@article {10747, title = {Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 Sep 03}, pages = {13168}, abstract = {

Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.

}, issn = {2045-2322}, doi = {10.1038/s41598-018-31406-5}, author = {Anfuso, Beatrice and El-Khobar, Korri E and Ie, Susan I and Avellini, Claudio and Radillo, Oriano and Raseni, Alan and Tiribelli, Claudio and Sukowati, Caecilia H C} } @article {10847, title = {Serum Stem Cell Growth Factor Beta for the Prediction of Therapy Response in Hepatocellular Carcinoma.}, journal = {Biomed Res Int}, volume = {2018}, year = {2018}, month = {2018}, pages = {6435482}, abstract = {

Introduction: Chronic inflammatory response is one of major contributors in the development of hepatocellular carcinoma (HCC). Inflammatory molecules, such as cytokines and growth factors in the circulation, can be useful in the diagnosis and prognosis of the patients. The stem cell growth factor beta (SCGF), a newly found protein, is a secreted sulfated glycoprotein and it functions as a growth factor for primitive hematopoietic progenitor cells. The level of SCGF had been reported to be elevated in several cancer types. However, there is very few or even no information on this protein in the study of HCC, even more in clinical studies.

Methods: A multiplex immunoassay panel of 48 cytokines and growth factors were utilized to screen 68 sera from 29 HCC patients at pretreatment (T0), 1 month (T1), and 6 months (T6) after treatment by either radiofrequency ablation (RF) or transarterial chemoembolization (TACE). Treatment response was evaluated according to mRECIST criteria.

Results: Immunoassay screening showed that the levels of IL-17, CTACK, TNF, IL-2R, IL-8, and SCGF were different in Complete Responders (CR) and Nonresponders (NR) groups. At T0 and T1, the SCGF level was significantly the highest in NR (23.8 and 40.7 ng/mL, respectively), followed by early recurrence (25.4 and 25.0 ng/mL), and CR (6.7 and 5.3 ng/mL), independently from HCV, stages, and treatment type. Low basal SCGF level was associated with longer disease-free survival compared to high SCGF.

Conclusion: In this study, for the first time, we demonstrate that the high level of serum SCGF at pre- and posttreatment is associated with HCC nonresponsiveness.

}, keywords = {Aged, Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Female, Hematopoietic Cell Growth Factors, Humans, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Retrospective Studies, Stem Cells, Treatment Outcome}, issn = {2314-6141}, doi = {10.1155/2018/6435482}, author = {Sukowati, Caecilia H C and Patti, Riccardo and Pascut, Devis and Ladju, Rusdina B and Tarchi, Paola and Zanotta, Nunzia and Comar, Manola and Tiribelli, Claudio and Croc{\`e}, Lory S} } @article {8499, title = {An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0158817}, abstract = {

Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100\% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86\% of males and 15\% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0158817}, author = {Marin, Veronica and Rosso, Natalia and Dal Ben, Matteo and Raseni, Alan and Boschelle, Manuela and Degrassi, Cristina and Nemeckova, Ivana and Nachtigal, Petr and Avellini, Claudio and Tiribelli, Claudio and Gazzin, Silvia} } @article {1815, title = {X-ray fluorescence elemental mapping and microscopy to follow hepatic disposition of a Gd-based magnetic resonance imaging contrast agent.}, journal = {Clin Exp Pharmacol Physiol}, volume = {38}, year = {2011}, month = {2011 Dec}, pages = {834-45}, abstract = {

1. Spatially resolved X-ray fluorescence (XRF) spectroscopy with synchrotron radiation is a technique that allows imaging and quantification of chemical elements in biological specimens with high sensitivity. In the present study, we applied XRF techniques at a macro and micro level to carry out drug distribution studies on ex vivo models to confirm the hepatobiliary disposition of the Gd-based magnetic resonance imaging contrast agent B22956/1. 2. Gd presence was selectively quantified allowing the determination of the time dependent disappearance of the drug from blood and its hepatic accumulation in mice after administration. Elemental mapping highlighted the drug distribution differences between healthy and diseased livers. XRF microanalyses showed that in CCl(4) -induced hepatitis, B22956/1 has greatly reduced hepatic accumulation, shown as a 20-fold reduction of Gd presence. Furthermore, a significant increase of Fe presence was found in steatotic compared with healthy livers, in line with the disease features. 3. The present results show that XRF might be useful in preclinical pharmacological studies with drugs containing exogenous elements. Furthermore, quantitative and high-sensitivity elemental mapping allows simultaneous detection of chemical variation, showing pathological conditions. This approach was useful in suggesting reduced B22956/1 accumulation in steatotic livers, thus opening possible new diagnostic perspectives for this drug.

}, keywords = {Animals, Contrast Media, Fatty Liver, Female, Gadolinium, Hepatitis, Iron, Liver, Magnetic Resonance Imaging, Mice, Mice, Inbred CBA, Organometallic Compounds, Spectrometry, X-Ray Emission}, issn = {1440-1681}, doi = {10.1111/j.1440-1681.2011.05618.x}, author = {Delfino, Riccarda and Altissimo, Matteo and Menk, Ralf Hendrik and Alberti, Roberto and Klatka, Tomasz and Frizzi, Tommaso and Longoni, Antonio and Salom{\`e}, Murielle and Tromba, Giuliana and Arfelli, Fulvia and Clai, Milan and Vaccari, Lisa and Lorusso, Vito and Tiribelli, Claudio and Pascolo, Lorella} }