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https://www.readbyqxmd.com/read/29774134/an-undifferentiated-carcinoma-at-klatskin-position-with-long-term-complete-remission-after-chemotherapy
#1
Bruno Christian Köhler, Benjamin Goeppert, Nina Waldburger, Kai Schlamp, Peter Sauer, Dirk Jäger, Karl Heinz Weiss, Stephan Macher-Göppinger, Henning Schulze-Bergkamen, Peter Schirmacher, Christoph Springfeld
Background: Neoplasms anatomically adjacent to the bile duct usually derive from malignantly transformed cholangiocytes forming cholangiocarcinoma (CCA). CCAs are divided in extrahepatic (eCCA) and intrahepatic (iCCA) tumors. Patients with irresectable CCAs are treated with systemic chemotherapy and have an unfavorable prognosis with a median survival of about one year. Here, we report a case of an undifferentiated carcinoma in Klatskin-position with long-term remission after systemic chemotherapy...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29774067/estrogen-receptors-orchestrate-cell-growth-and-differentiation-to-facilitate-liver-regeneration
#2
Ta-Lun Kao, Yu-Ping Kuan, Wei-Chung Cheng, Wei-Chun Chang, Long-Bin Jeng, Shuyuan Yeh, Wen-Lung Ma
Background and Aims: Improving liver regeneration (LR) capacity and thereby liver function reserve is a critical bridging strategy for managing liver failure patients. Since estrogen signaling may participate in LR, our aim was to characterize the roles of ERα and ERβ in LR. Methods: LR capacity and estradiol levels following 2/3rd partial hepatectomy (PHx) were compared in ERα-KO or ERβ-KO vs. wildtype mice. The ERα- or ERβ-related transcriptome and interactome were analyzed from regenerating livers, and then bioinformatics was used for pathway discovery and analysis of interactome-transcriptome relationships...
2018: Theranostics
https://www.readbyqxmd.com/read/29758112/novel-and-emerging-therapies-for-cholestatic-liver-diseases
#3
Jordan Goldstein, Cynthia Levy
While bile acids are important for both digestion and signaling, hydrophobic bile acids can be harmful especially when in high concentrations. Mechanisms for protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signaling, among others. By altering or overwhelming these defense mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation...
May 14, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29753567/junctional-adhesion-molecules-jam-b-and-jam-c-promote-autoimmune-mediated-liver-fibrosis-in-mice
#4
Edith Hintermann, Monika Bayer, Clara Benedetta Conti, Sina Fuchs, Michel Fausther, Patrick S Leung, Michel Aurrand-Lions, Richard Taubert, Josef M Pfeilschifter, Mireen Friedrich-Rust, Detlef Schuppan, Jonathan A Dranoff, M Eric Gershwin, Michael P Manns, Beat A Imhof, Urs Christen
Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively...
May 9, 2018: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29720662/de-novo-formation-of-the-biliary-system-by-tgf%C3%AE-mediated-hepatocyte-transdifferentiation
#5
Johanna R Schaub, Kari A Huppert, Simone N T Kurial, Bernadette Y Hsu, Ashley E Cast, Bryan Donnelly, Rebekah A Karns, Feng Chen, Milad Rezvani, Hubert Y Luu, Aras N Mattis, Anne-Laure Rougemont, Philip Rosenthal, Stacey S Huppert, Holger Willenbring
Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche 1 . Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS) 2 ...
May 2, 2018: Nature
https://www.readbyqxmd.com/read/29709678/lysyl-oxidase-like-protein-2-loxl2-modules-barrier-function-in-cholangiocytes-in-cholestasis
#6
Marion J Pollheimer, Silvia Racedo, Amanda Mikels-Vigdal, Derek Marshall, Christopher Bowlus, Carolin Lackner, Tobias Madl, Tom H Karlsen, Johannes R Hov, Susan K Lyman, Joanne Adamkewicz, Victoria Smith, Emmanuel Moreau, Gernot Zollner, Tor Jacob Eide, Tatjana Stojakovic, Hubert Scharnagl, Hans-Jürgen Gruber, Rudolf E Stauber, Michael Trauner, Peter Fickert
BACKGROUND: The lysyl oxidase-like protein 2 (LOXL2) promotes stabilization of the extracellular matrix, chemotaxis, cell growth and cell mobility. We aimed to (i) identify stimuli of LOXL2 in cholangiopathies, (ii) characterize the effects of LOXL2 on biliary epithelial cells' (BECs) barrier function, (iii) compare LOXL2 expression in PSC, PBC, and disease controls, and (iv) to determine LOXL2 expression and cellular sources in 4 mouse models for cholangiopathies. METHODS: Cultured murine BECs were challenged with well-known triggers of cellular senescence, hypoxia, phospholipid-deficient Abcb4-/- mouse bile and chenodeoxycholic acid (CDCA) and investigated for LOXL2, SNAIL1 and E-cadherin expression and transepithelial electrical resistance (TEER) with and without LOX-inhibition...
April 27, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29678444/biliary-epithelium-a-neuroendocrine-compartment-in-cholestatic-liver-disease
#7
REVIEW
Laurent Ehrlich, Marinda Scrushy, Fanyin Meng, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser
Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM) that can lead to ductopenia, cirrhosis, and even malignant transformation. In this review, we examine cholestatic liver diseases characterized by extensive biliary fibrosis such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), polycystic liver disease (PLD), and MDR2-/- and BDL mouse models. Following biliary injury, cholangiocytes, the epithelial cells that line the bile ducts, become reactive and adopt a neuroendocrine phenotype in which they secrete and respond to neurohormones and neuropeptides in an autocrine and paracrine fashion...
April 17, 2018: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/29673755/understanding-liver-regeneration-from-mechanisms-to-regenerative-medicine
#8
REVIEW
Hélène Gilgenkrantz, Alexandra Collin de l'Hortet
Liver regeneration is a complex and unique process. When two-thirds of a mouse liver is removed, the remaining liver recovers its initial weight in approximately 10 days. The understanding of the mechanisms responsible for liver regeneration may help patients needing large liver resections or transplantation and may be applied to the field of regenerative medicine. All differentiated hepatocytes are capable of self-renewal, but different subpopulations of hepatocytes seem to have distinct proliferative abilities...
April 16, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29665133/isolation-of-a-unique-hepatic-stellate-cell-population-expressing-integrin-%C3%AE-8-from-embryonic-mouse-livers
#9
Tomohiro Ogawa, Yuchang Li, Ingrid Lua, Andrea Hartner, Kinji Asahina
BACKGROUND: Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. However, little is known about their phenotype and role in liver development. The aim of this study is to identify specific markers for embryonic HSCs. RESULTS: Using antibodies against ALCAM and PDPN, we separated mesothelial cells (MCs) and HSCs from developing livers and identified integrin α8 (ITGA8) as a marker for embryonic desmin+ HSCs that are preferentially localized near the developing liver surface and α-smooth muscle actin+ perivascular mesenchymal cells around the vein...
April 17, 2018: Developmental Dynamics: An Official Publication of the American Association of Anatomists
https://www.readbyqxmd.com/read/29643975/physiological-hypoxia-enhances-stemness-preservation-proliferation-and-bidifferentiation-of-induced-hepatic-stem-cells
#10
Xiaosong Zhi, Jun Xiong, Mengchao Wang, Hongxia Zhang, Gang Huang, Jian Zhao, Xiaoyuan Zi, Yi-Ping Hu
Induced hepatic stem cells (iHepSCs) have great potential as donors for liver cell therapy due to their self-renewal and bipotential differentiation properties. However, the efficiency of bidifferentiation and repopulation efficiency of iHepSCs is relatively low. Recent evidence shows that physiological hypoxia, a vital factor within stem cell "niche" microenvironment, plays key roles in regulating tissue stem cell biological behaviors including proliferation and differentiation. In this study, we found that physiological hypoxia (10% O2 ) enhanced the stemness properties and promoted the proliferation ability of iHepSCs by accelerating G1/S transition via p53-p21 signaling pathway...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29627454/expression-patterns-of-yes-associated-protein-1-in-the-developing-mouse-liver
#11
Wei Wei, Jeremy Lotto, Pamela A Hoodless
The Hippo signalling pathway regulates many cellular processes, but has been specifically associated with control organ size and tumor growth. Yes-associated protein 1 (YAP1) is a transcriptional cofactor, in the Hippo pathway, that regulates gene expression when localized in the nucleus. Elevated expression of YAP1 in adult mouse liver leads to hepatomegaly and can cause hepatocellular carcinoma; while the loss of function studies reveal its importance in regulating cholangiocyte development. Here, we report the expression of YAP1 in mouse embryonic and postnatal hepatic cells, using AFP-GFP transgenic mice to identify the hepatocyte lineage...
April 5, 2018: Gene Expression Patterns: GEP
https://www.readbyqxmd.com/read/29606616/direct-conversion-of-mouse-fibroblasts-into-cholangiocyte-progenitor-cells
#12
Kyung Tae Lim, Jonghun Kim, Seon In Hwang, Ludi Zhang, Heonjong Han, Dasom Bae, Kee-Pyo Kim, Yi-Ping Hu, Hans R Schöler, Insuk Lee, Lijian Hui, Dong Wook Han
Disorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1β and Foxa3 could directly convert mouse fibroblasts into bipotential hepatic stem cell-like cells, termed iHepSCs. However, the efficiency of converting fibroblasts into iHepSCs is low, and these iHepSCs exhibit extremely low differentiation potential into cholangiocytes, thus hindering the translation of iHepSCs to the clinic...
March 29, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29604222/biliary-atresia-clinical-and-research-challenges-for-the-21-st-century
#13
Jorge A Bezerra, Rebecca G Wells, Cara L Mack, Saul J Karpen, Jay H Hoofnagle, Edward Doo, Ronald J Sokol
Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research...
March 31, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29601088/blocking-h1-h2-histamine-receptors-inhibits-damage-fibrosis-in-mdr2-mice-and-human-cholangiocarcinoma-tumorigenesis
#14
Lindsey Kennedy, Laura Hargrove, Jennifer Demieville, Allen Karstens, Hannah Jones, Sharon DeMorrow, Fanyin Meng, Pietro Invernizzi, Francesca Bernuzzi, Gianfranco Alpini, Steven Smith, Austin Akers, Victoria Meadows, Heather Francis
BACKGROUND: Primary Sclerosing Cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that: (i) histamine (HA) increases biliary hyperplasia via H1/H2 histamine receptors (HRs) and (ii) HA levels increase and mast cells (MCs) infiltrate during PSC and CCA. We aimed to examine the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA. METHODS: Wild-type and Mdr2-/- mice were treated by osmotic minipumps with saline, mepyramine or ranitidine (10mg/kg BW/day) or a combination of mepyramine/ranitidine for 4 wks...
March 30, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29580318/%C3%AE-7-nachr-knockout-mice-decreases-biliary-hyperplasia-and-liver-fibrosis-in-cholestatic-bile-duct-ligated-mice
#15
Laurent Ehrlich, April O'Brien, Chad Hall, Tori White, Lixian Chen, Nan Wu, Julie Venter, Marinda Scrushy, Muhammad Mubarak, Fanyin Meng, David Dostal, Chaodong Wu, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser
α7-nAChR is a nicotinic acetylcholine receptor (specifically expressed on hepatic stellate cells, Kupffer cells, and cholangiocytes) that regulates inflammation and apoptosis in the liver. Thus, targeting α7-nAChR may be therapeutic in biliary diseases. METHODS: Bile-duct ligation (BDL) was performed on wild-type (WT) and α7-nAChR-/- mice. We first evaluated the expression of α7-nAChR by immunohistochemistry (IHC) in liver sections. IHC was also performed to assess intrahepatic bile-duct mass (IBDM), and Sirius Red staining was performed to quantify the amount of collagen deposition...
March 26, 2018: Gene Expression
https://www.readbyqxmd.com/read/29564205/from-gut-feeling-to-objectivity-machine-preservation-of-the-liver-as-a-tool-to-assess-organ-viability
#16
REVIEW
Christopher J E Watson, Ina Jochmans
Purpose of Review: The purpose of this review was to summarise how machine perfusion could contribute to viability assessment of donor livers. Recent Findings: In both hypothermic and normothermic machine perfusion, perfusate transaminase measurement has allowed pretransplant assessment of hepatocellular damage. Hypothermic perfusion permits transplantation of marginal grafts but as yet has not permitted formal viability assessment. Livers undergoing normothermic perfusion have been investigated using parameters similar to those used to evaluate the liver in vivo...
2018: Current Transplantation Reports
https://www.readbyqxmd.com/read/29552372/cellular-crosstalk-during-cholestatic-liver-injury
#17
Joanne Thomson, Laura Hargrove, Lindsey Kennedy, Jennifer Demieville, Heather Francis
The functions of the liver are very diverse. From detoxifying blood to storing glucose in the form of glycogen and producing bile to facilitate fat digestion, the liver is a very active and important organ. The liver is comprised of many varied cell types whose functions are equally diverse. Cholangiocytes line the biliary tree and aid in transporting and adjusting the composition of bile as it travels to the gallbladder. Hepatic stellate cells and portal fibroblasts are located in different areas within the liver architecture, but both contribute to the development of fibrosis upon activation after liver injury...
June 2017: Liver Research
https://www.readbyqxmd.com/read/29550924/role-of-lactoferrin-and-its-receptors-on-biliary-epithelium
#18
Romina Mancinelli, Francesca Olivero, Guido Carpino, Diletta Overi, Luigi Rosa, Maria Stefania Lepanto, Antimo Cutone, Antonio Franchitto, Gianfranco Alpini, Paolo Onori, Piera Valenti, Eugenio Gaudio
Human lactoferrin is an iron-binding glycoprotein present at high concentrations in breast milk and colostrum. It is produced by many exocrine glands and widely distributed in a variety of body fluids. This protein has antimicrobial, immunomodulatory, antioxidant, and anticancer properties. Two important hLf receptors have been identified: LDL receptor related protein (LRP1), a low specificity receptor, and intelectin-1 (ITLN1), a high specificity receptor. No data are present on the role of hLf on the biliary epithelium...
March 17, 2018: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/29545603/notch2-controls-hepatocyte-derived-cholangiocarcinoma-formation-in-mice
#19
Jingxiao Wang, Mingjie Dong, Zhong Xu, Xinhua Song, Shanshan Zhang, Yu Qiao, Li Che, John Gordan, Kaiwen Hu, Yan Liu, Diego F Calvisi, Xin Chen
Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes...
March 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29545201/bromodomain-and-extraterminal-bet-proteins-regulate-hepatocyte-proliferation-in-hepatocyte-driven-liver-regeneration
#20
Jacquelyn O Russell, Sungjin Ko, Harvinder S Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P Monga
Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins such as JQ1 have shown efficacy in preclinical cancer models, including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration...
March 12, 2018: American Journal of Pathology
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