Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

Management of chronic hepatitis B infection: Current treatment guidelines, challenges, and new developments

Chronic hepatitis B(CHB)virus infection is a global public health problem,affecting more than 400 million people worldwide.The clinical spectrum is wide,ranging from a subclinical inactive carrier state,to progressive chronic hepatitis,cirrhosis,decompensation,and hepatocellular carcinoma.However,complications of hepatitis B virus(HBV)-related chronic liver disease may be reduced by viral suppression.Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon,entecavir,or tenofovir,but the optimal treatment for an individualpatient is controversial.The indications for treatment are contentious,and increasing evidence suggests that HBV genotyping,as well as serial on-treatment measurements of hepatitis B surface antigen and HBV DNA kinetics should be used to predict antiviral treatment response.The likelihood of achieving a sustained virological response is also increased by extending treatment duration,and using combination therapy.Hence the paradigm for treatment of CHB is constantly evolving.This article summarizes the different indications for treatment,and systematically reviews the evidence for the efficacy of various antiviral agents.It further discusses the shortcomings of current guidelines,use of rescue therapy in drug-resistant strains of HBV,and highlights the promising clinical trials for emerging therapies in the pipeline.This concise overview presents an updated practical approach to guide the clinical management of CHB.

Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments

Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.

Emerging role of Hippo pathway in gastric and othergastrointestinal cancers

More evidence has underscored the importance of Hippo signaling pathway in gastrointestinal tissue homeostasis, whereas its deregulation induces tumorigenesis. Yes-associated protein 1(YAP1) and its close paralog TAZ, transcriptional co-activator with a PDZbinding motif, function as key effectors negatively controlled by the Hippo pathway. YAP1/TAZ exerts oncogenic activities by transcriptional regulation via physical interaction with TEAD transcription factors. In various cancers, Hippo pathway cross-talks with pro- or anti-tumorigenic pathways such as GPCR, Wnt/β-catenin, Notch and TGF-β signaling and is deregulated by multiple factors including cell density/junction and micro RNAs. As YAP1 expression is significantly associated with poor prognosis of gastric and other gastrointestinal cancers, detailed delineation of Hippo regulation in tumorigenesis provides novel insight for therapeutic intervention. In current review, we summarized the recent research progresses on the deregulation of Hippo pathway in the gastrointestinal tract including stomach and discuss the molecular consequences leading to tumorigenesis.

Oncogenic induction of cellular high CpG methylation by Epstein-Barr Barr virus in malignant epithelial cells

Epstein-Barr virus(EBV)is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma(NPC)and^10%of gastric cancer(GC)worldwide.Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC.However,even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC(EBVa GC),suggesting a predominant role of epigenetic abnormities,especially promoter Cp G methylation,in the pathogenesis of NPC and EBVa GC.High frequencies of promoter methylation of tumor suppressor genes(TSGs)have been frequently reported in NPC and EBVa GC,with several EBV-induced methylated TSGs identified.Further characterization of the epigenomes(genome-wide Cp G methylation profile—methylome)of NPC and EBVa GC shows that these EBV-associated tumors display a unique high Cp G methylation epigenotype with more extensive gene methylation accumulation,indicating that EBV acts as a direct epigenetic driver for these cancers.Mechanistically,oncogenic modulation of cellular Cp G methylation machinery,such as DNA methyltransferases(DNMTs),by EBV-encoded viral proteins accounts for the EBV-induced high Cp G methylation epigenotype in NPC and EBVa GC.Thus,uncovering the EBV-associated unique epigenotype of NPC and EBVa GC would provide new insight into the molecular pathogenesis of these unique EBVassociated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.

The Composition of Colonic Commensal Bacteria According to Anatomical Localization in Colorectal Cancer

结直肠癌是由遗传突变、表观遗传改变、慢性炎症、饮食和生活方式等多因素引起的多阶段疾病。最新研究表明,肠道菌群是结直肠癌发展过程中的重要参与者。肠道菌群稳态的失调,可通过诱发炎症、调控宿主防御、氧化应激和改变细菌代谢产物等机制促进结直肠癌的发生发展。值得注意的是,肠道横、纵截面上不同解剖部位的驻留菌群有所不同。根据细菌在肠道中定植部位的不同,可将其划分为4种类型:肠腔共生菌、肠黏膜驻留菌、上皮驻留菌和淋巴组织驻留菌。由于结肠共生细菌的易位与结直肠癌的发展密切相关,结直肠癌相关细菌可有望成为用于结直肠癌诊断的非侵入且准确性高的新型生物标志物。本文旨在总结和概述肠道不同解剖部位中的肠道菌群在结直肠癌发生发展中的作用。

Efficacy of Vaccine Protection Against COVID-19 Virus Infection in Patients with Chronic Liver Diseases

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Vaccination against coronavirus disease 2019 is a use-ful weapon to combat the virus. Patients with chronic liver diseases (CLDs), including compensated or decompensated liver cirrhosis and noncirrhotic diseases, have a decreased immunologic response to coronavirus disease 2019 vaccines. At the same time, they have increased mortality if infected. Current data show a reduction in mortality when patients with chronic liver diseases are vaccinated. A suboptimal vac-cine response has been observed in liver transplant recipi-ents, especially those receiving immunosuppressive therapy, so an early booster dose is recommended to achieve a better protective effect. Currently, there are no clinical data com-paring the protective efficacy of different vaccines in patients with chronic liver diseases. Patient preference, availability of the vaccine in the country or area, and adverse effect profiles are factors to consider when choosing a vaccine. There have been reports of immune-mediated hepatitis after coronavi-rus disease 2019 vaccination, and clinicians should be aware of that potential side effect. Most patients who developed hepatitis after vaccination responded well to treatment with prednisolone, but an alternative type of vaccine should be considered for subsequent booster doses. Further prospec-tive studies are required to investigate the duration of immu-nity and protection against different viral variants in patients with chronic liver diseases or liver transplant recipients, as well as the effect of heterologous vaccination.

Intratumoral Bacteria Dysbiosis Is Associated with Human Papillary Thyroid Cancer and Correlated with Oncogenic Signaling Pathways

Emerging evidence suggests that microbial dysbiosis plays vital roles in many human cancers.However,knowledge of whether the microbial community in thyroid tumor is related to tumorigenesis remains elusive.In this study,we aimed to explore the microbial community in thyroid tissues and its contribution to papillary thyroid cancer(PTC).In parallel,we performed microbial profiling and transcriptome sequencing in the tumor and adjacent normal tissues of a large cohort of 340 PTC and benign thyroid nodule(BTN)patients.Distinct microbial signatures were identified in PTC,BTN,and their adjacent nontumor tissues.Intra-thyroid tissue bacteria were verified by means of bacteria staining,fluorescence in situ hybridization,and immunoelectron microscopy.We found that 17 bacterial taxa were differentially abundant in PTC compared with BTN,which included enrichment in PTC of the pathobionts Rhodococcus,Neisseria,Streptococcus,Halomonas,and Devosia,and depletion of the beneficial bacteria Amycolatopsis.These differentially abundant bacteria could differentiate PTC tumor tissues(PTC-T)from BTN tissues(BTN-T)with an area under the curve(AUC)of 81.66%.Microbial network analysis showed increased correlation strengths among the bacterial taxa in PTC-T in comparison with BTN-T.Immunefunction-corresponding bacteria(i.e.,Erwinia,Bacillus,and Acinetobacter)were found to be enriched in PTC with Hashimoto’s thyroiditis.Moreover,our integrative analysis revealed that the PTC-enriched bacteria had a positive association with key PTC-oncogenic pathway-related genes,including BRAF,KRAS,IRAK4,CTNNB1,PIK3CA,MAP3K7,and EGFR.In conclusion,our results suggest that intratumor bacteria dysbiosis is associated with the thyroid tumorigenesis and oncogenic signaling pathways of PTC.

Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease progression.As an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease development.Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue concentration.This has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer progression.Zinc transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc intake.Additionally,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on cancer.We also compile a summary of clinical trials involving zinc ions.Given the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Klebsiella pneumoniae invasive liver abscess syndrome with purulent meningitis and septic shock: A case from China's Mainland

@Yun Qian$Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China$Institute of Gastroenterology, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Chi-Chun Wong$Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong!Hong Kong, China@San-Chuan Lai$Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China$Institute of Gastroenterology, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Zheng-Hua Lin$Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China$Institute of Gastroenterology, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Wei-Liang Zheng$Department of Radiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Hui Zhao$Emergency Department, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Kong-Han Pan$Department of Critical Care Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Shu-Jie Chen$Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China$Institute of Gastroenterology, Zhejiang University!Hangzhou 310016, Zhejiang Province, China@Jian-Min Si$Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University!Hangzhou 310016, Zhejiang Province, China$Institute of Gastroenterology, Zhejiang University!Hangzhou 310016, Zhejiang Province,

Epidemiology and Clinical Outcomes of Metabolic(Dysfunction)-associated Fatty Liver Disease

Metabolic(dysfunction)-associated fatty liver disease(MAFLD)is currently the most common chronic liver disease and affects at least a quarter of the global adult population.It has rapidly become one of the leading causes of hepatocellular carcinoma and cirrhosis in Western countries.In this review,we discuss the nomenclature and definition of MAFLD as well as its prevalence and incidence in different geographical regions.Although cardiovascular disease remains the leading cause of death in MAFLD patients,the proportion of patients dying from hepatic complications increases sharply as the disease progresses to advanced liver fibrosis and cirrhosis.In addition,patients with MAFLD are at increased risk of various extrahepatic cancers.Although a causal relationship between MAFLD and extrahepatic cancers has not been established,clinicians should recognize the association and consider cancer screening(e.g.,for colorectal cancer)as appropriate.

Non-invasive tests of non-alcoholic fatty liver disease

For the detection of steatosis,quantitative ultrasound imaging techniques have achieved great progress in past years.Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis.Some blood biomarkers correlate with non-alcoholic steatohepatitis,but the accuracy is modest.Regarding liver fibrosis,liver stiffness measurement by transient elastography(TE)has high accuracy and is widely used across the world.Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability.Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response.This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease(NAFLD).Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD,assess its severity,and predict the prognosis.Further studies are needed to determine the role of the tests as monitoring tools.We cannot overemphasize the importance of context in selecting appropriate tests.

Optimal surveillance program for hepatocellular carcinoma- getting ready, but not yet

Hepatocellular carcinoma(HCC) secondary to chronic viral hepatitis is a major health problem in AsianPacific regions due to the endemics of chronic hepatitis B and C virus infection. HCC surveillance has been recommended to patients who are at risk to develop HCC. Unfortunately, a significant proportion of patients still died in long run due to tumor recurrence. The key components of an optimal surveillance program include an accurate tumor biomarker and optimal surveillance interval. Serum alpha-fetoprotein(AFP), despite of being the most widely used biomarker for HCC surveillance, it was criticized as neither sensitive nor specific. Other HCC biomarkers, including lectin-reactive AFP(AFP-L3), des-gamma carboxyprothrombin, are still under investigations. Recent study showed cancerassociated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing to be accurate with both sensitivity and specificity close to 90% in detecting HCC in a case-control study. Concerning the optimal surveillance interval, we believe one size does not fit all patients. Accurate risk prediction to assist prognostication with well-validated HCC risk scores would be useful to decide the need for HCC surveillance. These key components of an optimal HCC surveillance program should be further validated at a surveillance setting.

The association of diet, gut microbiota and colorectal cancer： what we eat may imply what we get

尽管有 colonoscopy 在癌症治疗屏蔽和最近的进展的成功， colorectal 癌症(CRC ) 仍然是通常诊断的大多数和致命的癌症之一，与在开发人们正在适应西方的生活方式的国家的显著地增加的发生。饮食在 CRC 的风险上有重要影响。多重流行病学的研究建议了那过多的动物蛋白质和脂肪吸入，特别红的肉和处理的肉，当纤维能免于 colorectal tumorigenesis 时，能增加开发 CRC 的风险。机制被动物 studies.Diet 调查了能重塑内脏 microbiota 的社区结构并且由 modulating 影响它的功能代谢物的生产。丁酸盐，短链的丰满的酸(SCFA ) 之一，它为 colonocytes 充当有利来源，能保护结肠的上皮的房间免受 tumorigenesis 的伤害经由反煽动性并且通过房间新陈代谢， microbiota 动态平衡， antiproliferative， immunomodulatory 和 genetic/epigenetic 的 antineoplastic 性质规定方法。相反，蛋白质发酵和胆汁酸 deconjugation，它引起通过 proinflammatory 和 proneoplastic 方法损坏到结肠的房间，导致 increasedriskofdevelopingCRC.In 结论，有增加的许多纤维的 abalanced 饮食应该被采用减少风险并且阻止 CRC。

Gut microbiome alters functions of mutant p53 to promote tumorigenesis

In a recent study in Nature,Kadosh et al.1 established a landmark relationship between the gut microbiome and host epigenetics in intestinal oncogenesis.They demonstrated the substantial plasticity of mutant p53 in WNT-driven tumorigenesis,and the crucial involvement of gut microbiome in modulating this plasticity.

The paradox of immunotherapy in NASH-HCC

A recent study published in Nature by Dominik Pfister et al.1 unveiled a darker side of immune checkpoint blockade(ICB)immunotherapy in the context of nonalcoholic steatohepatitis-associated hepatocellular carcinoma(NASH-HCC),whereby anti-PD1 treatment paradoxically accelerates hepatocarcinogenesis.

Advances in the diagnosis and treatment of liver fibrosis

Liver fibrosis is the center of diagnosis and management of essentially all chronic liver diseases. While liver biopsy examination still has a role in diagnosis and drug development, it is replaced by non-invasive assessments of liver biopsy in majority of the clinical scenarios. Radiological approaches, namely transient elastography, acoustic radiation force impulse imaging, shear wave elastography, magnetic resonance elastography provide accurate diagnosis of advanced fibrosis and cirrhosis. Serum test formulae based on common laboratory parameters or more specialized parameters including those commercially available panels FibroTest?, FibroMeter? and Enhanced Liver Fibrosis are also available. Combining different modalities may further improve the accuracy. The role of all these non-invasive assessments has been further expanded from diagnostic to prognostic, e.g. risk prediction of hepatocellular carcinoma (HCC) by LSM-HCC score. Treatment of liver fibrosis can be achieved by controlling the underlying diseases, with chronic viral hepatitis as the most established disease model. Currently there are multiple clinical trials evaluating different treatment options to improve fibrosis in patients with non-alcoholic fatty liver disease. Specific anti-fibrotic treatment targets e.g. direct downregulation of hepatic stellate cell, collagen synthesis inhibitors and transforming growth factor-βantagonists have been tested in laboratory and pending further studies in clinical settings.