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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 | New therapeutic opportunities for Hepatitis C based on small RNA显示文摘Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy. | Qiu-wei Pan Scot D Henry Bob J Scholte Hugo W Tilanus Harry LA Janssen Luc JW van der Laan | 2007 | World Journal of Gastroenterology2007，13，33： | 4 |
| 3 | Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients显示文摘 | J.J. Bonenkamp I. Songun K. Welvaart C.J.H. van de Velde J. Hermans M. Sasako J.T.M. Plukker P. van Elk H. Obertop D.J. Gouma C.W. Taat J. van Lanschot S. Meyer P.W. de Graaf M.F. von Meyenfeldt H. Tilanus | 1995 | The Lancet . 1995 (8952)1995，，： | 2 |
| 4 | Comparison of the 6th and 7th Editions of the UICC-AJCC TNM Classification for Esophageal Cancer显示文摘 | Koen Talsma Pieter Hagen Brechtje Grotenhuis Ewout Steyerberg Hugo Tilanus Jan Lanschot Bas Wijnhoven | 2012 | Annals of Surgical Oncology2012，，7： | 2 |
| 5 | Increased incidence of early de novo cancer in liver graft recipients treated with cyclosporine: An association with C显示文摘 | Angela S. W. Tjon Jerome Sint Nicolaas Jaap Kwekkeboom Robert A. de Man Geert Kazemier Hugo W. Tilanus Bettina E. Hansen Luc J. W. van der Laan Thanyalak Tha‐In Herold J. Metselaar | 2010 | Liver Transpl2010，，7： | 2 |
| 6 | A prospective study on elective umbilical hernia repair in patients with liver cirrhosis and ascites显示文摘 | Hasan H. Eker G.H. van Ramshorst B. de Goede H.W. Tilanus H.J. Metselaar R.A. de Man J.F. Lange G. Kazemier | 2011 | Surgery2011，，3： | 2 |
| 7 | Extended Transthoracic Resection Compared With Limited Transhiatal Resection for Adenocarcinoma of the Mid/Distal Esophagus: Five-Year Survival of a Randomized Clinical Trial显示文摘 | Jikke M. T. Omloo Sjoerd M. Lagarde Jan B. F. Hulscher Johannes B. Reitsma Paul Fockens Herman van Dekken Fiebo J. W. ten Kate Huug Obertop Hugo W. Tilanus J Jan B. van Lanschot | 2007 | Annals of Surgery2007，，6： | 2 |
| 8 | Neoadjuvant chemoradiotherapy for esophageal cancer: a review of meta-analyses 显示文摘 | Wijnhoven BP van Lanschot J J Tilanus HW | 2009 | World J Surg2009，33，12： | 1 |
| 9 | HLA-DR1 and rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB1*0102 is the predominant HLA-DR1 subtype显示文摘 | de Vries N Ronningen KS Tilanus MG | 1993 | Tissue Antigens1993，41，1： | 1 |
| 10 | Barrett’s Esophagus and Esophageal Adenocarcinoma Are Common After Treatment for Achalasia显示文摘 | I. Leeuwenburgh P. Scholten T. J. Caljé R. J. Vaessen H. W. Tilanus B. E. Hansen E. J. Kuipers | 2013 | Digestive Diseases and Sciences2013，，1： | 1 |
| 11 | Recurrence pattern of oesophageal carcinoma after limited resection does not support wide local excision with extensive lymph node dissection显示文摘 | van Lanschot J J B Tilanus H W Voormolen M H J | 1994 | Br J Surg1994，81，9： | 1 |
| 12 | Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome 显示文摘 | Moroso V van der Meer A Tilanus HW | 2011 | Transpl Int2011，24，9： | 1 |
| 13 | Increased incidence of adenocarcinomas at the gastro-esophageal junction in Dutch males since the 1990s显示文摘 | Wijnhoven BP Louwman MW Tilanus HW | 2002 | Eur J Gastroenterol Hepatol2002，14，2： | 1 |
| 14 | Electrocautery therapy for refractory anastomotic strictures of the esophagus显示文摘 | Hordijk ML Siersema PD Tilanus HW | 2006 | Gastrointest Endosc2006，63，1： | 1 |
| 15 | Genomic array and expression analysis of frequent high-level amplifications in adenocarcinomas of the gastro-esophageal junction 显示文摘 | Van Dekken H Vissers K Tilanus HW | 2006 | Cancer Genet Cytogenet2006，166，2： | 1 |
| 16 | Phase Ⅱ study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus显示文摘 | Polee MB Tilanus HW Eskens FA | 2003 | Ann Oncol2003，14，8： | 1 |
| 17 | Information systems in logistics and transport显示文摘 | Tilanus B | 1997 | Bsenier Scienee1997，，5： | 1 |
| 18 | Relationship between anticoagulant medication and massive intraocular hemorrhage in age-related macular degeneration显示文摘 | M. A. D. Tilanus Willem Vaandrager Marinus H. M. Cuypers Adrianus M. Verbeek Carel B. Hoyng | 2000 | Graefe’s Archive for Clinical and Experimental Ophthalmology2000，，6： | 1 |
| 19 | Liver transplantation and hepatitis C显示文摘 | M. Willems H. Metselaar H. Tilanus S. Schalm R. de Man | 2002 | Transplant International (-)2002，，2： | 1 |
| 20 | Effects of a rehabilitation programme on daily functioning, participation, health-related quality of life, anxiety and depression in liver transplant recipients显示文摘 | B.T.J. Van Ginneken H.J.G. Van Den Berg-emons H.J. Metselaar H.W. Tilanus G. Kazemier H.J. Stam | 2010 | Disability & Rehabilitation2010，，25： | 1 |
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