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| 1 | m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment显示文摘AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor(TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors(HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatmentwith the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight(75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin(TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mT OR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways. | Suomi MG Fouraschen Petra E de Ruiter Jaap Kwekkeboom Ron WF de Bruin Geert Kazemier Herold J Metselaar Hugo W Tilanus Luc JW van der Laan Jeroen de Jonge | 2013 | World Journal of Transplantation2013，3，3： | 6 |
| 2 | Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial显示文摘 | Surya SAY Biere Mark I van Berge Henegouwen Kirsten W Maas Luigi Bonavina Camiel Rosman Josep Roig Garcia Suzanne S Gisbertz Jean HG Klinkenbijl Markus W Hollmann Elly SM de Lange H Jaap Bonjer Donald L van der Peet Miguel A Cuesta | 2012 | The Lancet . 2012 (9829)2012，，： | 3 |
| 3 | Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial显示文摘 | Surya SAY Biere Mark I van Berge Henegouwen Kirsten W Maas Luigi Bonavina Camiel Rosman Josep Roig Garcia Suzanne S Gisbertz Jean HG Klinkenbijl Markus W Hollmann Elly SM de Lange H Jaap Bonjer Donald L van der Peet Miguel A Cuesta | 2012 | The Lancet2012，，9829： | 1 |
| 4 | An overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization显示文摘 | Karin W MSc Jaap H | 2008 | J Dev Behav Pediatr2008，29，： | 1 |
| 5 | Phage therapy reduces Campylobacterjejuni colonization in broilers显示文摘 | JAAP A W MARCEL A P V B MARK A M | 2005 | Veterinary Microbilogy2005，109，： | 1 |
| 6 | Investigation of three types of catalysts for the hydration of ethylene oxide(EO)to monoethylene glycol(MEG)显示文摘 | Van Hal Jaap W Ledford John S Zhang Xian Kuan | 2007 | Catalysis Today2007，123，： | 1 |
| 7 | Natural deep eutectic solvents as new potential media for green technology显示文摘 | Yuntao D Jaap V S Geert-Jan W | 2013 | Analytica Chimiea Acta2013，766，6： | 1 |
| 8 | The analytical pyrolysis of particulate residues of decomposing Myriophyllum hetero- phyllum显示文摘 | BOON JAAP J WINDIG W WETZE1 R G | 1983 | Aquatic Botany1983，15，3： | 1 |
| 9 | Biochemical and molecular aspects of growth and fruiting of the edible mushroom Agaricus bisporus 显示文摘 | Piet W J De Groot Jaap V | 1998 | Mycological Research1998，102，11： | 1 |
| 10 | Lysozyme distribution and conformation in a biodegradable polymer matrix as determined by FTIR techniques显示文摘 | Marco V W Ron V H Jaap V W | 2000 | J Control Release2000，68，： | 1 |
| 11 | Postmortem proteome degradation profiles of longissimus muscle in Yorkshire and Duroc pigs and their relationship with pork quality traits显示文摘 | MARINUS F W TE PAS JAAP J | 2009 | Meat Science2009，，83： | 1 |
| 12 | Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial显示文摘 | Surya SAY Biere Mark I van Berge Henegouwen Kirsten W Maas Luigi Bonavina Camiel Rosman Josep Roig Garcia Suzanne S Gisbertz Jean HG Klinkenbijl Markus W Hollmann Elly SM de Lange H Jaap Bonjer Donald L van der Peet Miguel A Cuesta | 2012 | The Lancet2012，，9829： | 1 |
| 13 | Clostridium difficile infection in Europe: a hospital-based survey显示文摘 | Martijn P Bauer Daan W Notermans Birgit HB van Benthem Jon S Brazier Mark H Wilcox Maja Rupnik Dominique L Monnet Jaap T van Dissel Ed J Kuijper | 2011 | The Lancet2011，，9759： | 1 |
| 14 | Games solved:Now and in the future显示文摘 | van den Herik H Jaap Uiterwijk Jos W H M van Rijswijck Jack | 2001 | Artificial Intelligence2001，134，： | 1 |
| 15 | Clostridium difficile infection in Europe: a hospital-based survey显示文摘 | Martijn P Bauer Daan W Notermans Birgit HB van Benthem Jon S Brazier Mark H Wilcox Maja Rupnik Dominique L Monnet Jaap T van Dissel Ed J Kuijper | 2011 | The Lancet2011，，9759： | 1 |
| 16 | Catalysis Today 显示文摘 | Jaap W van Hal John S Ledford Xiankuan Zhang | 2007 | 123(112/3/4): 310-3252007，123，11234： | 1 |
| 17 | Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial显示文摘 | Robert F van Es Jan JC Jonker Freek WA Verheugt Jaap W Deckers Diederick E Grobbee | 2002 | The Lancet2002，，9327： | 1 |
| 18 | Understanding customer switc- hing behavior in a liberalizing service market,an exploratory study显示文摘 | JAAP E W PETER C V | 2007 | Journal of Service Research2007，10，2： | 1 |
| 19 | Games solved: now and in the future 显示文摘 | H Jaap van den Herik Jos W H M Uiterwijk Jaek van Rijswijck | 2002 | Artificial Intelligence2002，134，12： | 1 |
| 20 | Investigation of thee types of catalysts for the hydration of ethylene oxide (EO) to monoethylene glycol (MEG) 显示文摘 | Jaap W V H John S L Zhang X K | 2007 | Catalysis Today2007，123，： | 1 |
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