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| 1 | Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1α in advanced hepatocellular carcinoma显示文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α) is a gene that regulates tumor survival,neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma(HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC.AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179.METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice wereseparated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment,received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179.RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1 b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies(each biopsy was divided into 2 specimens, the tip and the root).CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity.This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either m RNA level or DCE-MRI within 1 cycle of therapy. | Jennifer Wu Merly Contratto Krishna P Shanbhogue Gulam A Manji Bert H O'Neil Anne Noonan Robert Tudor Ray Lee | 2019 | World Journal of Clinical Oncology2019，10，3： | 2 |
| 2 | Catalase HPII from Escherichia coli Exhibits Enhanced Resistance to Denaturation显示文摘 | Switala J O'Neil J O Loewen P C | 1999 | Biochemistry1999，38，13： | 1 |
| 3 | The value of the world’s ecosystemservices and natural capita1显示文摘 | Costanza R Arge R Groot R Farberk S Grasso M HannonB Limburg K Naeem S O’Neil R Paruelo J Raskin R Suttonkk P &Belt M | 1997 | Nature1997，387，： | 1 |
| 4 | Salinity effects on the microwave emission of soil显示文摘 | Jackson T J O'Neil P E | 1990 | Remote Sens Environ1990，31，： | 1 |
| 5 | FBW7 mutations in leukemic ceils mediate NOTCH pathway activation and resistance to gamma- secre-tase inhibitors 显示文摘 | O' Neil J Grim J Strack P | 2007 | Exp Med2007，204，8： | 1 |
| 6 | Recombinant chicken IFN-γ expressed in Escherichia coli: Analysis of C-terminal truneation and effeet on biologie aetivity显示文摘 | Miehalski W P Shiell B J O'Neil T E | 1999 | Journal of Interferon & Cytokine Researeh1999，19，4： | 1 |
| 7 | Requirement of borate cross-linking of cell wall rhamnogalacturonanⅡfor Arabidopsis growth 显示文摘 | O'Neil M A Eberhard S Albersheim P | 2001 | Science2001，294，5543： | 1 |
| 8 | An optimality proof of the LRU-K page replacement algorithm显示文摘 | O'NEIL E 1 O'NEIL P E WEIKUM G | 1999 | Journal of the ACM1999，46，1： | 1 |
| 9 | Experi- mental investigation of high-burning-rate com- posite solid propellants显示文摘 | Manship T D Heister S D O'Neil P D | 2012 | Journal of Propulsion and Power2012，28，6： | 1 |
| 10 | Sublingual capnometry and indexes of tissue perfusion in patients with circulatory failure显示文摘 | Rackow EC O'Neil P Astiz ME | 2001 | Chest2001，120，5： | 1 |
| 11 | Multi-table joins through bitmapped join indices显示文摘 | O'Neil P E Graefe G | 1995 | SIGMOD Record1995，24，3： | 1 |
| 12 | The escrow transactional method显示文摘 | O'NEIL P E | 1986 | ACM Trans Database Syst1986，，11： | 1 |
| 13 | Improved query performance with variant indexes显示文摘 | NEIL O P QUASS D | 1997 | ACM Sigmod Record1997，26，2： | 1 |
| 14 | The role of long lived free radicals in the ageing of irradiated ultra high molecular weight polyethylene显示文摘 | O'Neil P O Birknshaw C Leahy J J | 1999 | Polym Degradation Stability1999，63，1： | 1 |
| 15 | Using clinical experience in discussion within problem-based learning groups显示文摘 | O'neil P Duplock A Willis S | 2006 | Adv Health Sci Educ Theory Pract2006，11，4： | 1 |
| 16 | A Phase I study of bortezomib plus irinotecan in patients with advanced solid tumors显示文摘 | Ryan D P O'Neil B H Supko J G | 2006 | Cancer2006，107，11： | 1 |
| 17 | Bacterial commu- nity structure and function change in association with coloni zer plants during early primary succession in a glacier forefield 显示文摘 | Knelman J E Legg T M O'Neil S P etal | 2012 | Soil Biology and Biochemistry2012，46，： | 1 |
| 18 | Oxygen gain analysis for proton exchange membrane fuel ceils 显示文摘 | O'Neil K Meyers J P Darling R M Perry M L | 2012 | International Journal of Hydrogen Energy2012，37，： | 1 |
| 19 | Effect of donor-acceptor orientation on ultrafast photoinduced electron transfer and dark charge recombination in porphyrin-quinone molecules 显示文摘 | Sakata Y Tsue H O'Neil M P | 1994 | J Am Chem Soc1994，116，： | 1 |
| 20 | Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer显示文摘 | Murray GI Duncan ME O' Neil P | 1998 | J Pathol1998，185，3： | 1 |
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