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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 | Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma显示文摘Glioblastoma multiforme(GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM(r GBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery(GKRS) salvage therapy. Following a Pub Med search for studies usingGKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rG BM treatment. In this review, we compare overall survival following diagnosis, overall survival following salvage treatment, progression-free survival, time to recurrence, local tumor control, and adverse radiation effects. This report discusses results for rG BM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates(from diagnosis, range:16.7-33.2 mo; from salvage, range:9-17.9 mo). Three studies identified median progression-free survival(range:4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects(range:0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rG BM patient. However, there needs to be a randomized clinical trial to test GKRS for rG BM before the possibility of selection bias can be dismissed. | Erik W Larson Halloran E Peterson Wayne T Lamoreaux Alexander R MacKay Robert K Fairbanks Jason A Call Jonathan D Carlson Benjamin C Ling John J Demakas Barton S Cooke Christopher M Lee | 2014 | World Journal of Clinical Oncology2014，5，2： | 5 |
| 3 | Chronic overexpression of PNPLA3^sup I148M^ in mouse liver causes hepatic steatosis显示文摘 | Li John Zhong Huang Yongcheng Karaman Ruchan Ivanova Pavlina T Brown H Alex Roddy Thomas Castro-Perez Jose Cohen Jonathan C Hobbs Helen H | 2012 | EN2012，，11： | 3 |
| 4 | Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience显示文摘 | Phil A Hart Mark D Topazian Thomas E Witzig Jonathan E Clain Ferga C Gleeson Robin R Klebig Michael J Levy Randall K Pearson Bret T Petersen Thomas C Smyrk Aravind Sugumar Naoki Takahashi Santhi S Vege Suresh T Chari | 2013 | Gut2013，，11： | 2 |
| 5 | Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience显示文摘 | Phil A Hart Mark D Topazian Thomas E Witzig Jonathan E Clain Ferga C Gleeson Robin R Klebig Michael J Levy Randall K Pearson Bret T Petersen Thomas C Smyrk Aravind Sugumar Naoki Takahashi Santhi S Vege Suresh T Chari | 2013 | Gut2013，，11： | 2 |
| 6 | Defying gravity显示文摘 | Jonathan H C Stephen F T | 1998 | Civil Engineering1998，68，2： | 1 |
| 7 | Intensive chemotherapy and radicaf resections for primary nonse minomatous mediastinaf germ ceff tumors显示文摘 | Garret L W Grant D T Jonathan C N | 2000 | Ann Thorac Surg2000，69，： | 1 |
| 8 | Quality of life, functional outcome and cost of early glottis cancer 显示文摘 | Jonathan C Jonas T | 2003 | Lar2003，113，： | 1 |
| 9 | Follicle stimula ting hormone (FSH) actives the P mitogen activated protein ki- nase pathway, inducing small heat shock protein phosphorylation and cell rounding in immature rat ovarian granulosa cells显示文摘 | Evelyn T M Joshu A C Jonathan C R J | 1998 | En docrinology1998，139，7： | 1 |
| 10 | Striping within the network subsystem显示文摘 | C Brendan S T Jonathan M S | 1995 | IEEE Network Magazine1995，9，4： | 1 |
| 11 | Meta-Analysis of Calcium Supplementation for the Prevention of Postmenopausal Osteoporosis显示文摘 | Beverley S George W Ann C Nicole Z Vivian R Lauren G Zulma O Joan P Jonathan A Peter T Gordon G | 2002 | Endocrine Reviews2002，23，4： | 1 |
| 12 | Feature-subspace aggregating: Ensembles for stable and unstable learners 显示文摘 | KAI M T JONATHAN R W SWEE C T | 2011 | Machine Learning2011，82，3： | 1 |
| 13 | Meta-Analysis of Raloxifene for the Prevention and Treatment of Postmenopausal Osteoporosis显示文摘 | Ann C Peter T Nicole Z Vivian R Bruce W Jonathan A George W Beverley S Gordon G | 2002 | Endocrine Reviews2002，23，4： | 1 |
| 14 | Meta-Analysis of the Efficacy of Vitamin D Treatment in Preventing Osteoporosis in Postmenopausal Women显示文摘 | Emmanuel P George W Beverley S William G Bruce W Nicole Z Ann C Jonathan A Peter T Robert J Carol G Gordon G | 2002 | Endocrine Reviews2002，23，4： | 1 |
| 15 | Strand spaces:proving security protocols correct显示文摘 | Fdbrega J T Jonathan C H Joshua D G | 1999 | Journal of Computer Security1999，7，23： | 1 |
| 16 | Meta-Analysis of Risedronate for the Treatment of Postmenopausal Osteoporosis显示文摘 | Ann C Peter T Jonathan A Bruce W Nicole Z Alexandra P Vivian R Beverley S George W Gordon G | 2002 | Endocrine Reviews2002，23，4： | 1 |
| 17 | An area and power efficient radiation hardened by design flip-flop 显示文摘 | Jonathan E K Lawrence T C | 2006 | IEEE Transactions on Nuclear Science2006，53，6： | 1 |
| 18 | Confonnational epitoaes ou thediabetes autoantigen GAD65 identified by peptide phage display and molecular modeling 显示文摘 | Janet M D Jonathan C T | 2000 | The J Immunology2000，165，： | 1 |
| 19 | Quality of life, functional outcome and cost of early glottis cancer显示文摘 | Jonathan C Jonas T | 2003 | Laryngoscope2003，113，1： | 1 |
| 20 | Strand spaces:Proving security protocols correct显示文摘 | JAVIER F ABREGA T JONATHAN C | 1999 | Journal of Computer Security1999，7，23： | 1 |
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