L Bühler

University of Geneva, Genève, Geneva, Switzerland

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Publications (167)390.54 Total impact

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    ABSTRACT: The expression of plasma proteins changes dramatically as a result of cytokine induction, particularly interleukin-6, and their levels are used as clinical markers of inflammation. miRNAs are important regulators of gene expression and play significant roles in many inflammatory diseases and processes. The interactions between miRNAs and the genes that they regulate during the acute phase response have not been investigated. We examined the effects of IL-6 stimulation on the transcriptome and miRNome of human and mouse primary hepatocytes and the HepG2 cell line. Using an integrated analysis, we identified differentially expressed miRNAs whose seed sequences are significantly enriched in the 3' untranslated regions of differentially expressed genes, many of which are involved in inflammation-related pathways. Our finding that certain miRNAs may de-repress critical acute phase proteins within acute timeframes has important biological and clinical implications. Copyright © 2015. Published by Elsevier Inc.
    Genomics 05/2015; DOI:10.1016/j.ygeno.2015.05.001 · 2.79 Impact Factor
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    ABSTRACT: Background Lymph node involvement in pancreatic adenocarcinoma is a key prognostic factor. Therefore, extending the number of lymph node stations excised in pancreatoduodenectomy may be beneficial to patients with pancreatic adenocarcinoma. This systematic review and meta-analysis examines the outcomes of extended versus standard lymphadenectomy in the published literature.MethodsA meta-analysis of randomized controlled trials (RCTs) comparing extended with standard lymphadenectomy in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma was performed. Perioperative outcomes were assessed as pooled odds ratios (ORs) and weighted mean differences. Overall survival was analysed for patients with positive and negative lymph nodes. Results were reported according to the PRISMA statement.ResultsFive RCTs were included, accounting for 724 patients. Extended lymphadenectomy was associated with greater operative time [mean difference: 63 min, 95% confidence interval (CI) 29–96; P < 0.001], increased need for blood transfusions (mean difference: 0.20, 95% CI 0.01–0.30; P = 0.030) and greater postoperative morbidity (OR 1.5, 95% CI 1.25–2.00; P = 0.030), as well as with prolonged diarrhoea after circumferential autonomic nerve dissection around major vessels (OR 12.2, 95% CI 5.3–28.5; P < 0.001). Median survival was similar across the groups in the whole cohort, as well as in subgroups of patients with, respectively, positive and negative lymph node patients.Conclusions Extended lymphadenectomy has a harmful impact on patients undergoing oncological pancreatoduodenectomy compared with standard lymphadenectomy.
    HPB 04/2015; 17(7). DOI:10.1111/hpb.12407 · 2.05 Impact Factor
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    ABSTRACT: Robotic technology commenced to be adopted for the field of general surgery in the 1990s. Since then, the da Vinci surgical system (Intuitive Surgical Inc, Sunnyvale, CA, USA) has remained by far the most commonly used system in this domain. The da Vinci surgical system is a master-slave machine that offers three-dimensional vision, articulated instruments with seven degrees of freedom, and additional software features such as motion scaling and tremor filtration. The specific design allows hand-eye alignment with intuitive control of the minimally invasive instruments. As such, robotic surgery appears technologically superior when compared with laparoscopy by overcoming some of the technical limitations that are imposed on the surgeon by the conventional approach. This article reviews the current literature and the perspective of robotic general surgery. While robotics has been applied to a wide range of general surgery procedures, its precise role in this field remains a subject of further research. Until now, only limited clinical evidence that could establish the use of robotics as the gold standard for procedures of general surgery has been created. While surgical robotics is still in its infancy with multiple novel systems currently under development and clinical trials in progress, the opportunities for this technology appear endless, and robotics should have a lasting impact to the field of general surgery.
    Langenbeck s Archives of Surgery 02/2015; DOI:10.1007/s00423-015-1278-y · 2.16 Impact Factor
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    ABSTRACT: In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate into areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration in 3 out of 5 MSC donors. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time PCR, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5 and CCR6 in MSC. Expression of these chemokine receptors were not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblast. In conclusion, we reported that two inflammatory cytokines, MIP-1δ and MIP-3α are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts in the stromal reaction around tumors.
    Stem Cells and Development 01/2015; 24(10). DOI:10.1089/scd.2014.0176 · 4.20 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) are adult progenitor cells that contribute to stromal tissue renewal [1]. Originally found in the bone marrow [2], MSCs are present in all types of tissues [3] and were recently recognized as closely related to blood vessel pericytes [4]. MSC-based cell therapy is currently investigated with the aim to treat acute and chronic liver injury [5]. Indeed, it was suggested that MSCs might be able to transdifferentiate into hepatocytes [6]. Several other studies demonstrated that MSCs have immunosuppressive and anti-inflammatory properties [7], [8] and [9], which could represent another mechanism by which MSCs improve chronic liver injury.
    Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.030 · 10.40 Impact Factor
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    ABSTRACT: Advanced surgical procedures have traditionally been a domain of open surgery. However, minimally invasive approaches are evolving with the development of robotic technology which appears capable to overcome technical limitations of conventional laparoscopy. While traditionally perceived as impossible indications for minimally invasive surgery, reports on robotic organ transplantations have surfaced with promising results.
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    ABSTRACT: Regenerative medicine aims to replace a body function or specific cell loss. It includes therapies at the forefront of modem medicine, issuing from translational biomedical research. Transplantation of organs and cells has revolutionized the management of patients for whom medical treatment is a failure. Unfortunately, organ shortage is limiting treatment possibility. As an example, among the 15,000 patients with type I diabetes in Switzerland, only approximately 30 can receive a pancreas or an islet transplant per year. Second example, 500 patients die each year in Switzerland from alcoholic cirrhosis because no treatment is available. Transplantation of islet cells, hepatocytes, mesenchymal stem cells or dopaminergic neurons represents hope fora therapy available for large populations of patients.
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    ABSTRACT: Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
    PLoS ONE 03/2014; 9(3):e91268. DOI:10.1371/journal.pone.0091268 · 3.53 Impact Factor
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    ABSTRACT: Magnetic resonance imaging (MRI) gadolinium-perfusion was applied in simulated Donation after Cardiac Death (DCD) in porcine kidneys to measure intrarenal perfusion. Adenosine triphosphate (ATP) resynthesis during oxygenated hypothermic perfusion was compared to evaluate the "ex vivo organ viability". Adenine nucleotide (AN) was measured by P nuclear magnetic resonance (NMR) spectroscopy. Whereas this latter technique requires sophisticated hardware, gadolinium-perfusion can be realized using any standard proton-MRI scanner. The aim of this work was to establish a correlation between the two methods. Twenty-two porcine kidneys presenting up to 90 min warm ischemia were perfused with oxygenation at 4°C using our magnetic resonance-compatible machine. During the perfusion, P NMR spectroscopy and gadolinium-perfusion sequences were performed. Measures obtained from the gadolinium-perfusion were the speed of elimination of the cortical gadolinium and the presence or absence of a corticomedullar shunt. For ATP resynthesis analysis, P chemical shift imaging was acquired and analyzed. All the kidneys have been submitted to histologic examination. ATP resynthesis was observed in all organs presenting a cortical gadolinium elimination slope of (-) 23° or greater. In organs with lower gadolinium elimination, no AN or only precursors were detected. This study reveals a link between the two methods and demonstrates ex vivo viability in 93% of the analyzed kidneys. Benefits and side effects of both methods are discussed. Oxygenated hypothermic perfusion enables the evaluation of kidneys in DCD simulated situation; gadolinium-perfusion can be introduced into any center equipped with a proton-MRI scanner allowing results superposable with ATP measurement.
    Transplantation 01/2014; 97(2):148-53. DOI:10.1097/01.TP.0000438023.02751.22 · 3.78 Impact Factor
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    ABSTRACT: Minimally invasive approaches for cholecystectomy are evolving in a surge for the best possible clinical outcome for the patients. As one of the most recent developments, a robotic set of instrumentation to be used with the da Vinci Si Surgical System has been developed to overcome some of the technical challenges of manual single incision laparoscopy. From February 2011 to February 2013, all consecutive robotic single site cholecystectomies (RSSC) were prospectively collected in a dedicated database. Demographic, intra- and postoperative data of all patients that underwent RSSC at our institution were analyzed. Data were evaluated for the overall patient cohort as well as after stratification according to patient BMI (body mass index) and surgeon's experience. During the study period, 82 patients underwent robotic single site cholecystectomy at our institution. The dominating preoperative diagnosis was cholelithiasis. Mean overall operative time was 91 min. Intraoperative complications occurred in 2.4% of cases. One conversion to open surgery due to the intraoperative finding of a gallbladder carcinoma was observed and two patients needed an additional laparoscopic trocar. The rate of postoperative complications was 4.9% with a mean length of stay of 2.4 days. No significant differences were observed when comparing results between robotic novices and robotic experts. Patients with higher BMI trended towards longer surgical console and overall operative time, but resulted in similar rates of conversions and complications when compared to normal weight patients. Robotic Single-Site cholecystectomy can be performed safely and effectively with low rates of complications and conversions in patients with differing BMI and by surgeons with varying levels of experience.
    Journal of Hepato-Biliary-Pancreatic Sciences 01/2014; 21(1). DOI:10.1002/jhbp.36 · 2.31 Impact Factor
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    ABSTRACT: The progress of medical therapies, which rely on the transplantation of microencapsulated living cells, depends on the quality of the encapsulating material. Such material has to be biocompatible, and the microencapsulation process must be simple and not harm the cells. Alginate-poly(ethylene glycol) hybrid microspheres (alg-PEG-M) were produced by combining ionotropic gelation of sodium alginate (Na-alg) using calcium ions with covalent crosslinking of vinyl sulfone-terminated multi-arm poly(ethylene glycol) (PEG-VS). In a one-step microsphere formation process, fast ionotropic gelation yields spherical calcium alginate gel beads, which serve as a matrix for simultaneously but slowly occurring covalent cross-linking of the PEG-VS molecules. The feasibility of cell microencapsulation was studied using primary human foreskin fibroblasts (EDX cells) as a model. The use of cell culture media as polymer solvent, gelation bath, and storage medium did not negatively affect the alg-PEG-M properties. Microencapsulated EDX cells maintained their viability and proliferated. This study demonstrates the feasibility of primary cell microencapsulation within the novel microsphere type alg-PEG-M, serves as reference for future therapy development, and confirms the suitability of EDX cells as control model.
    Materials 12/2013; 7(1). DOI:10.3390/ma7010275 · 1.88 Impact Factor
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    ABSTRACT: Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been extensively investigated in small animal models to treat both acute and chronic liver injuries. Mechanisms of action are not clearly elucidated but may include their ability to differentiate into hepatocyte-like cells, to reduce inflammation, and to enhance tissue repair at the site of injury. This approach is controversial and evidence in large animals is missing. Side effects of MSC infusion such as the contribution to a fibrotic process have been reported in experimental settings. Nevertheless, MSCs moved quickly from bench to bedside and over 280 clinical trials are registered, of which 28 focus on the treatment of liver diseases. If no severe side-effects were observed so far, long-term benefits remain uncertain. More preclinical data regarding mechanisms of action, long term safety and efficacy are warranted before initiating large scale clinical application. The proposal of this review is to visit the current state of knowledge regarding mechanisms behind the therapeutic effects of MSCs in the treatment of experimental liver diseases, to address questions about efficacy and risk, and to discuss recent clinical advances involving MSC-based therapies.
    Stem Cell Research 08/2013; 11(3):1348-1364. DOI:10.1016/j.scr.2013.08.011 · 3.91 Impact Factor
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    ABSTRACT: Two types of hydrogel microspheres have been developed. Fast ionotropic gelation of sodium alginate (Na-alg) in the presence of calcium ions was combined with slow covalent cross-linking of poly(ethylene glycol) (PEG) derivatives. For the first type, the fast obtainable Ca-alg hydrogel served as spherical matrix for the simultaneously occurring covalent cross-linking of multi-arm PEG derivative. A two-component interpenetrating network was formed in one step upon extruding the mixture of the two polymers into the gelation bath. For the second type, heterobifunctional PEG was grafted onto Na-alg prior to gelation. Upon extrusion of the polymer solution into the gelation bath, fast Ca-alg formation ensured the spherical shape and was accompanied by cross-linker-free covalent cross-linking of the PEG side chains. Thus, one-component hydrogel microspheres resulted. We present the physical properties of the hydrogel microspheres and demonstrate the feasibility of cell microencapsulation for both types of polymer networks.
    Macromolecular Symposia 07/2013; 329(1). DOI:10.1002/masy.201200099
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    ABSTRACT: Experiments injecting pluripotent cells into blastocyst embryos open exciting possibilities for the generation of self‐specific organs in xenogeneic animals.
    American Journal of Transplantation 06/2013; 13(6):1377. DOI:10.1111/ajt.12322 · 6.19 Impact Factor
  • Transplantation 01/2012; 94(10S):1016. DOI:10.1097/00007890-201211271-02009 · 3.78 Impact Factor
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    ABSTRACT: In humans, circulating CD4(+)CD25(high) T cells contain mainly regulatory T cells (Treg; FoxP3(+)IL-7Rα(low)), but a small subset is represented by activated effector T cells (Tact; FoxP3(-)IL-7Rα(high)). The balance between Tact and Treg may be important after transplantation. The aim of this study was first to analyze and correlate CD4(+)CD25(high) Tact and Treg with the clinical status of kidney transplant recipients and second to study prospectively the effect of two immunosuppressive regimens on Tact/Treg during the first year after transplantation. CD4(+)CD25(high) Tact and Treg were analyzed by flow cytometry, either retrospectively in 90 patients greater than 1 year after kidney transplantation (cross-sectional analysis) or prospectively in 35 patients receiving two immunosuppressive regimens after kidney transplantation (prospective analysis). A higher proportion of Tact and a lower proportion of Treg were found in the majority of kidney recipients. In chronic humoral rejection, a strikingly higher proportion of Tact was present. A subgroup of stable recipients receiving calcineurin inhibitor-free immunosuppression (mycophenolate mofetil, azathioprine, or sirolimus) had Tact values that were similar to healthy individuals. In the prospective analysis, the proportion of Tact significantly increased in both immunosuppression groups during the first year after transplantation. These data highlight distinct patterns in the proportion of circulating Tact depending on the clinical status of kidney recipients. Moreover, the prospective analysis demonstrated an increase in the proportion of Tact, regardless of the immunosuppressive regimen. The measurement of Tact, in addition to Treg, may become a useful immune monitoring tool after kidney transplantation.
    Clinical Journal of the American Society of Nephrology 08/2011; 6(8):2025-33. DOI:10.2215/CJN.09611010 · 5.25 Impact Factor
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    ABSTRACT: Streptozotocin (STZ) is the most widely used diabetogenic agent in animal models of islet transplantation. However, the immunomodifying effects of STZ and the ensuing hyperglycemia on lymphocyte subsets, particularly on T regulatory cells (Tregs), remain poorly understood. This study evaluated how STZ-induced diabetes affects adaptive immunity and the consequences thereof on allograft rejection in murine models of islet and skin transplantation. The respective toxicity of STZ and hyperglycemia on lymphocyte subsets was tested in vitro. The effect of hyperglycemia was assessed independently of STZ in vivo by the removal of transplanted syngeneic islets, using an insulin pump, and with rat insulin promoter diphtheria toxin receptor transgenic mice. Early lymphopenia in both blood and spleen was demonstrated after STZ administration. Direct toxicity of STZ on lymphocytes, particularly on CD8(+) cells and B cells, was shown in vitro. Hyperglycemia also correlated with blood and spleen lymphopenia in vivo but was not lymphotoxic in vitro. Independently of hyperglycemia, STZ led to a relative increase of Tregs in vivo, with the latter retaining their suppressive capacity in vitro. The higher frequency of Tregs was associated with Treg proliferation in the blood, but not in the spleen, and higher blood levels of transforming growth factor-β. Finally, STZ administration delayed islet and skin allograft rejection compared with naive mice. These data highlight the direct and indirect immunosuppressive effects of STZ and acute hyperglycemia, respectively. Thus, these results have important implications for the future development of tolerance-based protocols and their translation from the laboratory to the clinic.
    Diabetes 07/2011; 60(9):2331-40. DOI:10.2337/db11-0159 · 8.47 Impact Factor
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    ABSTRACT: No guidelines exist concerning treatment of asymptomatic bacteriuria in renal transplant recipients (RTR). Because of scarce clinical symptoms and fear of complications, such episodes are frequently treated based on subjective criteria without clear clinical benefit, with the risk of selecting resistant pathogens. We retrospectively analysed the outcome of 334 asymptomatic Escherichia coli (E. coli) and Enterococcus faecalis (E. faecalis) bacteriuria that occurred in 77 RTR later than 1 month post-transplantation. We distinguished: Type I, high-grade bacteriuria with pyuria; Type II, high-grade bacteriuria without pyuria; Type III, low-grade bacteriuria with pyuria and Type IV, low-grade bacteriuria without pyuria. None of the 334 episodes was followed by acute rejection or chronic pyelonephritis. One hundred and one (30%) episodes were treated [32 (62%) Type I, 38 (45%) Type II, 13 (36%) Type III and 18 (11%) Type IV]. Evolution to symptomatic urinary tract infection (UTI) was similar between treated and untreated episodes (0/101 versus 4/233, P = 0.32). The four UTI resolved favourably without further complication upon treatment. Persistent asymptomatic bacteriuria occurred in 45 (46%) treated episodes (2 Type I, 27 Type II, 8 Type III and 9 Type IV), with selection of resistant pathogen in 35 cases (78%). Spontaneous bacterial clearance occurred in 138 (59%) untreated episodes (15 Type I, 23 Type II, 9 Type III and 91 Type IV). Negative control cultures tended to be more frequent in treated Type I (P = 0.09) and in untreated Type II episodes (P = 0.08). Restricting antibiotic treatments for asymptomatic low-grade bacteriuria and high-grade bacteriuria in the absence of pyuria, occurring later than 1 month posttransplantation, might be safe in RTR.
    Nephrology Dialysis Transplantation 05/2011; 26(12):4109-14. DOI:10.1093/ndt/gfr198 · 3.49 Impact Factor
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    ABSTRACT: The major challenge in transplantation medicine remains long-term allograft acceptance, with preserved allograft function under minimal chronic immunosuppression. To safely achieve the goal of sustained donor-specific T and B cell non-responsiveness, research efforts are now focusing on therapies based on cell subsets with regulatory properties. In particular the transfusion of human regulatory T cells (Treg) is currently being evaluated in phase I/II clinical trials for the treatment of graft versus host disease following hematopoietic stem cell transplantation, and is also under consideration for solid organ transplantation. The purpose of this review is to recapitulate current knowledge on naturally occurring as well as induced human Treg, with emphasis on their specific phenotype, suppressive function and how these cells can be manipulated in vitro and/or in vivo for therapeutic purposes in transplantation medicine. We highlight the potential but also possible limitations of Treg-based strategies to promote long-term allograft survival. It is evident that the bench-to-beside translation of these protocols still requires further understanding of Treg biology. Nevertheless, current data already suggest that Treg therapy alone will not be sufficient and needs to be combined with other immunomodulatory approaches in order to induce allograft tolerance.
    Self/Nonself - Immune Recognition and Signaling 01/2011; 2(1):26-34. DOI:10.4161/self.2.1.15422
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    ABSTRACT: Embryonic stem cells (ESC) can differentiate into all cell lineages, and ESC-like cells were shown to induce hematopoietic chimerism and tolerance in allogeneic models. The aim of our study was to test the capacity of mouse ESC (mESC) to engraft in rats in a xenotransplantation setting. Forty-six rats were transplanted intravenously with 1 million mESC, without immunosuppression (group 1, n = 23) or with cyclosporine (group 2, n = 23). Three months after mESC transplantation, skin grafts were performed from allogeneic, xenogeneic identical to mESC, or xenogeneic third party donors. At day 27 post-transplant, we detected circulating mouse cells in the blood of 4/23 and 5/23 animals of group 1 and group 2, respectively. Chimerism was confirmed by PCR. We also identified long-term surviving murine cells within livers of chimeric animals. Skin grafts showed no difference in survival between allogeneic and xenogeneic donors. Transplantation of xenogeneic mouse ESC induced short-term chimerism in the blood and persistent tissue chimerism in the liver of recipient rats, but did not induce tolerance to skin grafts. Improved immunosuppressive protocols should be tested to prolong chimerism and allow tolerance.
    Xenotransplantation 10/2010; 17(5):362-9. DOI:10.1111/j.1399-3089.2010.00603.x · 1.78 Impact Factor

Publication Stats

3k Citations
390.54 Total Impact Points

Institutions

  • 1995–2015
    • University of Geneva
      • • Faculty of Medicine
      • • Department of Surgery
      • • Division of Nephrology
      Genève, Geneva, Switzerland
  • 2009
    • Sichuan University
      • Department of General Surgery
      Hua-yang, Sichuan, China
  • 2000–2009
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1997–2008
    • Hôpitaux Universitaires de Genève
      • Département de chirurgie
      Genève, Geneva, Switzerland
  • 1999–2003
    • Massachusetts General Hospital
      • Transplantation Biology Research Center
      Boston, MA, United States
    • Kantonspital Aarau AG
      Aaray, Aargau, Switzerland
  • 1998–2003
    • Harvard Medical School
      • Department of Surgery
      Boston, Massachusetts, United States