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| 1 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | Jonathan D Roth Michael Feigh Sanne S Veidal Louise KD Fensholdt Kristoffer T Rigbolt Henrik H Hansen Li C Chen Mathieu Petitjean Weslyn Friley Niels Vrang Jacob Jelsing Mark Young | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 2 | Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH. | Kirstine S Tolbol Maria NB Kristiansen Henrik H Hansen Sanne S Veidal Kristoffer TG Rigbolt Matthew P Gillum Jacob Jelsing Niels Vrang Michael Feigh | 2018 | World Journal of Gastroenterology2018，24，2： | 5 |
| 3 | Effect of Prometheus liver assist system on systemic hemodynamics in patients with cirrhosis: A randomized controlled study显示文摘AIM: To evaluate treatment safety and hemodynamic changes during a single 6-h treatment with the Prometheus? liver assist system in a randomized, controlled study. METHODS: Twenty-four patients were randomized to either the study group or to one of two control groups: Fractionated Plasma Separation Adsorption and Dialysis, Prometheus? system (Study group; n = 8); Molecular Adsorbent Recirculation System (MARS)? (Control group 1, n = 8); or hemodialysis (Control group 2; n = 8). All patients included in the study had decompensated cirrhosis at the time of the inclusion into the study. Circulatory changes were monitored with a Swan-Ganz catheter and bilirubin and creatinine were monitored as measures of protein-bound and water-soluble toxins. RESULTS: Systemic hemodynamics did not differ between treatment and control groups apart from an increase in arterial pressure in the MARS group (P = 0.008). No adverse effects were observed in any of the groups. Creatinine levels significantly decreased in the MARS group (P = 0.03) and hemodialysis group (P = 0.04). Platelet count deceased in the Prometheus group (P = 0.04).CONCLUSION: Extra-corporal liver support with Prometheus is proven to be safe in patients with end- stage liver disease but does not exert the beneficial effects on arterial pressure as seen in the MARS group. | Thomas Dethloff Flemming Tofteng Hans-Jorgen Frederiksen Michael Hojskov Bent Adel Hansen Fin Stolze Larsen | 2008 | World Journal of Gastroenterology2008，14，13： | 4 |
| 4 | Environmental factors in inflammatory bowel disease: A case-control study based on a Danish inception cohort显示文摘 | Tanja Stenbaek Hansen Tine Jess Ida Vind Margarita Elkjaer Malene Fey Nielsen Michael Gamborg Pia Munkholm | 2011 | Journal of Crohn’s and Colitis2011，，6： | 3 |
| 5 | Tackling the Wicked Problem of Measuring What Matters:Framing the Questions显示文摘Purpose:Making policy makers,researcher,education leaders,and assessment developers aware that what matters in education assessment is a wicked problem that cannot be easily solved following traditional approaches.Design/Approach/Methods:Starting from the questions that what matters in education assessment,this article presented such questions as a wicked problem because there is no consensus,not right or wrong answer,and certain solutions may lead to side effects on students and society.Therefore,a new approach of ecology should be involved,and different education outcomes or intended qualities of learners are presented in complex relationships.Findings:Deciding what matters in education assessment is a wicked question.It is not a tame or technology problem and can be resolved by any conventional approaches.What is pivotal now is to decipher what matters in education and then what should be measured and ultimately how to measure.The ecology and collaborate approach deliberated in this article could expedite such a process.Originality/Value:This article advocates paradigm change in understanding and resolving one of the most urgent problems in education.It provides an ecology explanation of the relationships that exist among the different education outcomes and students’qualities.By guiding through the dissecting of the problem step by step,this article has demonstrated a unique angle of understanding the wicked problem. | Yong Zhao Michael Wehmeyer James Basham David Hansen | 2019 | ECNU Review of Education2019，2，3： | 3 |
| 6 | Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source显示文摘BACKGROUND The trans-fat containing AMLN(amylin liver non-alcoholic steatohepatitis,NASH)diet has been extensively validated in C57BL/6J mice with or without the Lep^ob/Lep^ob(ob/ob)mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.Due to a recent ban on trans-fats as food additive,there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat(Primex shortening)substituted by equivalent amounts of palm oil[Gubra amylin NASH,(GAN)diet]for 8,12 and 16 wk.C57BL/6J mice were fed the same diets for 28 wk.AMLN and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)level.RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance.Biopsy-confirmed steatosis,lobular inflammation,hepatocyte ballooning,fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet.C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsyconfirmed NASH in ob/ob and C57BL/6J mice,making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments. | Michelle L Boland Denise Oro Kirstine S T■lb■l Sebastian T Thrane Jens Christian Nielsen Taylor S Cohen David E Tabor Fiona Fernandes Andrey Tovchigrechko Sanne S Veidal Paul Warrener Bret R Sellman Jacob Jelsing Michael Feigh Niels Vrang James L Trevaskis Henrik H Hansen | 2019 | World Journal of Gastroenterology2019，25，33： | 3 |
| 7 | Genomic surveillance of Nevada patients revealed prevalence of unique SARS-CoV-2 variants bearing mutations in the RdRp gene显示文摘Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform,which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads,without the need of culture-based amplification.High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak.We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine(F) from proline (P),in the first reported isolate of SARS-CoV-2,Wuhan-Hu-1.This 323F variant was present at a very high frequency in Northern Nevada.Structural modeling determined this mutation in the interface domain,which is important for the association of accessory proteins required for the polymerase.In conclusion,we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations,which is important for understanding the evolution and circulation of SARS-CoV-2variants of public health importance,while it circulates in humans. | Paul D.Hartley Richard L.Tillett David P.AuCoin Joel R.Sevinsky Yanji Xu Andrew Gorzalski Mark Pandori Erin Buttery Holly Hansen Michael A.Picker Cyprian C.Rossetto Subhash C.Verma | 2021 | Journal of Genetics and Genomics2021，48，1： | 2 |
| 8 | Effect of thrombocytopenia on treatment tolerability and outcome in patients with chronic HCV infection and advanced hepatic fibrosis显示文摘 | Raoel Maan Adriaan J. van der Meer Bettina E. Hansen Jordan J. Feld Heiner Wedemeyer Jean-Fran?ois Dufour Hooman F. Zangneh Frank Lammert Michael P. Manns Stefan Zeuzem Harry L.A. Janssen Robert J. de Knegt Bart J. Veldt | 2014 | Journal of Hepatology2014，，： | 2 |
| 9 | Carbonitride precipitation in niobium/vanadium microalloyed steels显示文摘 | J. G. Speer J. R. Michael S. S. Hansen | 1987 | Metallurgical Transactions A1987，，2： | 2 |
| 10 | Qualities of sessile serrated adenoma/polyp/lesion and its borderline variant in the context of synchronous colorectal carcinoma显示文摘 | Mahin Mohammadi Michael Holmsgaard Kristensen Hans J?rgen Nielsen Jesper Hansen Bonde Susanne Holck | 2012 | Journal of Clinical Pathology2012，，10： | 2 |
| 11 | Measurement of pulsatile hormone release from perifused pituitary cells immobilized on microcarriers显示文摘 | Michael Conn P | 1990 | Methlds in Neurosciences1990，，2： | 1 |
| 12 | Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice显示文摘 | Rikke Rie Hansen Arafat Nasser Sarah Falk Signe B. Baldvinsson Pernille H. Ohlsson Justyna M.C. Bahl Michael F. Jarvis Ming Ding Anne-Marie Heegaard | 2012 | European Journal of Pharmacology . 2012 (1-3)2012，，： | 1 |
| 13 | Pattern-selective color image fusion显示文摘 | Luca Bogoni Michael Hansen | 2001 | Pattern Recognition2001，34，8： | 1 |
| 14 | Prediction of cochlear implant performance by genetic mutation: The spiral ganglion hypothesis显示文摘 | Robert W. Eppsteiner A. Eliot Shearer Michael S. Hildebrand Adam P. DeLuca Haihong Ji Camille C. Dunn Elizabeth A. Black-Ziegelbein Thomas L. Casavant Terry A. Braun Todd E. Scheetz Steven E. Scherer Marlan R. Hansen Bruce J. Gantz Richard J.H. Smith | 2012 | Hearing Research (-)2012，，1： | 1 |
| 15 | Multi criteria design optimization of backhoe loader front mechanism显示文摘 | HANSEN Michael Rygaard ANDERSEN Torbenole | 2003 | American Society of Mechanical Engineers Design Engineering Division (Publication) DE2003，116，1： | 1 |
| 16 | Predictors of Early, Late, and Very Late Stent Thrombosis After Primary Percutaneous Coronary Intervention With Bare-Metal and Drug-Eluting Stents for ST-Segment Elevation Myocardial Infarction显示文摘 | Bruce Brodie Yashashwi Pokharel Ankit Garg Grace Kissling Charles Hansen Sally Milks Michael Cooper Christopher McAlhany Tom Stuckey | 2012 | JACC: Cardiovascular Interventions2012，，10： | 1 |
| 17 | Exaggeration of nonculprit stenosis severity during acute myocardial infarction: implications for immediate multivessel revascularization显示文摘 | Colm G Hanratty Yutaka Koyama Helge H Rasmussen Greg I.C Nelson Peter S Hansen Michael R Ward | 2002 | Journal of the American College of Cardiology2002，，5： | 1 |
| 18 | Expression and Immunogenicity of Proteins Encoded by Specific to Mycobacterium avlum subsp, paratuberculosis 显示文摘 | John P Bannantine Janis K Hansen Michael Paustian | 2004 | Journal of Clinical Microbiology2004，42，1： | 1 |
| 19 | Carbonitride precipitation in niobium/vanadium microalloyed steels显示文摘 | Speer J G Michael J R Hansen S S | 1987 | Metall Trans A1987，18，2： | 1 |
| 20 | Two-Year Interim European CLinicaL ResuLts of NucLeus RepLacement Using an In Situ Cured BaLLoon Contained InjectabLe PoLyurethane Device显示文摘 | John Sherman MichaeL Ahrens Hansen Yuan | 2008 | Proceedings of the NASS 23rd AnnuaL Meeting/The Spine JournaL2008，8，： | 1 |
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