Day 2 :
Keynote Forum
Mark A Feitelson
Temple University, USA
Keynote: Symbiotic bacteria provide chemoprevention against hepatitis B virus mediated hepatocellular carcinoma in hepatitis B x transgenic mice
Time : TBD
Biography:
Mark A Feitelson received his PhD in Microbiology and Immunology in 1979 from the UCLA School of Medicine. He was an American Cancer Society Post-doctoral Fellow at Stanford University from 1980-82, and was then recruited to the Fox Chase Cancer Center by Dr. Baruch Blumberg (Nobel laureate). In 1991, he became Associate Professor of Pathology and Cell Biology and Head of the Molecular Diagnostics Lab in Microbiology at Thomas Jefferson University. In 2007, he moved to Temple University, where he is now Professor of Biology. His research on hepatitis B and liver cancer has been supported by NIH for more than 25 years, has more than 130 publications, and is presently Head of the Professional Science Master’s program in Biotechnology at Temple University.
Abstract:
Chronic infection with hepatitis B virus (HBV) is associated with the development of progression of chronic liver disease (CLD) and the appearance of hepatocellular carcinoma (HCC). HCC is a prevalent cancer worldwide with few treatment options. Given that HCC develops most often on the background of chronic inflammation, experiments were designed to test the hypothesis that selected probiotic bacteria that suppress inflammation could be used as a simple and inexpensive means to prevent or delay the appearance of HCC. To test this, hepatitis B x (HBx) transgenic mice, which develop progressive liver lesions that culminate in HCC, were treated with a mixture of probiotic bacteria (Synbiotic 2000). The result showed a significant reduction in the number and size of dysplastic and HCC nodules compared to control transgenic mice. Microarray analysis of selected immune and cancer associated markers showed a strong reduced expression in the liver of mice treated with Synbiotic 2000 compared to controls. Thus, Synbiotic 2000 attenuates the pathogenesis of HCC, and may be useful in cancer chemoprevention, not only for HCC, but perhaps against other cancers that often develop on the background of chronic inflammation.
Keynote Forum
Eve-Isabelle Pecheur
Cancer Research Center of Lyon, France
Keynote: Hepatitis C virus infection: A subtle but toxic combination of lipids, proteins and sugars
Time : TBD
Biography:
Eve-Isabelle Pecheur has completed her PhD in 1997 from University Paris XI and Post-doctoral studies from Groningen University of Medical Sciences (Netherlands). She leads a research group at the Cancer Research Center of Lyon. She has published more than 50 papers in reputed journals. She is serving as an Editorial Board Member of Antiviral Research, and as an Academic Editor of PLoS ONE.
Abstract:
Viruses are obligate intracellular agents that depend on host cells for successful propagation, hijacking cellular machineries to their own profit. The hepatitis C virus (HCV) is a strictly human pathogen, causing chronic liver injuries accompanied by lipid disorders. Upon infection, in addition to protein-protein and protein-RNA interactions usual for such a positive-strand RNA virus, HCV relies on protein-sugar and protein-lipid interactions at multiple steps of its life cycle to establish persistent infection. En route from the blood stream to hepatocytes of the liver, its target cells, HCV encounters a specific micro-environment at the surface of hepatocytes, comprising glycoproteins, proteoglycans and polysaccharides, called the glycocalyx. Protein-sugar interactions therefore occur, that I will explore to address how HCV infection modulates the hepatocyte glycocalyx, and in return how this peculiar region of the cell adapts to the persistent presence of the virus. After this journey through the glycocalyx, HCV penetrates into the hepatocyte, which relies on subtle protein-protein and protein-lipid interactions dissected through structural, biochemical and biophysical analyses. HCV infection subsequently leads to a major reshuffle of the endoplasmic reticulum, the intracellular compartment where viral replication takes place, implying intense underlying protein-lipid interactions. I will also explore how de novo production and assembly of viral particles are inseparable from cellular lipid metabolism, since lipoproteins are structural components of neoformed virions. Each of these steps are potential therapeutic targets, which will be discussed at the light of current antiviral strategies.
- Track 6: Hepatitis Antigens and Antibodies
Track 7: Hepatocellular Carcinoma and Pancreatic Cancer
Track 8: Pancreatic and Biliary Duct Diseases
Track 9: Transplantation and Surgery
Session Introduction
Wafa Amer
University Hospital of Cologne, Germany
Title: Tumor tracking and evolution analysis of hepatocellular carcinoma progression by ultra-deep sequencing of the entire mitochondrial genome
Biography:
Wafa Amer is a Physician, awarded MBBCh in 2010 from Misurata University, Libya. She has migrated to Germany to learn state-of-the-art techniques and did her Master thesis at the Institute for Pathology at the University Hospital of Cologne, Germany.
Abstract:
Hepatocellular carcinoma (HCC) is the third most lethal cancer due to its late detection, high recurrence and limited therapeutic option. Since mitochondrial (mt) genome is highly susceptible to DNA alterations due to the lack of protective histones and limited repair system, the mt-mutation pattern can be targeted as a novel tool of tumor evolution analysis. Herein, we aimed to characterize intratumor clonal structure by ultra-deep sequencing of entire mt-genome for better understanding how HCC originate, develop and progress. In total, 48 HCC nodules and corresponding peri-tumor areas were analyzed. Primer sets spanning the whole mt-DNA were designed and multiplex-PCR setup was established. Target enriched libraries of mt-DNA was sequenced by MiSeq-platform and NGS data was interpreted by the CLC Software. Notably, 100% of reads mapped to the mt-target regions indicating efficient mt-primer design and a good run performance. Whole mt-genome screening revealed a wide spectrum of mt-alterations, typically distributed in the D-Loop region and the respiratory chain complex genes. Particularly in HCC nodules of non-cirrhotic origin mt-mutations were higher than cirrhosis-related HCC. However, high mt-mutation rate was also observed in the peri-tumor areas suggesting that mt-genome is susceptible at earliest stage of hepatocarcinogenesis. Furthermore, most HCC nodules of individual sample have identical mt-mutations indicating the monoclonal HCC origin. Interestingly, the increasing numbers and frequency of particular panel of mt-hot-spot mutations refer to the progression of HCC dedifferentiation. In conclusion, our mt-genome screening based approach representing rapid and sensitive molecular tool and provide novel insights in cancer diagnostics and therapeutic strategies.
Zhiyu Xiao
Sun Yat-sen University, China
Title: PTPN13 causes apoptosis-dependent resistance to 5-FU in hepatocellular carcinoma
Biography:
Zhiyu Xiao has completed his PhD from Sun Yat-sen University School of Medicine in 2011. He is now an Associate Professor of Sun Yat-sen Memorial Hospital. He has been engaged in the clinical and basic research of hepatocellular carcinoma for many years. He published several papers in reputed journals.
Abstract:
Drug resistance is a major factor contributing to the extremely poor prognosis of patients suffering from advanced-staged hepatocellular carcinoma (HCC). 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent against HCC. Here, we found that protein tyrosine phosphatase, non-receptor type 13 (PTPN13, also known as FAP-1) was expressed at high levels in HCC patients who developed recurrence after chemotherapy and that changes in PTPN13 expression before and after chemotherapy were inversely correlated with recurrence time. In parental cells, after treatment with 5-FU, upregulation of total and surface Fas, downregulation of PTPN13 and activation of apoptosis were observed, while in 5-FU resistant cells, upregulation of PTPN13 resulted in resistance to apoptosis. After stable knockdown of PTPN13 in 5-FU resistant cells, improved chemotherapeutic efficiency was detected both in vitro and in vivo. More importantly, we provide evidence that miR-200c is upstream of PTPN13 using bioinformatics methods confirmed by luciferase reporter assays. We also demonstrate that miR-200c sensitizes 5-FU resistant cells to apoptosis. Moreover, resistance to 5-FU-induced apoptosis was effectively overcome by the addition of the apoptosis activator procaspase-activating compound 1 (PAC-1). 5-FU and PAC-1 synergistically inhibited HCC cell proliferation measured using in vitro, ex vivo and in vivo models. In conclusion, the upregulation of PTPN13 is one of the mechanisms that mediate 5-FU resistance in HCC. Combining 5-FU with the apoptotic pathway activator PAC-1 can overcome this resistance, suggesting that this combination may be a novel approach for the treatment of chemoresistant HCC.
Zhong Li
Shanghai Institute of Cell Therapy, China
Title: A splicing variant of merlin promotes metastasisin hepatocellular carcinoma
Time : TBD
Biography:
Zhong Li has completed his PhD from Shanghai Medical University and Postdoctoral studies from Shanghai Institute of Biochemistry, University of Rochester and Connecticut Health Center. He is the Vice President of Shanghai Institute of Cell Therapy, an immunotherapy researdch organization. He has published more than 31 papers in reputed journals and has been serving as a member of Precision Medicine Association affilated to China Medicinal Biotech Association.
Abstract:
Merlin (moesin-ezrin-radixin-like protein), encoded by the neurofibromatosis type 2 (Nf2) tumor suppressor gene, is a member of the band 4.1 family. As one of the most versatile tumor suppressors, it is capable of integrating several different mechanisms that regulate cell proliferation, motility, survival and signaling pathways. As we know, Merlin has at least five splicing forms. However, little is known about the functional importance of these splicing forms. To understand the roles of Merlin in the process of tumorigenesis and tumor metastasis, we studied Merlin and its splicing forms in hepatocellular carcinoma (HCC). Our data shows that Merlin is present at low levels in HCC specimen, particularly in metastatic tumors, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 (ï„2–4Merlin) is amplified in HCC and portal vein tumor thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that ï„2–4Merlin interferes with the capacity of wild-type Merlin to bind b-catenin and ERM, and it localizes in the cytoplasm rather than at the cell surface. Furthermore, ï„2–4Merlin overexpression increases the expression levels of b-catenin and stemness-related genes , induces the epithelium–mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the ï„2–4Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis.
Mohammed Omar Khalifa
Ain Shams University School of Medicine, Egypt
Title: Epidemiological characteristics of hepatocellular carcinoma in Egypt: A retrospective analysis of 1313 cases
Time : TBD
Biography:
Mohammed Omar Khalifa has completed his MD from Ain Shams University, Cairo, Egypt. He is an Assistant Professor of Tropical Medicine Department. He has published many papers in reputed journals.
Abstract:
Background & Aim: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Egypt has the highest prevalence of HCV in the world and the prevalence of HCC is increasing in the last years. The aim was to study epidemiological characteristics of HCC in Egypt. Methods: Retrospective chart review of 1456 Egyptian patients with HCC was done. Records of 1313 patients (1035 males, 278 females; median age 56 years) fulfilling diagnostic criteria for HCC, were analyzed for clinical, etiological, radiological and tumor characteristics. Results: The majority of cases (75%) were from rural areas. The most frequent age category affected by HCC was between 51 and 60 years (45.7%); 50% of the patients reported accidental discovery of their hepatic focal lesions. The major presenting symptom was newly developed right hypochondrial pain (66.3%). HCV Ab was detected in 91.32% of the studied patients while HBV infection was reported in 2.51%. 59.3% of patients had AFP levels below 200ng/ml. On studying tumor characteristics, the right lobe of the liver was more frequently occupied by the focal lesions (75.4%) than the left lobe (15.7%) and 12.5% of patients had bilobar affection. Five hundred and six patients (38.6%) had more than one hepatic focal lesion and 228 patients (17.4%) had tumors occupying >50% of the liver. Conclusion: HCC is a major health problem in Egypt and its incidence is increasing. The high prevalence of HCV infection makes screening programs and surveillance of those patients a very important tool to early detect cases of small HCCs.
Mahmoud M Zakaria Ibrahim
Mansoura University, Egypt
Title: Anticancer activity of Aloe vera and Calligonum comosum extracts separately on hepatocellular carcinoma cells
Biography:
Mahmoud M Zakaria Ibrahim has worked in the Department of Laboratories (Microbiology, Clinical Chemistry and Clinical Hematology Labs.) of Urology & Nephrology Center, Mansoura University. He is currently working as a Molecular Biologist in Research Building (Gene Expression, Tissue Culture, Stem Cell Labs). He has obtained his Master’s degree in Immunology and PhD degree in Human Physiology (2012). He has publicized 11 manuscripts in reputed journals in the field of cancer research and stem cell differentiation. He is currently a Supervisor of Gene Expression Lab.
Abstract:
Objective: The present study aimed to investigate the in vitro anticancer effect of Aloe vera and Calligonum comosum extracts against hepatocellular carcinoma (HepG2) cells. Methods: HepG2 cells were tested against different doses of A. vera and C. comosum. Viability of the cells was assessed by MTT assay. Evaluation of apoptosis and DNA damage in HepG2 cells were performed using Annexin V Apoptosis Detection Kit. The expression of p53 and anti-apoptotic (Bcl-2) were tested by Real Time-PCR and flow cytometer analyzer. Hematoxylin & Eosin stained sections from untreated and treated HepG2 cells were observed using light microscopy. Results: The IC50 values of A. vera and C. comosum extracts were (10.45±0.31) and (9.6±0.01) µg/ml respectively. The extracts separately increased cytotoxicity against HepG2 cells in a time and dose dependent manners. Also, it apparently induced apoptosis through increase P53 and decrease Bcl-2 genes expressions. Conclusion: The results indicated that the extracts could have anti-hepatocarcinogenic effect at least in part through modulation of apoptosis.
Kai-Fu Tang
The First Affiliated Hospital of Wenzhou Medical University, China
Title: The role of dicer in hepatitis B virus (HBV)-related hepatocarcinogenesis
Time : TBD
Biography:
Kai-Fu Tang has completed his MD in 1995 from Chongqing Medical University and PhD from Chongqig University. He is the Director of the Digestive Cancer Center of Wenzhou Medical University. He has published more than 30 papers and has been serving as an Editorial Board Member for several journals.
Abstract:
Hepatitis B virus (HBV) infection is one of the major causes of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying HBV-related HCC are still incompletely understood. Knockout of Dicer in hepatocytes led to spontaneouse HCCs , we found that Dicer is downregulated in the liver tissues of chronic hepatitis B patients and HCC tissues. Therefore, we proposed that decreased Dicer expression is critical for the development of HCC. Here, I will address the molecular mechanism underlying why Dicer downregulation lead to the development of HCC. Firstly, Dicer is essential for the maintenance of genome stability, decreased Dicer expression causes DNA damage, which may induce gene mutation and lead to carcinogenesis. Secondly, Dicer interacts with SIRT7 and holds a proportion of SIRT7 in the cytoplasm, decreased Dicer expression leads to H3K18 hypoacetylation upon DNA damaging. H3K18 deacetylation is critical to the maintenance of oncogenic transformation. Therefore, Dicer may participate in carcinogenesis via regulating H3K18 deacetylation. Thirdly, Dicer processes 7SL RNA into small fragments, which function as dominant-negative regulators of the full-length 7SL RNA, and interfere with signal recognition particle (SRP) complex formation. Decreased Dicer expression enhances SRP-mediated protein targeting, and increases hepatitis B surface antigen (HBsAg) secretion. HBsAg repress MICA and MICB expression via induction of cellular miRNAs in HCC cells. Therefore, Dicer may participate in antitumor immune response. Fourthly, Dicer may regulate tumor development via different miRNAs.
Biography:
Bingshui Xiu has completed his PhD from Beijing Institute of Basic Medical Sciences. She has published more than 14 papers in SCI journals
Abstract:
There are about 150 thousands of HCV infection individuals in China, which is a major public health problem of China. The correct detection of HCV is foundation for blood screen, clinical diagnosis and antiviral treatment. In this report, we summarize the main procedure and tests used in HCV detection in China. According to Blood Donation Law of China established in 1998, anti-HCV screen is enforceable, which dramatically decrease the HCV transmission by blood. In 2015, NAT were forcibly used in blood screen all over China, the procedure to HCV screen changed accordingly, but its effect needs to be evaluated further. In HCV diagnosis, anti-HCV assay is common in preliminary diagnosis. NAT, especially real-time reverse transcriptase polymerase chain reaction, are commonly used to monitor the virological responses during the antiviral treatment in China. According to Hepatitis C Prevention Guidelines announced in 2015, HCV genotype assay has important clinical implication as a marker of responsiveness to IFN. But HCV serotype tests for 1b and 2a are gaining more attention for their convenience. Recently, direct-acting antivirals (DAAs) to HCV (daclatasvir, ombitasvir and ledipasvir) were used. HCV mutation assay and new biomarkers for DAA treatment and prognosis of HCV infection are urgently needed.
Biography:
Arnolfo Petruzziello is the Head of the Diagnostic Virology and Molecular Biology Unit of National Cancer Research IRCCS Italia Fondazione G. Pascale in Naples. He has done Post-graduation in Microbiology and Virology and PhD in Molecular and Cellular Pathology. He is an Editorial Board Member and peer-reviewer for: World Journal of Gastroenterology and Archives of Microbiology and Biotechnology.
Abstract:
Background: Hepatocellular carcinoma (HCC) is the third most common cause for cancer death in the world, especially in patients with chronic hepatitis C virus (HCV) infection. The rate of progression from chronic hepatitis to HCC is variable and several factors have been identified as important predictors of progression, some related to the host (older age, longer duration of infection, male sex or alcohol consumption >50 g/day), others to the environment (Hepatitis B virus or HCV infection). Despite several studies suggesting an association between HCV genotype 1b and risk of HCC, no consenus has emerged yet on this matter, which is still controversial. The purpose of this study was to clarify whether the genotype 1b is associated with a higher risk of HCC than other genotypes. Material & Methods: A total of 121 consecutive cases of HCC, fulfilling the diagnostic criteria from the Barcelona 2000 EASL conference, and 125 patients with other malignant tumors as control, enrolled between February 2013 and November 2015, were included in the study. Serum of each HCC or control patient was evaluated for serological evidence of HCV infection (Vitros Ortho Clinical Diagnostics), viral load estimation by Taqman Real time PCR system (Roche Diagnostic) and genotyping by HCV LiPA test (Siemens) . Results: About eighty per cent (80.8%) of HCC patients had positive anti-HCV which was significantly greater than the control group (34.4%, p=0.01). Anti-HCV positive patients have a risk of progression to HCC almost 8 times than the control group (OR= 8.04). The male/female ratio for the HCC cases was 3.06:1. Males with HCC significantly showed to have about 4 times risk of exposure to HCV infection (OR=3.9). Majority of HCC patients were >70 years (71.0% vs. 58.0% in the control group) and over eighty per cent of them had underlying cirrhosis at presentation (84.0%). HCV RNA seropositive rate was significantly higher (71.2%) among HCC patients if compared to the control group (44.2%, p=0.01). No difference in levels of viral load was found between HCC patients and the control group. The most prevalent genotype in HCC patients was 1b (59.4% vs. 26.4% in the control group, p=0.05), whereas the most predominant genotype in the control group was 2a/2c (63.2% vs. 21.7% in HCC patients, p=0.01). Moreover, the genotype 3a, completely absent in the control group, is the third most common genotype in the HCC patients (5.9%). Conclusion: HCV genotype 1b is associated with a statistically higher risk of developing HCC compared to other genotypes. Patients with cirrhosis that are infected with this genotype require more intensive surveillance for the early detection and aggressive management of neoplasia
Ishank Goel
Datta Meghe Institute of Medical Sciences, India
Title: Hepatic involvement in Dengue in children- An ominous sign
Biography:
Ishank Goel is a 2nd year resident at the DMIMS University, Sawangi (Meghe), Wardha, Maharashtra, India. He has presented oral presentations and poster at NAPCON-2014 and 2015, CME Colors Hospital, Nagpur, India and various other conferences in India. He has attended and served in many social health camps. He also has done a case prensentation in a national level conference. He is a certified NALS and PALS provider.
Abstract:
This cross sectional observational study was done in the paediatric wards and ICU of Acharya Vinoba Bhave Rural Hospital, Sawangi, Wardha, Maharashtra, Central India. In our study, children below 16 years with serology positive dengue fever were included. The dengue score formulated in our institute which was pre-designed and pre-validated was used to grade these children according to symptomatology. A score of >20 out of 30 indicated a poor prognosis, 11-19 indicated good prognosis (with some morbidities) and a score of 0-10 indicated excellent prognosis. Outcome was measured in terms of death, ventilatory support, encephalitis, need for transfusion of blood products, shock, prolonged mean duration of stay. In our study, out of the 120 tested patients, 50 children with dengue serology positive were further graded according to their presenting symptoms like tachypnea (4), urine output (4), deranged LFTs (4), hypotension (4), pulse pressure (3), convulsions (3), capillary leak (2), platelet count (2), heart rate (2), fever (1) and rash (1). We found that 42 out of the 50 (84%) had hepatic involvement in the form of deranged LFTs or organomegaly and the remaining 8 had no hepatic involvement. Out of the 42, liver involvement was seen as follows: raised alanine transaminase (ALT) (80.9%), raised aspartate aminotransferase (AST) (71.4%), hepatomegaly (66.7%), reduced serum albumin (59.5%), raised alkaline phosphatase (42.8%) and prolonged prothrombin time (PT) (30.9%). We found that hepatic involvement had a statistically significant association with poor outcome in patients of dengue (along with other markers like tachypnea, urine output and hypotension).
Krutika A Kurhade
Datta Meghe Institute of Medical Sciences, India
Title: To study the value of first day bilirubin in predicting development of significant hyperbilirubinemia in healthy term neonates
Biography:
Krutika A Kurhade is a 2nd year resident in the Department of Paediatrics in DMIMS, Sawangi, Meghe. She worked as a Clinical Observer in Paediatrics in Eric Williams Medical Sciences Complex Trinidad & Tobago, UWI and in Lad Child Care Hospital, Nagpur, Mahrashtra, India. She also worked as a House Officer in the MICU of IGGMC, Nagpur, India. She has attented various social health camps in the Vidarbha region, presented a paper and case presentation in two national level conferences. She has also attended many other national level CMEs and conferences on topics of nutrition, neurology and genetics.
Abstract:
In this prospective observational study, the value of first day bilirubin in predicting development of significant hyperbilirubinemia in healthy term neonates was evaluated in the maternal and neonatal wards of AVBR hospital, Sawangi, Wardha. The study included 388 full term healthy neonates out of 6082 deliveries in study period. Newborns with Rh incompatibility, prematurity etc. were excluded. Transcutaneous bilirubin (TCB) was measured on 12, 24, 48 and 72 hours of life. To assess the correlation between TCB and serum bilirubin, blood was sent to the biochemistry laboratory for measuring serum bilirubin levels (at 72 hours of life) by modified Van den Bergh's test. There were 193 cases of neonatal hyperbilirubinemia out of 388 cases (49.74%). We determined a cut off value of 5 mg/dl for the prediction of neonatal hyperbilirubinemia at 24 hours of life (NPV=77). The mean value of bilirubin at 12, 24, 48 and 72 hours was found as 3.69, 5.17, 9.05 and 13.18 respectively. Neonatal hyperbilirubinemia was found to be more on 24 and 72 hours (49.74%) as compared to 12 hours (35.2%) and 48 hours (44.32%). Average values of bilirubin in newborns developing hyperbilirubinemia at 12, 24, 48 and 72 hours were 5.02, 6.88, 12.15 and 16.95 respectively. A TCB measurement of 5 mg/dl in first 24 hours of life predicted nearly all the term newborns had hyperbilirubinemia (≥13) mg/dl at 72 hours of life. A TCB measurement of 4 mg/dl at 12 hours predicted 35.56% of the cases who developed hyperbilirubinemia at 72 hours of life. Correlation of TCB and serum bilirubin was found to be significant (correlation coefficient (r) 0.9379). First day TCB level can predict development of subsequent hyperbilirubinemia.
Yuling Sun
The First Affiliated Hospital of Zhengzhou University, China
Title: Gut microbiota are disturbed in patients with Budd-Chiari syndrome in China
Biography:
Yuling Sun has completed his PhD from Zhejiang University School of Medicine. He is the Director of the department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University. He has published more than 12 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Abstract:
Increasing evidence has indicated that there were distinct variations in Budd–Chiari syndrome (BCS) prevalence, its etiological distributions, clinical characteristics, and sites of occlusion, and the selected treatment modalities for BCS patients between China and the western countries. The clinical manifestation of BCS is heterogeneous. The triad of abdominal pain, hepatomegaly and ascites is commonly present in patients. The blood failure of draining from the liver leads to congestion resulting in portal hypertension or inferior venacaval (IVC) hypertension, inducing various changes of physiological functions. Through the "gut-liver axis", the liver function is closely linked to gut microbiota; however little is known about the gut microbiota profile in patients with Budd-Chiari syndrome.88 patients (31 HC, 20 LC, 31 BCS) who were matched with their age, gender and BMI carried out in accordance with the criteria of gut microbiota. We first established the framework of gut microbial communities in Chinese patients with Budd-Chiari syndrome. Unusually abundant rare species of bacteria were found in the BCS patients. At the phylum level, Tenericutes were significantly decreased when compared with the liver cirrhosis and health control group. The high abundance of Megamonas sequences was a feature of BCS group, could be used as a microbial signature for the differential diagnosis. Our research represents an important step for Original basic between Budd-Chiari syndrome and gut microbiota.
Rosa M Pascale
University of Sassari, Italy
Title: YAP signalling deregulation and genetic susceptibility to hepatocarcinogenesis, stemness and aggressivity of liver cancer
Biography:
Rosa M Pascale is currently working as an eminent Faculty member at Department of Biomedical Sciences, University of Sassari in Italy. She has published numerous research papers and articles in reputed journals and has various other achievements in the related studies. She has extended her valuable service towards the scientific community with her extensive research work.
Abstract:
Background & Aim: Recent observations suggests, contribution of Yes-associated protein (YAP) upregulation to hepatocellular carcinoma progression (HCC). We analyzed the connection of YAP deregulation with genetic susceptibility to hepatocarcinogenesis and HCC stemness and aggressivity. Methods: HCC from F344 and BN rats are genetically susceptible and resistant to hepatocarcinogenesis, respectively; human HCC from patients with poorer prognosis (<3 years survival, after partial liver resection, HCCP) or with better outcome (>3 years survival; HCCB) were used. Gene expression was evaluated by qPCR and immunoblotting, and functional experiments were done using HepG2, Huh7, and Hep3B liver cell lines. Results: Higher upregulation of Yap and of its target CTGF was seen in F344 rat HCC than in BN HCC which was associated with highest increase in Yap-tyr357, p73 phosphorylation, and Caspase 3 cleavage in HCC from resistant BN rats. Upregulation of YAP, CTGF, 14-3-3 and YAP-14-3-3 complex, TEAD and YAP-TEAD complex reached highest values in human HCCP. In contrast, YAP-ser127 decreased with lowest values in HCCP, and YAP-tyr357, p73 phosphorylation and Caspase 3 cleavage showed highest increase in human HCCB. Stem cell markers NANOG, OCT3-4, and CD133 upregulation progressively increased from human HCCB to human HCCP and was significantly correlated to YAP and YAP-TEAD expression. Growth rate was 2.5-3 times lower, between 48 and 96 hours, in HepG2 than in Huh7 and Hep3B cells. These modifications were associated with lower YAP and NANOG, OCT3-4, and CD133 expression in HepG2 than in Huh7 and Hep3B cells at 48 hours. YAP downregulation by specific siRNA in Huh7 and HepG3 cells led to significant decrease in NANOG, OCT3-4, and CD133 expression. In contrast, sharp upregulation of stem cell markers was induced in HepG2 cells by forced YAP overexpression. Conclusions: Our results indicate: YAP signalling deregulation in HCC is under genetic control; Genetic resistance to HCC is associated with highest phosphorylation of Yap at tyr357 and p73, and highest apoptosis; YAP changes favoring YAP-14-3-3 and YAP-TEAD complexes formation, associated with cell survival, contribute to HCC aggressivity. In contrast, YAP changes favoring apoptosis, such as YAP phosphorylation at tyr357, are associated with better HCC prognosis and; YAP upregulation favors HCC stemness and aggressivity.
Amedeo Columbano
University of Cagliari, Italy
Title: Metabolic reprogramming is a very early event in HCC development
Biography:
Amedeo Columbano has completed his PhD from Cagliari University and Post-doctoral studies from the Department of Pathology (Toronto, Canada). He is the Director of the PhD program in Molecular and Translational Medicine at Cagliari University. He has published more than 100 papers in reputed journals and has been serving as a referee for the most important Hepatology journals.
Abstract:
Warburg metabolism is associated with cancer, but remains unclear whether it characterizes early phases of tumorigenesis. Here, we performed a metabolic characterization by assessing expression level, activity and modulation of several enzymes with key roles in glycolysis, pentose phosphate pathway (PPP) and oxidative phosphorylation. Preneoplastic hepatic lesions and hepatocellular carcinomas (HCC) were induced in rats by a single dose of diethylnitrosamine (DENA) followed by 2-acetylaminoaminofluorene (2-AAF) and partial hepatectomy. Expression of metabolic genes was also analysed in macrodissected preneoplastic nodules and HCC cells obtained by perfusion of HCC-bearing rats and in two different cohorts of human patients carrying HCC. A switch from OXPHOS to PPP was observed in very early preneoplastic lesions generated 10 weeks after DENA treatment. This metabolic reprogramming was observed only in the most aggressive preneoplastic lesions positive for CK-19. PPP induction shown by increased glucose 6-phosphate dehydrogenase (G6PD) was associated with inhibition of succinate dehydrogenase by the chaperone TRAP1 and increased expression and activity of citrate synthase. Activation of the NRF2/KEAP1 pathway and down-regulation of miR-1 accompanied the metabolic reprogramming in CK-19+ preneoplastic lesions. Accordingly, NRF2 silencing decreases G6PD and increases miR1 expression, consequently inhibiting PPP, while forced expression of miR1 downregulated G6PD expression in HCC cells. Finally, an inverse correlation between miR1 and its target gene G6PD was found in human HCCs. The results demonstrate that metabolic reprogramming takes place at early stages of hepatocarcinogenesis and is likely the consequence of the concomitant activation/increase of the NRF2-KEAP1 pathway and TRAP1.
Nikhat Ahmed Siddiqui
Ziauddin University, Pakistan
Title: A proteomic approach for the involvement of the ANXA4 in HCC: Moving towards an understanding of tumor progression
Time : TBD
Biography:
Nikhat Ahmed has completed her PhD from University of Surrey, UK and Post-doctoral studies from Tufts University, School of Medicine. She was the chair and Dean of Science at University Of Karachi and presently, she is the Dean of Research, at Ziauddin University, Karachi, Pakistan a premier organization. She is representing Pakistan, as Council member of AOHUPO (Asian Ocenia Human Proteome Organization), and has published more than 65 papers in reputed journals and has been serving as Editor and Editorial Board Member of journal of repute.
Abstract:
Proteomics-based clinical studies have been shown to be promising strategies for the discovery of novel biomarkers of a particular disease. To gain insight into development of Hepatocellular carcinoma utilizing promising strategies (2 dimensional electrophoresis and ESI-QTOF-MS/MS) we aimed to identify potential biomarkers for hepatocellular carcinoma (HCC) and analyzed a set of 115 samples (HCC=50, Fibrosis= 50 & Control= 15). From the series of seventeen differentially expressed proteins, collectively we identify annexin A4 (ANXA4) an intracellular Ca2+ sensor, as a new biomarker for early diagnostic and prognostic potential. Expression of ANXA4 was found to be up- regulated (fold change ≥ + 2.0, P ≤ 0.05) in HCC as compared to fibrosis and control. After validated current finding, we applied in silico analysis to integrate the data generated from proteomics technologies. We extend this current understanding to demonstrate the significantly induced phosphorylation and S-nitrosylation signals by insilico study, suggesting a role of ANXA4 in cell survival may have implications for cancer progression and chemoresistance. Moreover, we revealed interacting partner of ANXA4 bestowed with critical capabilities, namely apoptosis, cell cycling, anticoagulation, cell motility and stress resistance that together demonstrate their possible role in cancer progression. Overall, our results shed new light on the potential of biomarker ANXA4 as biomarker used for early diagnosis, prognosis prediction, and personalized treatment of HCC.
Zhaohui Tang
Shanghai Jiaotong University School of Medicine, China
Title: Viewing cellular origin of intrahepatic cholangiocarcinoma from perspective of tumor heterogeneity
Biography:
Zhaohui Tang is the Director of general surgery department in Xinhua Hospital affiliated to Shanghai JiaoTong University School of Medicine. He is good at diagnosis and treatment of hepatobiliary diseases, especially in the field of intrahepatic cholangiocarcinoma. There are differences related to the prognosis after surgery of ICC patients due to the enormous heterogeneities of ICC. Multiple cellular origins may play a key role in the development of ICC, so he proposed that view cellular origin from perspective of tumor heterogeneity, which may contribute to the improvement of ICC current classification methods, providing guidance for treatment.
Abstract:
Intrahepatic cholangiocarcinoma (ICC) is an extraordinarily heterogeneous malignant disease among the tumors that have so far been identified. The cancer cell-of-origin has important implications for tumor cell fate and cancer phenotype. Recent data suggest that multiple cellular origins of ICC including differentiated hepatocytes, intrahepatic biliary epithelial cells (IBECs)/cholangiocytes, pluripotent stem cells such as hepatic stem/progenitor cells (HPCs), biliary tree stem/progenitor cells (BTSCs), and within peribiliary glands (PBGs). Both somatic mutagenesis and epigenomic features are highly cell-type-specific, that is, multiple cellular origins may profoundly influence genomic landscapes, key signaling pathways, driving phenotypic variation and pose significant challenges to personalized medicine, drug response and patient outcome. Specifically, the cellular origin of ICC can be accurately determined based on the distribution of mutations along its genome through Roadmap Epigenomics Program. Understanding ICC heterogeneity of cellular origins and molecular mechanism may contribute to establish hierarchical model of carcinogenesis and improve anatomical-based classification. The advent of personalized medicine for ICC treatment may enable the actual origin of the cellular and molecular mechanism of ICC to be determined to improve diagnosis, therapies and prognosis.
Abdul Malik
King Saud University, Saudi Arabia
Title: Ligase chain reaction as a modality for the detection of point mutation in the precore region of HBV related HCC cases from northern India
Biography:
Abdul Malik has completed his PhD in 2007 from JamiaMilliaIslamia, New Delhi and Post doctoral studies at Department of Medicine, Maulana Azad Medical College, New Delhi. Currently, he is working as an Assistant Professor, College of Applied Medical Science, King Saud University, Saudi Arabia, since January 2011. He has published papers in reputed journals in the field of virology and has also presented them in International Conferences.
Abstract:
Background & Aim: Mutant Hepatitis B with precore stop codon has been reported to be associated with severe liver damage in HBeAg negative patients with hepatocellular carcinoma. Clinically, the biological importance of pre-core G1896A mutation is not well established. The purpose of the present study was to determine hepatitis B virus genotypes and also to elucidate the association of G1896A mutation of precore gene and the severity of liver damage in HBV related HCC cases. Methods: Detection of HBV DNA sequences was carried out by polymerase chain reaction (PCR) using primers derived from the precore region of HBV genome. Ligase Chain Reaction (LCR) assay was performed to screen the presence or absence of G1896A mutation. Direct nucleotide sequencing was done to confirm the results of LCR. A total of 116 HBV related cases who attended the medical Out Patients Department and wards of LokNayak Hospital, New Delhi, India were screened over the period of 3 years. Patients having super-infection with HDV/HCV/HIV and past history of interferon therapy were excluded. Results: Sequence analysis of viral DNA established that the G1896A mutation was observed in 32 cases in HCC cases. Phylogenetic analysis revealed 60% isolates belonged to genotype A, while 20% belonged to genotype Dand 20% belonged to genotype E. Conclusion: The present data suggests that precore G1896A mutations is responsible for 27.2% of the patients of Asian Indian origin suffering from HBV related HCC cases and these cases are more symptomatic and aggressive in patients with the mutant form of the virus as compared with the wild form.