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Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells

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World Journal of Stem cells 2021年第7期13卷 795-824页

作者： caecilia H c Sukowati Korri Elvanita El-Khobar c.audio tiribelli centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy Hepatitis Unit Eijkman Institute for Molecular BiologyJakarta 10430Indonesia

Hepatocellular carcinoma(Hcc)is a heterogeneous malignancy related to diverse etiological *** oncogenic mechanisms and genetic variations lead to multiple Hcc molecular ***,an immune-based strategy using immune checkpoint inhibitors(IcIs)was presented in Hcc therapy,especially with IcIs against the programmed death-1(PD-1)and its ligand ***,despite the success of anti-PD-1/PD-L1 in other cancers,a substantial proportion of Hcc patients fail to *** this review,we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of Hcc heterogeneity and hepatic cancer stem cells(cScs).Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to ***-L1 expression in tumoral tissues is differentially expressed in cScs,particularly in those with a close association with the tumor *** information will be beneficial for the selection of patients and the management of the IcIs against PD-1/PD-L1.

关键词： Hepatocellular carcinoma Programmed death-1 Programmed death ligand 1 cancer stem cells cancer heterogeneity Genetic variants

Hepatitis B virus genotypes in precision medicine of hepatitis Brelated hepatocellular carcinoma:Where we are now

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1097-1103页

作者： caecilia H c Sukowati Sri Jayanti Turyadi Turyadi David H Muljono c.audio tiribelli Eijkman Research center for Molecular Biology Research Organization for HealthNational Research and Innovation Agency of IndonesiaJakarta 10340Indonesia Liver cancer Unit Fondazione Italiana Fegato ONLUSTrieste 34149Italy Faculty of Medicine Hasanuddin UniversityMakassar 90245South SulawesiIndonesia Faculty of Medicine and Health University of SydneySydney 2050Australia

Hepatitis B virus(HBV)infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma(Hcc).HBV genetics are diverse where it is classified into at least 9 genotypes(A to I)and 1 putative genotype(J),each with specific geographical distribution and possible different clinical outcomes in the *** diversity may be associated with the precision medicine for HBV-related Hcc and the success of therapeutical approaches against Hcc,related to different pathogenicity of the virus and host *** Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the Hcc and its precision medicine,in addition to the recent advances in cellular and molecular biology technologies.

关键词： Hepatitis B virus Hepatocellular carcinoma Genotypes Pathogenesis Precision medicine

Oncogenicity of viral hepatitis B and c in the initiation of hepatic cancer stem cells

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Hepatoma Research 2019年第1期5卷 17-25页

作者： caecilia H.c.Sukowati Peter A.c.Reyes Gianluca Tell c.audio tiribelli Fondazione Italiana Fegato Trieste 34149Italy Dipartimento di Area Medica University of UdineUdine 33100Italy Hepatology Society of the Philippines Loyola Heights Quezon City 1108Philippines

chronic infection of hepatitis B virus(HBV)or/and hepatitis c virus(HcV)is one of major risk factors in the development of the hepatocellular *** studies had shown the capacity of viral proteins in inducing the presence of the population of so-called the cancer stem cells(cSc).The integration of HBV S and X gene in the host genome indicates its direct *** addition,the presence HBV and HcV proteins were shown to modulate intracellular molecular pathways and epigenetic *** review summarizes current literature regarding direct oncogenic properties of HBV and HcV in the initiation of cSc both in in vitro and in vivo studies.

关键词： cancer stem cells hepatocellular carcinoma hepatitis B virus hepatitis c virus

Role of hepatitis B virus in development of hepatocellular carcinoma:Focus on covalently closed circular DNA

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World Journal of Hepatology 2022年第5期14卷 866-884页

作者： claryssa Bianca Elizabeth Sidhartha c.audio tiribelli Korri Elvanita El-Khobar caecilia H c Sukowati Department of Biomedicine Indonesia International Institute for Life SciencesJakarta 13210Indonesia centro Studi Fegato Fondazione Italiana Fegato ONLUSTrieste 34149Italy Eijkman center for Molecular Biology National Research and Innovation Agency(BRIN)Jakarta 10340Indonesia

chronic infection with hepatitis B virus(HBV)remains a major global health problem,especially in developing *** may lead to prolonged liver damage,fibrosis,cirrhosis,and hepatocellular *** chronic HBV infection is related to host immune response and the stability of the covalently closed circular DNA(cccDNA)in human *** addition to being essential for viral transcription and replication,cccDNA is also suspected to play a role in persistent HBV infections or hepatitis relapses since cccDNA is very stable in non-dividing human *** the pathogenicity and oncogenicity of HBV components would be essential in the development of new diagnostic tools and treatment *** review summarizes the role and molecular mechanisms of HBV cccDNA in hepatocyte transformation and hepatocarcinogenesis and current efforts to its detection and targeting.

关键词： Hepatitis B virus covalently closed circular DNA Hepatocellular carcinoma Hepatocarcinogenesis

Management of restless legs syndrome in chronic liver disease:A challenge for the correct diagnosis and therapy

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World Journal of Hepatology 2018年第3期10卷 379-387页

作者： Rita Moretti Paola caruso Marzia Tecchiolli Silvia Gazzin c.audio tiribelli Department of Medical Surgical and Health SciencesUniversity of TriesteTrieste 34149Italy Italian Liver Foundation Centro Studi FegatoTrieste 34149Italy

AIM To investigate the association between restless legs syndrome(RLS) and well-defined chronic liver disease, and the possible therapeutic options. METHODS Two hundred and eleven patients with chronic liver disease, complaining of sleep disturbances, painful leg sensation and daily sleepiness, were included. Patients with persistent alcohol intake, recent worsening of clinical conditions, or hepatitis c virus were excluded. Diagnosis of RLS was suggested by the Johns Hopkins questionnaire and verified by fulfilling the diagnostic criteria by Allen. All patients were tested, both at baseline and during follow-up, with the Hamilton rating scale for depression, sleep quality assessment(PSQI), Epworth sleepiness scale(ESS), International Restless Legs Syndrome Study Group evaluation, and international RLS severity(IRLS) scoring system. Ironfree level, ferritin, folate, vitamin B12 and D-OH25 were detected. Neurological examinations and blood testoccurred at the beginning of the therapy, after 2 wk, and at the 28^(th), 75 th, 105 th, 135 th, 165 th and 205 th day. Regarding therapy, pramipexole or gabapentin were *** Patients were moderately depressed, with evident nocturnal sleep problems and concomitant daily sleepiness. Sleep problems and involuntary leg movements had been underestimated, and RLS s yndrome had not be e n c ons ide re d be fore t he neurological visit. All(211/211) patients fulfilled the RLS diagnostic criteria. Twenty-two patients considered their symptoms as mild, according to IRSL, but 189 found them moderate to very severe. No correlation was found between ammonium level and ESS or PSQI. Augmentation was rather precocious in our patients(135 th day), and more frequent(35%) than previous data(8.3%-9.1%). The dosage of dopamine agonists was found to be associated with augmentation and appears in range with the literature. Previous intake of alcohol and lower levels of vitamins have been related to the phenomenon in our *** RLS

关键词： Restless legs syndrome chronic liver disease Dopamine agonist treatment Augmentation

Significance of hepatitis virus infection in the oncogenicinitiation of hepatocellular carcinoma

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World Journal of Gastroenterology 2016年第4期22卷 1497-1512页

作者： caecilia Hc Sukowati Korri E El-Khobar Susan I Ie Beatrice Anfuso David H Muljono c.audio tiribelli Fondazione Italiana Fegato ONLUS AREA Science Park Basovizza34149 TriesteItaly Department of Medicine Surgeryand Health SciencesUniversity of TriesteTeaching Hospital Cattinara34149 TriesteItaly Laboratory of Hepatitis and Emerging Disease Eijkman Institute for Molecular BiologyJakarta 10430Indonesia Storr Liver centre The Westmead Institute for Medical ResearchThe University of Sydney at Westmead HospitalWestmead NSW 2145Australia

Hepatocellular carcinoma(Hcc) is one of the most common causes of cancer-related death worldwide. chronic infection of hepatitis B virus(HBV) and/or hepatitis c virus(HcV) is a major risk factor in the development of the Hcc, independently from excessive alcohol abuse and metabolic disease. Since the biology of HBV and HcV is different, their oncogenic effect may go through different mechanisms, direct and/or indirect. Viral hepatitis infection is associated with cellular inflammation, oxidative stress, DNA damage, that may lead to subsequent hepatic injuries such as chronic hepatitis, fibrosis, cirrhosis, and finally Hcc. Direct oncogenic properties of these viruses are related with their genotypic characteristics and the ability of viral proteins to interact with host proteins, thus altering the molecular pathways balance of the cells. In addition, the integration of HBV DNA, especially the gene S and X, in a particular site of the host genome can disrupt chromosomal stability and may activate various oncogenic mechanisms, including those in hematopoietic cells. Recently, several studies also had demonstrated that viral hepatitis could trigger the population of hepatic cancer stem cells. This review summarize available pre-clinical and clinical data in literature regarding oncogenic properties of HBV and HcV in the early initiation of Hcc.

关键词： Hepatocellular carcinoma Hepatitis B virus Hepatitis c virus Oncogenicity Viral pathogenicity

Genetic biomarkers for hepatocellular cancer risk in a caucasian population

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World Journal of Gastroenterology 2017年第36期23卷 6674-6684页

作者： Elena De Mattia Erika cecchin Jerry Polesel Alessia Bignucolo Rossana Roncato Francesco Lupo Marina crovatto Angela Buonadonna c.audio tiribelli Giuseppe Toffoli clinical and Experimental Phar-macology “Centro di Riferimento Oncologico”-National Cancer Institute Unit of cancer Epidemiology “Centro di Riferimento Oncologico”-National Cancer Institute General Surgery 2U and Liver Transplantation center A.O.U.Cittàdella Salute e della Scienza di TorinoUniversity of Torino cytogenetics and Molecular Biology Unit Santa Maria degli Angeli Hospital Pordenone Medical Oncology Unit “Centro di Riferimento Oncologico”-National Cancer Institute Fondazione Italiana Fegato AREA Science Park

AIM To uncover novel genetic markers that could contribute to predicting hepatocellular carcinoma(Hcc)susceptibility in caucasians. METHODS The present retrospective case-control study compared genotype frequencies between a cohort of Hcc cases and two,independent,Hcc-free,age/sex-matched control *** Hcc cohort comprised 192 homogeneous patients that had undergone orthotopic liver *** first control group comprised167 patients that were matched to the Hcc cohort for the percentage of hepatitis B(HBV)and/or hepatitis c(HcV)infections.A second control group included192 virus-free,healthy individuals that were used to evaluate the generalizability of the identified predictive *** cases and controls were *** three study populations were characterized with a panel of 31 markers derived from 21 genes that encoded key proteins involved in hepatocarcinogenesis-related *** study end-point was to assess the association between genetic variants and Hcc onset. RESULTS Five genetic markers were identified as risk factors for Hcc in high-risk patients infected with HBV/*** to a dominant model,reduced Hcc risk was associated with three polymorphisms:ERcc1rs3212986(OR=0.46,95%cI:0.30-0.71,P=0.0005),GST-P1 rs1138272(OR=0.41,95%cI:0.21-0.81,P=0.0097),and cYP17A1 rs743572(OR=0.50,95%cI:0.31-0.79,P=0.0032).conversely,according to a recessive model,increased Hcc risk was associated with two polymorphisms:XRcc3 rs1799794(OR=3.70,95%cI:1.02-13.39,P=0.0461)and ABcB1 rs1128503(OR=2.06,95%cI:1.18-3.61,P=0.0111).These associations remained significant in a subgroup analysis,where patients were stratified according to viral status(HBV-or HcV-positive serology).Two variants exhibited a serology-specific effect:ABcB1 rs1128503(OR=4.18,95%cI:1.55-11.29,P=0.0048)showed an effect in the HBV-positive subgroup;and ERcc1 rs3212986(OR=0.33,95%cI:0.18-0.60,P=0.0003)showed an effect in the HcV-positive *** the five markers identified,E

关键词： ERcc1 XRcc3 GST-P1 cYP17A1 MDR-1 Polymorphisms Hepatocellular carcinoma risk Early diagnosis Antiviral therapy Hepatitis B viral/hepatitis c viral

clinical Significance of Apurinic/Apyrimidinic Endodeoxyribonuclease 1 and MicroRNA Axis in Hepatocellular carcinoma

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Journal of clinical and Translational Hepatology 2023年第6期11卷 1291-1307页

作者： Giovanna Mangiapane Devis Pascut Emiliano Dalla Giulia Antoniali Monica Degrassi Lory Saveria crocè Veronica De Sanctis Silvano Piazza Giulia canarutto c.audio tiribelli Gianluca Tell Laboratory of Molecular Biology and DNA Repair Department of MedicineUniversity of UdineUdineItaly Fondazione Italiana Fegato-ONLUS Liver Cancer UnitTriesteItaly Department of Medical Sciences University of TriesteTriesteItaly clinica Patologie Fegato Azienda Sanitaria Universitaria Giuliano Isontina(ASUGI)TriesteItaly NGS core Facility Department CIBIOUniversity of TrentoTrentoItaly computational Biology International Centre for Genetic Engineering and BiotechnologyICGEBTriesteItaly

Background and Aims:Identification of prognostic factors for hepatocellular carcinoma(Hcc)opens new perspectives for *** and cellular onco-miRNAs are noncoding RNAs which can control the expression of genes involved in oncogenesis through post-transcriptional *** microRNAs(miRNAs)are considered novel prognostic and predictive factors in *** apurinic/apyrimidinic endodeoxyribonuclease 1(APE1)contributes to the quality control and processing of specific onco-miRNAs and is a negative prognostic factor in several *** present work aims to:a)define APE1 prognostic value in Hcc;b)identify miRNAs regulated by APE1 and their relative target genes and c)study their prognostic ***:We used The cancer Genome Atlas(commonly known as TcGA)data analysis to evaluate the expression of APE1 in *** identify differentially-expressed miRNAs(DEmiRNAs)upon APE1 depletion through specific small interfering RNA,we used NGS and nanostring approaches in the JHH-6 Hcc tumor cell *** analyses were performed to identify signaling pathways involving APE1-regulated *** analysis was performed to identify miRNAs correlating with serum APE1 ***:APE1 is considerably overexpressed in Hcc tissues compared to normal liver,according to the TcGA-liver Hcc(known as LIHc)*** analyses showed that APE1-regulated miRNAs are implicated in signaling and metabolic pathways linked to cell proliferation,transformation,and angiogenesis,identifying cyclin Dependent Kinase 6 and Lysosomal Associated Membrane Protein 2 as ***-33a-5p,miR-769,and miR-877 are related to lower overall survival in Hcc *** array profiling,we identified eight circulating DE-miRNAs associated with APE1 overexpression.A training phase identified positive association between sAPE1 and miR-3180-3p and ***:APE1 regulates specific miRNAs having prognostic value in Hcc.

关键词： APE1 miRNAs Prognostic factors Hepatocellular carcinoma

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胆红素的化学、转运和代谢方面的新概念

国外医学（消化系疾病分册） 1991年第2期11卷 99-101页

作者： tiribelli c 钟捷王成

胆红素的化学非结合性胆红素(UcB)是一个线状的4-吡咯结构,带有两半个相对二维的dipyrrome-thenone,连接在中心10位碳的亚甲基团上。由于内、外乙烯基在位置上以及其侧链部位等的变动可产生众多的异构体。在碱性溶液中UcB的降解过程一... 详细信息

胆红素的化学非结合性胆红素(UcB)是一个线状的4-吡咯结构,带有两半个相对二维的dipyrrome-thenone,连接在中心10位碳的亚甲基团上。由于内、外乙烯基在位置上以及其侧链部位等的变动可产生众多的异构体。在碱性溶液中UcB的降解过程一般避光进行,光线对该过程有促进作用,并会影响实验结果。由于UcB两个末端环乙烯基基团的不对称性分布,全部键化的嵴瓦状结构有二种镜象对映体(enantiomer),这些对映体通常以相等的浓度出现,故没有单纯的光学活性。

关键词：胆红素化学代谢胆细胞