadopted HCC management guideline）, sorafenib isthe standard of care for advanced HCC （i.e. , BCLCstage C） and the presence of PVTT is included inthis category. However, sorafenib treatment onlymarginally prolongs patient survival and, notably, itstherapeutic efficacy is reduced in patients with PVTT.In this context, there have been diverse efforts todevelop alternatives to current standard systemicchemotherapies or combination treatment options. Todate, many studies on transarterial chemoembolization,3-dimensional conformal radiotherapy, hepatic arterialchemotherapy, and transarterial radioembolizationreport better overall survival than sorafenib therapyalone, but their outcomes need to be verified in futureprospective, randomized controlled studies in orderto be incorporated into current treatment guidelines.Additionally, combination strategies have been appliedto treat HCC patients with PVTT, with the hope that thepossible synergistic actions among different treatmentmodalities would provide promising results. Thisnarrative review describes the current status of themanagement options for HCC with PVTT, with a focuson overall survival.
Nuclear magnetic resonance based metabolomics and liverdiseases： Recent advances and future clinical applications Metabolomics is defined as the quantitative measurementof the dynamic multiparametric metabolicresponse of living systems to pathophysiological stimulior genetic modification. It is an ＂omics＂ technique thatis situated downstream of genomics, transcriptomicsand proteomics. Metabolomics is recognized as apromising technique in the field of systems biology forthe evaluation of global metabolic changes. During thelast decade, metabolomics approaches have becomewidely used in the study of liver diseases for thedetection of early biomarkers and altered metabolicpathways. It is a powerful technique to improve ourpathophysiological knowledge of various liver diseases.It can be a useful tool to help clinicians in the diagnosticprocess especially to distinguish malignantand non-malignant liver disease as well as to determinethe etiology or severity of the liver disease. Itcan also assess therapeutic response or predict druginduced liver injury. Nevertheless, the usefulness ofmetabolomics is often not understood by clinicians,especially the concept of metabolomics profiling orfingerprinting. In the present work, after a concisedescription of the different techniques and processesused in metabolomics, we will review the mainresearch on this subject by focusing specifically on invitro proton nuclear magnetic resonance spectroscopybased metabolomics approaches in human studies. Wewill first consider the clinical point of view enlightenphysicians on this new approach and emphasis itsfuture use in clinical ＂routine＂.
Solid, non-skin, post-liver transplant tumors： Key role oflifestyle and immunosuppression management Liver transplantation has been the treatment of choicefor end-stage liver disease since 1983. Cancer hasemerged as a major long-term cause of death for liver transplant recipients. Many retrospective studiesthat have explored standardized incidence ratio havereported increased rates of solid organ cancers postlivertransplantation; some have also studied riskfactors. Liver transplantation results in a two to five-foldmean increase in the rate of solid organ cancers. Risk ofhead and neck, lung, esophageal, cervical cancers andKaposi＇s sarcoma is high, but risk of colorectal canceris not clearly demonstrated. There appears to be noexcess risk of developing breast or prostate cancer.Environmental risk factors such as viral infection andtobacco consumption, and personal risk factors such asobesity play a key role, but recent data also implicatethe role of calcineurin inhibitors, whose cumulative anddose-dependent effects on cell metabolism might play adirect role in oncogenesis. In this paper, we review theresults of studies assessing the incidence of non-skinsolid tumors in order to understand the mechanismsunderlying solid cancers in post-liver transplant patientsand, ultimately, discuss how to prevent these cancers.Immunosuppressive protocol changes, including acalcineurin inhibitor-free regimen, combined with dietaryguidelines and smoking cessation, are theoretically thebest preventive measures.
Endoscopic submucosal tunnel dissection for largesuperficial esophageal squamous cell neoplasms Endoscopic submucosal dissection （ESD） is a wellestablishedtreatment for superficial esophagealsquamous cell neoplasms （SESCNs） with no risk oflymphatic metastasis. However, for large SESCNs,especially when exceeding two-thirds of the esophagealcircumference, conventional ESD is time-consuming andhas an increased risk of adverse events. Based on thesubmucosal tunnel conception, endoscopic submucosaltunnel dissection （ESTD） was first introduced by us toremove large SESCNs, with excellent results. Studiesfrom different centers also reported favorable results.Compared with conventional ESD, ESTD has a morerapid dissection speed and R0 resection rate. Currentlyin China, ESTD for large SESCNs is an importantpart of the digestive endoscopic tunnel technique,as is peroral endoscopic myotomy for achalasiaand submucosal tunnel endoscopic resection forsubmucosal tumors of the muscularis propria. However,not all patients with SESCNs are candidates for ESTD,and postoperative esophageal strictures should alsobe taken into consideration, especially for lesionswith a circumference greater than three-quarters. Inthis article, we describe our experience, review theliterature of ESTD, and provide detailed informationon indications, standard procedures, outcomes, andcomplications of ESTD.
Distinctive aspects of peptic ulcer disease, Dieulafoy＇slesion, and Mallory-Weiss syndrome in patients withadvanced alcoholic liver disease or cirrhosis AIM To systematically review the data on distinctiveaspects of peptic ulcer disease （PUD）, Dieulafoy＇s lesion（DL）, and Mallory-Weiss syndrome （MWS） in patientswith advanced alcoholic liver disease （aALD）, includingalcoholic hepatitis or alcoholic cirrhosis.METHODS： Computerized literature search performedvia PubMed using the following medical subjectheading terms and keywords： ＂alcoholic liver disease＂,＂alcoholic hepatitis＂,＂ alcoholic cirrhosis＂, ＂cirrhosis＂,＂liver disease＂, ＂upper gastrointestinal bleeding＂, ＂nonvaricealupper gastrointestinal bleeding＂, ＂PUD＂, ＇＇DL＇＇,＇＇Mallory-Weiss tear＂, and ＂MWS＇＇.RESULTS： While the majority of acute gastrointestinal（GI） bleeding with aALD is related to portalhypertension, about 30%-40% of acute GI bleeding inpatients with aALD is unrelated to portal hypertension.Such bleeding constitutes an important complication ofaALD because of its frequency, severity, and associatedmortality. Patients with cirrhosis have a markedlyincreased risk of PUD, which further increases with the progression of cirrhosis. Patients with cirrhosis or aALDand peptic ulcer bleeding （PUB） have worse clinicaloutcomes than other patients with PUB, includinguncontrolled bleeding, rebleeding, and mortality. Alcoholconsumption, nonsteroidal anti-inflammatory druguse, and portal hypertension may have a pathogenicrole in the development of PUD in patients with aALD.Limited data suggest that Helicobacter pylori does notplay a significant role in the pathogenesis of PUD inmost cirrhotic patients. The frequency of bleeding fromDL appears to be increased in patients with aALD. DLmay be associated with an especially high mortality inthese patients. MWS is strongly associated with heavyalcohol consumption from binge drinking or chronicalcoholism, and is associated with aALD. Patients withaALD have more severe MWS bleeding and are morelikely to rebleed when compared to non-cirrhotics. Preendoscopicmanagement of acute GI bleeding in p