Publications by authors named "Mario Strazzabosco"

136 Publications

New insights on the role of vascular endothelial growth factor in biliary pathophysiology.

JHEP Rep 2021 Jun 4;3(3):100251. Epub 2021 Feb 4.

Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA.

The family of vascular endothelial growth factors (VEGFs) includes 5 members (VEGF-A to -D, and placenta growth factor), which regulate several critical biological processes. VEGF-A exerts a variety of biological effects through high-affinity binding to tyrosine kinase receptors (VEGFR-1, -2 and -3), co-receptors and accessory proteins. In addition to its fundamental function in angiogenesis and endothelial cell biology, VEGF/VEGFR signalling also plays a role in other cell types including epithelial cells. This review provides an overview of VEGF signalling in biliary epithelial cell biology in both normal and pathologic conditions. VEGF/VEGFR-2 signalling stimulates bile duct proliferation in an autocrine and paracrine fashion. VEGF/VEGFR-1/VEGFR-2 and angiopoietins are involved at different stages of biliary development. In certain conditions, cholangiocytes maintain the ability to secrete VEGF-A, and to express a functional VEGFR-2 receptor. For example, in polycystic liver disease, VEGF secreted by cystic cells stimulates cyst growth and vascular remodelling through a PKA/RAS/ERK/HIF1α-dependent mechanism, unveiling a new level of complexity in VEFG/VEGFR-2 regulation in epithelial cells. VEGF/VEGFR-2 signalling is also reactivated during the liver repair process. In this context, pro-angiogenic factors mediate the interactions between epithelial, mesenchymal and inflammatory cells. This process takes place during the wound healing response, however, in chronic biliary diseases, it may lead to pathological neo-angiogenesis, a condition strictly linked with fibrosis progression, the development of cirrhosis and related complications, and cholangiocarcinoma. Novel observations indicate that in cholangiocarcinoma, VEGF is a determinant of lymphangiogenesis and of the immune response to the tumour. Better insights into the role of VEGF signalling in biliary pathophysiology might help in the search for effective therapeutic strategies.
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http://dx.doi.org/10.1016/j.jhepr.2021.100251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189933PMC
June 2021

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

J Hepatol 2021 May 12. Epub 2021 May 12.

Section of Digestive Diseases, Department of internal Medicine, Yale School of Medicine, New Haven, CT 06520, U.S.A.. Electronic address:

Background And Aims: COVID-19 is associated with liver injury and elevated IL-6. We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19.

Methods: Coagulopathy, endotheliopathy, and ALT were retrospectively analyzed in a subset (n=68), followed by a larger cohort(n=3,780) of COVID-19 patients. Liver histology from 43 COVID-19 patients was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.

Results: Factor VIII, fibrinogen, D-dimer, vWF activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in COVID-19 patients with liver injury (elevated ALT). IL-6 positively correlated with vWF antigen(P=0.02), factor VIII activity(P=0.02), and D-dimer(P<0.0001). On liver histology, COVID-19 patients with elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet(P<0.0001) and vWF(P<0.01) staining, and IL-6 levels positively correlated with vWF staining(P<0.01). IL-6 trans-signaling leads to increased expression of procoagulant (Factor VIII, vWF) and proinflammatory factors, increased cell surface vWF(P<0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble gp130 (IL-6 trans-signaling inhibitor), JAK inhibitor Ruxolitinib, and STAT1/3 siRNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.

Conclusion: COVID-19 is associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury.

Lay Summary: Patients with SARS-CoV-2 infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in COVID-19 patients. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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http://dx.doi.org/10.1016/j.jhep.2021.04.050DOI Listing
May 2021

Fibrocystic liver disease: novel concepts and translational perspectives.

Transl Gastroenterol Hepatol 2021 5;6:26. Epub 2021 Apr 5.

Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

Fibrocystic liver diseases (FLDs) comprise a heterogeneous group of rare diseases of the biliary tree, having in common an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes (and therefore grouped among the "ciliopathies"). The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts [congenital hepatic fibrosis (CHF)], to the larger intrahepatic bile ducts [Caroli disease (CD), or Caroli syndrome (CS), when CD coexists with CHF], leading to biliary microhamartomas and segmental bile duct dilations. Biliary changes are accompanied by progressive deposition of abundant peribiliary fibrosis. Peribiliary fibrosis and biliary cysts are the fundamental lesions of FLDs and are responsible for the main clinical manifestations, such as portal hypertension, recurrent cholangitis, cholestasis, sepsis and eventually cholangiocarcinoma. Furthermore, FLDs often associate with a spectrum of disorders affecting primarily the kidney. Among them, the autosomal recessive polycystic kidney disease (ARPKD) is the most frequent, and the renal function impairment is central in disease progression. CHF, CD/CS, and ARPKD are caused by a number of mutations in polycystic kidney hepatic disease 1 (), a gene that encodes for fibrocystin/polyductin, a protein of unclear function, but supposedly involved in planar cell polarity and other fundamental cell functions. Targeted medical therapy is not available yet and thus the current treatment aims at controlling the complications. Interventional radiology or surgical treatments, including liver transplantation, are used in selected cases.
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http://dx.doi.org/10.21037/tgh-2020-04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838530PMC
April 2021

Rare and undiagnosed liver diseases: challenges and opportunities.

Transl Gastroenterol Hepatol 2021 5;6:18. Epub 2021 Apr 5.

Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.21037/tgh-2020-05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838528PMC
April 2021

Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic.

Expert Opin Investig Drugs 2021 Apr 23;30(4):377-388. Epub 2021 Feb 23.

Department of Molecular Medicine (DMM), University of Padua, Padua. Italy.

Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, 'Mesenchymal', 'Proliferation', 'Immune', 'Metabolic'. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified. We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA. eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.
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http://dx.doi.org/10.1080/13543784.2021.1880564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194059PMC
April 2021

Thermal ablation alone vs thermal ablation combined with transarterial chemoembolization for patients with small (<3 cm) hepatocellular carcinoma.

Clin Imaging 2021 Aug 11;76:123-129. Epub 2021 Feb 11.

Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, United States of America; Medical Oncology, Yale School of Medicine, New Haven, CT, United States of America. Electronic address:

Purpose: Thermal ablation (TA) and transarterial chemoembolization (TACE) may be used alone or in combination (TACE+TA) for the treatment of hepatocellular carcinoma (HCC). The aim of our study was to compare the time to tumor progression (TTP) and overall survival (OS) for patients who received TA alone or TACE+TA for HCC tumors under 3 cm.

Materials And Methods: This HIPAA-compliant IRB-approved retrospective analysis included 85 therapy-naïve patients from 2010 to 2018 (63 males, 22 females, mean age 62.4 ± 8.5 years) who underwent either TA alone (n = 64) or TA in combination with drug-eluting beads (DEB)-TACE (n = 18) or Lipiodol-TACE (n = 3) for locoregional therapy of early stage HCC with maximum tumor diameter under 3 cm. Kaplan-Meier analysis was performed using the log-rank test to assess TTP and OS.

Results: All TA and TACE+TA treatments included were technically successful. TTP was 23.0 months in the TA group and 22.0 months in the TACE+TA group. There was no statistically significant difference in TTP (p = 0.64). Median OS was 69.7 months in the TA group and 64.6 months in the TACE+TA group. There was no statistically significant difference in OS (p = 0.14). The treatment cohorts had differences in AFP levels (p = 0.03) and BCLC stage (p = 0.047). Complication rates between patient groups were similar (p = 0.61).

Conclusion: For patients with HCC under 3 cm, TA alone and TACE+TA have similar outcomes in terms of TTP and OS, suggesting that TACE+TA may not be needed for these tumors unless warranted by tumor location or other technical consideration.
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http://dx.doi.org/10.1016/j.clinimag.2021.01.043DOI Listing
August 2021

Intrahepatic cholangiocarcinoma: Morpho-molecular pathology, tumor reactive microenvironment, and malignant progression.

Adv Cancer Res 2021 9;149:321-387. Epub 2020 Dec 9.

Department of Molecular Medicine, University of Padova, Padova, Italy.

Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare, but highly lethal and biologically complex primary biliary epithelial cancer arising within liver. After hepatocellular carcinoma, iCCA is the second most common primary liver cancer, accounting for approximately 10-20% of all primary hepatic malignancies. Over the last 10-20 years, iCCA has become the focus of increasing concern largely due to its rising incidence and high mortality rates in various parts of the world, including the United States. The challenges posed by iCCA are daunting and despite recent progress in the standard of care and management options for iCCA, the prognosis for this cancer continues to be dismal. In an effort to provide a framework for advancing our understanding of iCCA malignant aggressiveness and therapy resistance, this review will highlight key etiological, biological, molecular, and microenvironmental factors hindering more effective management of this hepatobiliary cancer. Particular focus will be on critically reviewing the cell origins and morpho-molecular heterogeneity of iCCAs, providing mechanistic insights into high risk fibroinflammatory cholangiopathies associated with iCCA development, and notably discussing the deleterious role played by the tumor reactive desmoplastic stroma in regulating iCCA malignant progression, lymphangiogenesis, and tumor immunobiology.
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http://dx.doi.org/10.1016/bs.acr.2020.10.005DOI Listing
December 2020

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

J Hepatol 2021 Apr 13;74(4):919-930. Epub 2020 Nov 13.

Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8 T cells that either had OT-1 or lacked IL-17A/F (OT-1). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro.

Results: Transfer of OVA-specific OT-1 cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1 T cells. OT-1 T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1 CD8 T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1 T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8 T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1 T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes.

Conclusions: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8 T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis.

Lay Summary: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
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http://dx.doi.org/10.1016/j.jhep.2020.10.035DOI Listing
April 2021

Reliable prediction of survival in advanced-stage hepatocellular carcinoma treated with sorafenib: comparing 1D and 3D quantitative tumor response criteria on MRI.

Eur Radiol 2021 May 30;31(5):2737-2746. Epub 2020 Oct 30.

Division of Medical Oncology, Department of Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

Objectives: To compare 1D and 3D quantitative tumor response criteria applied to DCE-MRI in patients with advanced-stage HCC undergoing sorafenib therapy to predict overall survival (OS) early during treatment.

Methods: This retrospective analysis included 29 patients with advanced-stage HCC who received sorafenib for at least 60 days. All patients underwent baseline and follow-up DCE-MRI at 81.5 ± 29.3 days (range 35-140 days). Response to sorafenib was assessed in 46 target lesions using 1D criteria RECIST1.1 and mRECIST. In addition, a segmentation-based 3D quantification of absolute enhancing lesion volume (vqEASL) was performed on the arterial phase MRI, and the enhancement fraction of total tumor volume (%qEASL) was calculated. Accordingly, patients were stratified into groups of disease control (DC) and disease progression (DP). OS was evaluated using Kaplan-Meier curves with log-rank test and Cox proportional hazards regression model.

Results: The Kaplan-Meier analysis revealed that stratification of patients in DC vs. DP according to mRECIST (p = 0.0371) and vqEASL (p = 0.0118) successfully captured response and stratified OS, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). Multivariable Cox regression identified tumor progression according to mRECIST and qEASL as independent risk factors of decreased OS (p = 0.039 and p = 0.006, respectively).

Conclusions: The study identified enhancement-based vqEASL and mRECIST as reliable predictors of patient survival early after initiation of treatment with sorafenib. This data provides evidence for potential advantages 3D quantitative, enhancement-based tumor response analysis over conventional techniques regarding early identification of treatment success or failure.

Key Points: • Tumor response criteria on MRI can be used to predict survival benefit of sorafenib therapy in patients with advanced HCC. • Stratification into DC and DP using mRECIST and vqEASL significantly correlates with OS (p = 0.0371 and p = 0.0118, respectively) early after initiation of sorafenib, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). • mRECIST (HR = 0.325, p = 0.039. 95%CI 0.112-0.946) and qEASL (HR = 0.183, p = 0.006, 95%CI 0.055-0.613) are independent prognostic factors of survival in HCC patients undergoing sorafenib therapy.
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http://dx.doi.org/10.1007/s00330-020-07381-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043967PMC
May 2021

Health related quality of life in chronic liver diseases.

Liver Int 2020 11;40(11):2630-2642

Research Centre on Public Health (CESP), University of Milan-Bicocca, Milan, Italy.

Background & Aims: The impact of chronic liver diseases (CLDs) on health-related quality of life (HRQoL) is relevant to understand the burden of these conditions and inform decision-making processes related to their care. Studies simultaneously comparing the HRQoL of patients affected by the major CLDs to that of the general population are still lacking and are the subject of this study.

Methods: Using the EQ-5D-3L questionnaire, we analysed and compared HRQoL data from 2962 Italian patients affected by CLDs and forming a representative sample of the general Italian population (6800 individuals). Exploratory analyses were conducted to investigate the effects of each CLD on HRQoL, using the general population as reference and adjusting for possible confounders.

Results: Patients with CLDs (HBV, HCV, PSC, PBC, AIH, NAFLD/NASH) in the chronic hepatitis stage and with compensated cirrhosis (CC) showed HRQoL similar to the general population. However, AIH were more likely to report problems in self-care and lower EQ-5D VAS score, while NAFLD/NASH and HCV showed an increased risk of anxiety/depression. On the other hand, with progression to more advanced stages of liver disease (DC or HCC), HRQoL decreased significantly with higher risk of reporting problems in the physical domains, and significant reductions in the VAS and utility index scores.

Conclusions: Different subtypes of CLD affected different QoL domains. This study therefore provides a real estimate of the impact of CLDs on patients' HRQoL, and represents a much needed tool to inform decision-making while assessing the effectiveness and cost-effectiveness of the care of these patients.
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http://dx.doi.org/10.1111/liv.14647DOI Listing
November 2020

Value-based medicine, a compass to guide healthcare decisions in the COVID-19 aftermath.

Liver Int 2020 09;40(9):2076-2078

Liver Center and Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

The ongoing COVID-19 pandemics has claimed hundreds of thousands of lives among the elderly, the patients with chronic conditions and among underserved communities and people in social distress. In addition, the measures that succeeded in containing the epidemic created a profound economic crisis, which real dimension is still unclear. It is clear, however, that most healthcare systems were unprepared. Years of cost containments had eroded the ability of the healthcare sector to cope with the surge in cases. This editorial contends that rebuilding the healthcare systems will require forward thinking, a data-driven approach and avoidance of reactive decision making. The editorial proposes the Value Based Medicine approach as a way to avoid the errors of the past and to align decision making in healthcare with patient health and quality of life (Value). This is an approach that is gaining traction in several systems. It needs a built-in capability to collect and analyse outcome and costing data. Today the necessary informatic and computational capabilities are widely available.
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http://dx.doi.org/10.1111/liv.14605DOI Listing
September 2020

Cholangiocarcinoma 2020: the next horizon in mechanisms and management.

Nat Rev Gastroenterol Hepatol 2020 09 30;17(9):557-588. Epub 2020 Jun 30.

National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), San Sebastian, Spain.

Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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http://dx.doi.org/10.1038/s41575-020-0310-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447603PMC
September 2020

The Tumor Microenvironment in Cholangiocarcinoma Progression.

Hepatology 2021 Jan 6;73 Suppl 1:75-85. Epub 2020 Nov 6.

Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1002/hep.31410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714713PMC
January 2021

Surveillance for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease: Universal or Selective?

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, 16132 Genoa, Italy.

Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the sixth most common cancer, the fourth leading cause of cancer-related deaths worldwide, and accounts globally for about 800,000 deaths/year. Early detection of HCC is of pivotal importance as it is associated with improved survival and the ability to apply curative treatments. Chronic liver diseases, and in particular cirrhosis, are the main risk factors for HCC, but the etiology of liver disease is rapidly changing due to improvements in the prevention and treatment of HBV (Hepatitis B virus) and HCV (Hepatitis C virus) infections and to the rising incidence of the metabolic syndrome, of which non-alcoholic fatty liver (NAFLD) is a manifestation. NAFLD is now a recognized and rapidly increasing cause of cirrhosis and HCC. Indeed, the most recent guidelines for NAFLD management recommend screening for HCC in patients with established cirrhosis. Screening in NAFLD patients without cirrhosis is not recommended; however, the prevalence of HCC in this group of NAFLD patients has been reported to be as high as 38%, a proportion significantly higher than the one observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Unfortunately, solid data regarding the risk stratification of patients with non-cirrhotic NAFLD who might best benefit from HCC surveillance are scarce, and specific recommendations in this field are urgently needed due to the increasing NAFLD epidemic, at least in Western countries. To further complicate matters, liver ultrasonography, which represents the current standard for HCC surveillance, has a decreased diagnostic accuracy in patients with NAFLD, and therefore disease-specific surveillance tools will be required for the early identification of HCC in this population. In this review, we summarize the most recent evidence on the epidemiology and risk factors for HCC in patients with NAFLD, with and without cirrhosis, and the evidence supporting surveillance for early HCC detection in these patients, reviewing the potential limitations of currently recommended surveillance strategies, and assessing data on the accuracy of potential new screening tools. At this stage it is difficult to propose general recommendations, and best clinical judgement should be exercised, based on the profile of risk factors specific to each patient.
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http://dx.doi.org/10.3390/cancers12061422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352281PMC
May 2020

The Emerging Role of Macrophages in Chronic Cholangiopathies Featuring Biliary Fibrosis: An Attractive Therapeutic Target for Orphan Diseases.

Front Med (Lausanne) 2020 21;7:115. Epub 2020 Apr 21.

Department of Molecular Medicine, University of Padua, Padua, Italy.

Cholangiopathies are a heterogeneous group of chronic liver diseases caused by different types of injury targeting the biliary epithelium, such as genetic defects and immune-mediated attacks. Notably, most cholangiopathies are orphan, thereby representing one of the major gaps in knowledge of the modern hepatology. A typical hallmark of disease progression in cholangiopathies is portal scarring, and thus development of effective therapeutic approaches would aim to hinder cellular and molecular mechanisms underpinning biliary fibrogenesis. Recent lines of evidence indicate that macrophages, rather than more conventional cell effectors of liver fibrosis such as hepatic stellate cells and portal fibroblasts, are actively involved in the earliest stages of biliary fibrogenesis by exchanging a multitude of cues with cholangiocytes, which promote their recruitment from the circulating compartment owing to a senescent or an immature epithelial phenotype. Two cholangiopathies, namely primary sclerosing cholangitis and congenital hepatic fibrosis, are paradigmatic of this mechanism. This review summarizes current understandings of the cytokine and extracellular vesicles-mediated communications between cholangiocytes and macrophages typically occurring in the two cholangiopathies to unveil potential novel targets for the treatment of biliary fibrosis.
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http://dx.doi.org/10.3389/fmed.2020.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186419PMC
April 2020

Liver Matrix in Benign and Malignant Biliary Tract Disease.

Semin Liver Dis 2020 08 11;40(3):282-297. Epub 2020 Mar 11.

Division of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Michigan.

The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the "desmoplastic matrix" of cholangiocarcinoma along with their pro-oncogenic effects.
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http://dx.doi.org/10.1055/s-0040-1705109DOI Listing
August 2020

Clinical outcome indicators in chronic hepatitis B and C: A primer for value-based medicine in hepatology.

Liver Int 2020 01 12;40(1):60-73. Epub 2019 Nov 12.

International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.

Background & Aims: Chronic liver diseases (CLDs) are major health problems that require complex and costly treatments. Liver-specific clinical outcome indicators (COIs) able to assist both clinicians and administrators in improving the value of care are presently lacking. The Value-Based Medicine in Hepatology (VBMH) study aims to fill this gap, devising and testing a set of COIs for CLD, that could be easily collected during clinical practice. Here we report the COIs generated and recorded for patients with HBV or HCV infection at different stages of the disease.

Methods/results: In the first phase of VBMH study, COIs were identified, based on current international guidelines and literature, using a modified Delphi method and a RAND 9-point appropriateness scale. In the second phase, COIs were tested in an observational, longitudinal, prospective, multicentre study based in Lombardy, Italy. Eighteen COIs were identified for HBV and HCV patients. Patients with CLD secondary to HBV (547) or HCV (1391) were enrolled over an 18-month period and followed for a median of 4 years. The estimation of the proposed COIs was feasible in the real-word clinical practice and COI values compared well with literature data. Further, the COIs were able to capture the impact of new effective treatments like direct-acting antivirals (DAAs) in the clinical practice.

Conclusions: The COIs efficiently measured clinical outcomes at different stages of CLDs. While specific clinical practice settings and related healthcare systems may modify their implementation, these indicators will represent an important component of the tools for a value-based approach in hepatology and will positively affect care delivery.
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http://dx.doi.org/10.1111/liv.14285DOI Listing
January 2020

The challenges of primary biliary cholangitis: What is new and what needs to be done.

J Autoimmun 2019 12 20;105:102328. Epub 2019 Sep 20.

Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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http://dx.doi.org/10.1016/j.jaut.2019.102328DOI Listing
December 2019

Modeling of implementation of the new Organ Procurement and Transplantation Network/United Network for Organ Sharing policy for patients with hepatocellular carcinoma.

J Comp Eff Res 2019 09 12;8(12):993-1002. Epub 2019 Sep 12.

Section of Interventional Radiology, Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06510, USA.

To simulate effects of the new Organ Procurement and Transplantation Network/United Network for Organ Sharing policy on the patients' characteristics and post orthotopic liver transplantation (OLT) outcome. The United Network for Organ Sharing database was used to identify patients with hepatocellular carcinoma who were listed for OLT 2002-2014. All patients (actual group) versus simulated group with new 6-month delay in assigning Model for End-Stage Liver Disease score exception and Model for End-Stage Liver Disease exception cap of 34 were compared. With the new policy, 7,745 (30.4%) of the transplanted patients would have received a delayed transplantation or not be transplanted. The simulated group also showed significantly higher mean overall survival after OLT (p < 0.002) and received more locoreginal treatments (p < 0.001).
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http://dx.doi.org/10.2217/cer-2019-0076DOI Listing
September 2019

Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.

Nat Rev Gastroenterol Hepatol 2019 08;16(8):497-511

Liver Center, Department of Medicine, Yale University, New Haven, CT, USA.

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.
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http://dx.doi.org/10.1038/s41575-019-0156-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661007PMC
August 2019

Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota.

Cell Mol Gastroenterol Hepatol 2019 7;8(2):197-207. Epub 2019 May 7.

Section of Digestive Diseases, Yale Liver Center, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.

Cystic fibrosis (CF) is a monogenic disease caused by mutation of Cftr. CF-associated liver disease (CFLD) is a common nonpulmonary cause of mortality in CF and accounts for approximately 2.5%-5% of overall CF mortality. The peak of the disease is in the pediatric population, but a second wave of liver disease in CF adults has been reported in the past decade in association with an increase in the life expectancy of these patients. New drugs are available to correct the basic defect in CF but their efficacy in CFLD is not known. The cystic fibrosis transmembrane conductance regulator, expressed in the apical membrane of cholangiocytes, is a major determinant for bile secretion and CFLD classically has been considered a channelopathy. However, the recent findings of the cystic fibrosis transmembrane conductance regulator as a regulator of epithelial innate immunity and the possible influence of the intestinal disease with an altered microbiota on the liver complication have opened new mechanistic insights on the pathogenesis of CFLD. This review provides an overview of the current understanding of the pathophysiology of the disease and discusses a potential target for intervention.
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http://dx.doi.org/10.1016/j.jcmgh.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664222PMC
July 2020

The tumour microenvironment and immune milieu of cholangiocarcinoma.

Liver Int 2019 05;39 Suppl 1:63-78

Liver Center and Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut.

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.
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http://dx.doi.org/10.1111/liv.14098DOI Listing
May 2019

Cholangiocyte pathobiology.

Nat Rev Gastroenterol Hepatol 2019 05;16(5):269-281

Division of Gastroenterology and Hepatology, Mayo School of Medicine and Science, Mayo Clinic, Rochester, MN, USA.

Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.
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http://dx.doi.org/10.1038/s41575-019-0125-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563606PMC
May 2019

Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma.

J Hepatol 2019 04 14;70(4):700-709. Epub 2018 Dec 14.

Department of Molecular Medicine, University of Padua, Padova, Italy; International Center for Digestive Health (ICDH), University of Milan-Bicocca, Milan, Italy; Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA. Electronic address:

Background & Aims: In cholangiocarcinoma, early metastatic spread via lymphatic vessels often precludes curative therapies. Cholangiocarcinoma invasiveness is fostered by an extensive stromal reaction, enriched in cancer-associated fibroblasts (CAFs) and lymphatic endothelial cells (LECs). Cholangiocarcinoma cells recruit and activate CAFs by secreting PDGF-D. Herein, we investigated the role of PDGF-D and liver myofibroblasts in promoting lymphangiogenesis in cholangiocarcinoma.

Methods: Human cholangiocarcinoma specimens were immunostained for podoplanin (LEC marker), α-SMA (CAF marker), VEGF-A, VEGF-C, and their cognate receptors (VEGFR2, VEGFR3). VEGF-A and VEGF-C secretion was evaluated in human fibroblasts obtained from primary sclerosing cholangitis explants. Using human LECs incubated with conditioned medium from PDGF-D-stimulated fibroblasts we assessed migration, 3D vascular assembly, transendothelial electric resistance and transendothelial migration of cholangiocarcinoma cells (EGI-1). We then studied the effects of selective CAF depletion induced by the BH3 mimetic navitoclax on LEC density and lymph node metastases in vivo.

Results: In cholangiocarcinoma specimens, CAFs and LECs were closely adjacent. CAFs expressed VEGF-A and VEGF-C, while LECs expressed VEGFR2 and VEGFR3. Upon PDGF-D stimulation, fibroblasts secreted increased levels of VEGF-C and VEGF-A. Fibroblasts, stimulated by PDGF-D induced LEC recruitment and 3D assembly, increased LEC monolayer permeability, and promoted transendothelial EGI-1 migration. These effects were all suppressed by the PDGFRβ inhibitor, imatinib. In the rat model of cholangiocarcinoma, navitoclax-induced CAF depletion, markedly reduced lymphatic vascularization and reduced lymph node metastases.

Conclusion: PDGF-D stimulates VEGF-C and VEGF-A production by fibroblasts, resulting in expansion of the lymphatic vasculature and tumor cell intravasation. This critical process in the early metastasis of cholangiocarcinoma may be blocked by inducing CAF apoptosis or by inhibiting the PDGF-D-induced axis.

Lay Summary: Cholangiocarcinoma is a highly malignant cancer affecting the biliary tree, which is characterized by a rich stromal reaction involving a dense population of cancer-associated fibroblasts that promote early metastatic spread. Herein, we show that cholangiocarcinoma-derived PDGF-D stimulates fibroblasts to secrete vascular growth factors. Thus, targeting fibroblasts or PDGF-D-induced signals may represent an effective tool to block tumor-associated lymphangiogenesis and reduce the invasiveness of cholangiocarcinoma.
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http://dx.doi.org/10.1016/j.jhep.2018.12.004DOI Listing
April 2019

Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies.

Int J Mol Sci 2018 Dec 4;19(12). Epub 2018 Dec 4.

School of Medicine and Surgery, University of Milan-Bicocca, Via Cadore 48, 20900 Monza, Italy.

The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/β-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFβ, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli's disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development.
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http://dx.doi.org/10.3390/ijms19123875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321547PMC
December 2018

Diagnostic Value of Quantitative Perfusion Computed Tomography Technique in the Assessment of Tumor Response to Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

J Comput Assist Tomogr 2019 Mar/Apr;43(2):206-213

Aim: The aim of this study was to assess the role of dynamic contrast-enhanced perfusion computed tomography (pCT) imaging in the early detection of blood flow changes related to antiangiogenic treatment with sorafenib, in patients with advanced hepatocellular carcinoma (HCC), being the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria the standard of reference.

Methods: Between 2012 and 2016, 43 cirrhotic patients (male, n = 39; female, n = 4) with biopsy-proven multifocal HCC underwent multi-detector-row computed tomography, and pCT examinations were performed before and every 2 months after sorafenib administration. Perfusion CT technique is based on the acquisition of 16 dynamic slices/scan per 40 scans, performed on a 256-slice multi-detector-row computed tomography scanner, after intravenous bolus injection of 50 mL of iodinated contrast agent (350 mg I/mL) at a flow rate of 5 mL/s. According to mRECIST, patients were stratified into complete (CR) or partial response (PR) and stable (SD) or progressive disease (PD). The following pCT parameters were calculated: hepatic perfusion (mL/s per 100 g), time to peak (seconds), arterial perfusion (mL/s), and hepatic perfusion index (%). Perfusion CT values at baseline and first follow-up were reported for all mRECIST groups and then compared between the nonprogressor (CR, PR, SD) and progressor groups (PD).

Results: Most pCT values were significantly higher (P < 0.01) between baseline and follow-up in the CR and PR groups, whereas nonsignificant differences were found among SD patients, and a nonsignificant trend (P > 0.05) toward increase was observed among PD patients. Moreover, pCT values were significantly higher (P = 0.05) at baseline in the nonprogressor group compared with the progressor.

Conclusion: Preliminary results suggest that pCT adds quantitative data of vascularization, thus demonstrating its usefulness in the assessment of therapeutic response to sorafenib in advanced HCC, in line with mRECIST criteria, offering 1-step information on tissue cellularity and vascularization.
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http://dx.doi.org/10.1097/RCT.0000000000000807DOI Listing
April 2019

Animal models of cholestasis: An update on inflammatory cholangiopathies.

Biochim Biophys Acta Mol Basis Dis 2019 05 11;1865(5):954-964. Epub 2018 Aug 11.

Department of Molecular Medicine, University of Padua, Padua, Italy; Section of Digestive Disease, Liver Center, Yale University, Yale, USA. Electronic address:

Cholestasis is a frequent clinical condition initiating or complicating chronic liver diseases, particularly cholangiopathies, where the biliary epithelium is the primary target of the pathogenetic sequence. Until a few decades ago, understanding of cholestasis relied mostly on the experimental model of bile duct ligation in rodents. However, a simple model of biliary obstruction cannot reproduce the complex mechanisms and networks leading to cholestasis in cholangiopathies. These networks are underpinned by an intricate dysregulation of pro-inflammatory and pro-fibrotic signals involving besides cholangiocytes, multiple cell elements of both innate and adaptive immunity. Therefore, in the last years, a wide range of animal models of biliary injury have been developed, mostly in mice, following three main approaches, chemical induction, immunization and genetic manipulation. In this review, we will give an update of the animal models of the two main cholangiopathies, primary sclerosing cholangitis and primary biliary cholangitis, which have provided us with the most relevant insights into the pathogenesis of these still controversial diseases.
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http://dx.doi.org/10.1016/j.bbadis.2018.07.025DOI Listing
May 2019

Valproic Acid Inhibits Proliferation and Reduces Invasiveness in Glioma Stem Cells Through Wnt/β Catenin Signalling Activation.

Genes (Basel) 2018 Oct 26;9(11). Epub 2018 Oct 26.

School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy.

Glioblastoma is the most common malignant brain tumour in adults. The failure of current therapies can be ascribed to glioma stem cells (GSCs), which can rapidly repopulate the tumour following the initial treatment. The study of histone deacetylase inhibitors, such as valproic acid (VPA), is becoming an attractive field in cancer research. However, the exact mechanisms underlying its anti-cancer effect remain to be elucidated due to its pleiotropic effects on several cell-signalling pathways. Ingenuity Pathway Analysis (IPA) bioinformatics analysis was performed on genome-wide data regarding GSCs methylome to identify the signalling pathways mainly affected by methylation changes induced by VPA. Real time PCR and luciferase reporter assay were used to better investigate VPA effects on Wnt/β-catenin signalling pathway. VPA effect on GSC proliferation was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and Trypan blue assays. Finally, VPA impact on GSC motility was demonstrated by Boyden chamber assay and further confirmed evaluating the expression levels or localisation, through western blot or immunofluorescence, of Twist1, Snail1, E-Cadherin and N-Cadherin. The bioinformatics analyses performed on GSCs methylome highlighted that Wnt/β-catenin signalling was affected by the methylation changes induced by VPA, which could influence its activation status. In particular, we pointed out a general activation of this pathway after VPA exposure, which was accompanied by an inhibitory potential on GSCs proliferation. Finally, we also proved VPA's ability to inhibit GSCs invasion through Snail1 and Twist1 downregulation and E-Cadherin relocalisation. VPA treatment may represent a new, interesting therapeutic approach to affect GSC proliferation and motility, but further investigations are certainly needed.
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http://dx.doi.org/10.3390/genes9110522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267016PMC
October 2018

Liver diseases in the dish: iPSC and organoids as a new approach to modeling liver diseases.

Biochim Biophys Acta Mol Basis Dis 2019 05 5;1865(5):920-928. Epub 2018 Sep 5.

Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, (USA). Electronic address:

Liver diseases negatively impact the quality of life and survival of patients, and often require liver transplantation in cases that progress to organ failure. Understanding the cellular and molecular mechanisms of liver development and pathogenesis has been a challenging task, in part for the lack of adequate cellular models directly relevant to the human diseases. Recent technological advances in the stem cell field have shown the potentiality of induced pluripotent stem cells (iPSC) and liver organoids as the next generation tool to model in vitro liver diseases. Hepatocyte-like cells and cholangiocyte are currently being generated from skin fibroblasts and mononuclear blood cells reprogrammed into iPSC and have been successfully used for disease modeling, drug testing and gene editing, with the hope to be able to find application also in regenerative medicine. Protocols to generate other liver cell types are still under development, but the field is advancing rapidly. On the other end, liver cells can now be isolated from liver specimens (liver explants or liver biopsies) and cultured in specific conditions to form polarized 3D organoids. The purpose of this review is to summarize all these recent technological advances and their potential applications but also to analyze the current issues to be addressed before the technology can reach its full potential.
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http://dx.doi.org/10.1016/j.bbadis.2018.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658095PMC
May 2019