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Therapeutic Use of Viruses:Newcastle Disease Virus HK84 Oncolytic Treatment for Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 783-785页

作者： Leonardo Baiocchi Heather Francis gianfranco alpini Unit of Hepatology Tor Vergata UniversityRomeItaly Division of Gastroenterology and Hepatology Department of MedicineIndiana University School of MedicineIndianapolisINUSA Research Richard L.Roudebush VA Medical CenterIndianapolisINUSA

Hepatocellular carcinoma(HCC)is the most frequent primary liver tumor worldwide and,despite regional therapeutic and diagnostic differences,it stands among the three most lethal cancers found in *** or ablative treatments,together with liver transplant,are the most successful clinical approaches,frequently ensuring complete HCC healing and the best survival ***,curative techniques are applicable only in patients at early stages of the disease(limits:one nodule≤5 cm in diameter or not more than three nodules all less than 3 cm in diameter).1 A significant percentage of HCC patients(≥50%)have a more advanced stage at diagnosis and must rely on less effective treatment or palliative care,thus signifying the need for alternative systemic ***,a tyrosine kinase inhibitor(TKI)was the first effective HCC drug treatment discovered after negative results were obtained with canonical cytotoxic *** 2018 lenvatinib,another TKI,was approved in the USA as a first line treatment for *** immunotherapy combining the checkpoint inhibitor,atezolizumab with the VEGF-antibody bevacizumab,has improved survival rates compared with previous TKI-based monotherapies.2 Despite treatment improvements,1-year survival is attained by only two-thirds of patients,thus prompting investigation of more effective therapies for advanced stage HCC.

关键词： Carcinoma healing diagnosis

Role of the melatonin/menin signaling in the regulation of cholangiocarcinoma growth

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Cancer Biology & Medicine 2018年第S01期15卷 3-4页

作者： Shannon Glaser gianfranco alpini Central Texas Veterans Health Care System Baylor Scott&White and Texas A&M UniversityTempleTexasUSA

Objective:There is decreased expression of arylalkylamine N-acetyltransferase(the rate-limiting enzyme regulating melatonin synthesis)and the clock gene,Per1 and increased expression of the MT1 melatonin receptor subtype in cholangiocarcinoma(CCA).This study tested the hypothesis that the inhibitory effects of the melatonin/MT1/Per1 axis on CCA growth are mediated by inhibition of miR-24.

关键词： Role melatonin regulation

Functional roles of gut bacteria imbalance in cholangiopathies

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Liver Research 2019年第1期3卷 40-45页

作者： Keisaku Sato Fanyin Meng Giammarco Fava Shannon Glaser gianfranco alpini Division of Research Central Texas Veterans Health Care SystemTempleTXUSA Baylor Scott&White Digestive Disease Research Center Baylor Scott&White Health CareTempleTXUSA Department of Medical Physiology Texas A&M University College of MedicineTempleTXUSA Ospedali Riuniti di Ancona AnconaItaly

Cholangiopathies are caused by bile duct damage or inflammation followed by cholestasis leading to liver *** duct epithelial cells,cholangiocytes,are a primary target for *** reaction is often observed in cholangiopathies and the proliferation of cholangiocytes is associated with ductular reaction and liver *** evidence suggests that patients with chol-angiopathies have different gut bacterial profiles from healthy individuals,indicating the association between gut microbiota and *** acids are produced by hepatocytes and modified by gut *** acids regulate cholangiocyte proliferation but effects vary depending on the type of bile *** studies suggest that therapies targeting gut bacteria,such as antibiotics administration and gut bacteria depletion or therapies using gut bacteria-associated bile acids,such as ursodeoxycholic acid(UDCA)administration,may be useful for treatments of cholangiopathies,although data are contro-versial depending on animal models or *** review summarizes current understandings of functional roles of gut bacterial imbalance and strategies for treatments of cholangiopathies targeting gut bacteria.

关键词： Cholangiopathies Bile acids Gut bacteria Cholangiocytes Cholestasis Inflammation

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis

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Journal of Clinical and Translational Hepatology 2023年第4期11卷 949-957页

作者： Abigail Medford Jonathan Childs Ashleigh Little Sanjukta Chakraborty Leonardo Baiocchi gianfranco alpini Shannon Glaser Department of Medical Physiology Texas A&M University School of MedicineBryanTXUSA Hepatology Unit University of Tor VergataRomeItaly Division of Gastroenterology and Hepatology Department of MedicineIndiana University School of MedicineIndianapolisINUSA

The liver has a vital role in many metabolic and regulatory processes in the *** biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial *** this time there is no definitive cure for PBC;however,ursodeoxycholic acid(UDCA)has been shown to reduce injury when administered as the first line of *** therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease ***,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable *** review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

关键词： Cholestatic liver disease Therapeutic approaches Biliary epithelia ursodeoxycholic acid

Diagnostic and therapeutic potentials of microRNAs in cholangiopathies

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Liver Research 2017年第1期1卷 34-41页

作者： Lindsey Kennedy Heather Francis Fanyin Meng Shannon Glaser gianfranco alpini Research Central Texas Veterans Health Care SystemTempleTXUSA Department of Medicine Texas A&M Health Science CenterCollege of MedicineTempleTXUSA Baylor Scott&White Digestive Disease Research Center Baylor Scott&White HealthTempleTXUSA

Cholangiopathies are a group of rare,devastating diseases that arise from damaged cholangiocytes,the cells that line the intra-and extra-hepatic bile ducts of the biliary *** result in significant morbidity and mortality and are a major cause of liver transplantation.A better understanding of the underlying pathogenesis that influences cholangiocyte dysregulation and cholangiopathy progression is necessary,considering the dismal prognosis associated with these *** are a class of small,non-coding RNAs that regulate post-transcriptional mRNA expression of specific *** role of microRNAs has expanded to include the initiation and development of many diseases,including *** microRNA regulation of cholangiopathies may provide diagnostic and therapeutic benefit for these *** this review,the authors primarily focus on studies published within the last five years that help determine the diagnostic and therapeutic potential of microRNAs in cholangiopathies.

关键词： microRNAs Cholangiopathies Diagnosis Therapy

Bile acid interactions with cholangiocytes

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World Journal of Gastroenterology 2006年第22期12卷 3553-3563页

作者： Xuefeng Xia Heather Francis Shannon Glaser gianfranco alpini Gene LeSage University of Texas at Houston Medical School Houston TX United States Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of Medicine Temple TX United States Department of Medicine Division of Research and Education Scott & White Hospital and The Texas A&M University System Health Science Center College of MedicineTemple TX United States Central Texas Vctcrans Health Care System and Department of Medicine and Systems Biology and Translational Medicine United States

Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter （ASBT）（also referred to as Ibat; gene name Slc10a2） is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified （t-ASBT, multidrug resistance （MDR）3, an unidentified anion exchanger system and organic solute transporter （Ost） heteromeric transporter, Ostα- Ostβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3＇, 5＇monophosphate （cAMP）-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C （PKC）, phosphoinositide 3-kinase （PI3K）, mitogenactivated protein （MAP） kinase and extracellular signalregulated protein kinase （ERK） intracellular signals. Bile acids significantly alter cholangiocyte secretion,proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals,and in some instances trigger opposing effects on cholangiocyte secretion, pro

关键词： Cholangiocytes Bile acid Liver

c-Met targeted therapy of cholangiocarcinoma

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World Journal of Gastroenterology 2008年第19期14卷 2990-2994页

作者： Matei P Socoteanu Frank Mott gianfranco alpini Arthur E Frankel Scott & White Hospital and Clinics 5701 SAirport RdTemple

Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

关键词： Cholangiocarcinoma c-Met Chemotherapy Target therapy

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

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Liver Research 2020年第3期4卷 136-144页

作者： Xin Guo Bilian Zhu Hang Xu Honggui Li Boxiong Jiang Yina Wang Benrong Zheng Shannon Glaser gianfranco alpini Chaodong Wu Department of Nutrition Texas A&M UniversityCollege StationTXUSA Department of Nutrition and Food Hygiene School of Public HealthCheeloo College of MedicineShandong UniversityJinanChina Department of VIP Medical Service Center The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Medical Physiology Texas A&M University College of MedicineBryanTXUSA Hepatology and Gastroenterology MedicineIndiana UniversityIndianapolisINUSA Richard L.Roudebush VA Medical Center IndianapolisINUSA

Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be *** that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in ***:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD ***,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)*** latter were also fed an HFD and examined for NAFLD *** vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory ***:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT *** inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory *** NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT *** the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT ***:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induce

关键词： 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2) Hematopoietic cells Hepatic steatosis Inflammation Macrophages

Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes

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World Journal of Gastrointestinal Pathophysiology 2010年第2期1卷 38-49页

作者： Paolo Onori Eugenio Gaudio Antonio Franchitto gianfranco alpini Heather Francis Experimental Medicine University of L'Aquila Department of HumanAnatomy University of Rome "La Sapienza" Research Central Texas Veterans Health Care System Scott and White Digestive Disease Research Center Division of Gastro-enterology Department of MedicineTexas A&M Health Science CenterCollege of Medicine Division of Research and Education

Histamine has long been known to be involved in inflammatory *** discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist,Daniel Bovet began his *** 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy *** that time,histamine has been found to play a role in other events besides allergic *** believable to Bovet and his peers,histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases.

关键词： Histamine Receptors Cholangiocytes Cholestasis Cholangiocarcinoma