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International audience; A bioreactor using membrane technologies was used to demonstrate the feasibility of in-situ bio-methanation coupled to industrial wastewater treatment for biogas upgrading. High biogas productivity (1.7 Nm 3 Biogas/m 3 Bioreactor/day) with high CH4 content (97.9%) was reached. In-situ bio-methanation did not affect the COD removal efficiency of anerobic digestion (>94%). Process resilience has been tested for both substrate overload and H2 intermittence injection. Recovery of high CH4 content after 7 days without H2 injection occurred within few hours. Influence of microbial community has been studied showing that both hydrogenotrophic and homoacetogenic-acetoclastic pathways were involved.

International audience; A pilot-scale anaerobic membrane bioreactor (AnMBR) was designed and optimized for the treatment of real distillery wastewater. A low hydraulic retention time of 3.5 days was reached after only 3 weeks. The AnMBR could treat up to 3.97 g COD /L/day with high biogas production at 1.36 NL biogas /L bioreactor /day. The performances of an AnMBR and an anaerobic packed-bed bioreactor for treating the same wastewater were compared. The AnMBR had a shorter start-up period (21 days), a higher COD removal efficiency (96.9 %), and higher stability and methane production (0.26 L CH4 /g CODinput), indicating the interest of investigating AnMBR industrialization. The membrane performance was also studied, demonstrating a long cleaning cycle interval of at least 44 days. The transmembrane pressure and Food-to-Microorganism ratio were defined to minimize membrane fouling without affecting the anaerobic digestion performance.

International audience; Biotechnological application of microalgae cultures at large scale has significant potential in the various fields of biofuels, food and feed, cosmetic, pharmaceutic, environmental remediation and water treatment. Despite this great potential application, industrialisation of microalgae culture and valorisation is still faced with serious remaining challenges in culture scale-up, harvesting and extraction of target molecules. This review presents a general summary of current techniques for harvesting and extraction of biomolecules from microalgae, their relative merits and potential for industrial application. The cell wall composition and its impact on microalgae cell disruption is discussed. Additionally, more recent progress and promising experimental methods and studies are summarised that would allow the reader to further investigate the state of the art. A final survey of energetic assessments of the different techniques is also made. Bead milling and high-pressure homogenisation seem to give clear advantages in terms of target high value compounds extraction from microalgae, with enzyme hydrolysis as a promising emerging technique. Future industrialisation of microalgae for high scale biotechnological processing will require the establishment of universal comparisonstandards that would enable easy assessment of one technique against another.

Background: Second look surgery, complete cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has the rational to treat patients with high recurrence risk, at an early stage with low peritoneal carcinomatosis index (PCI) score and give a better chance of cure. The purpose of this study is to evaluate our results in terms of morbidity and oncologic benefit for the patient. Materials and Methods: Data were retrospectively collected from all patients with second look surgery and HIPEC between April 2012 and May 2018. Twelve patients with limited carcinomatosis initially resected or perforated tumour (in the literature, 70% and 50% of risk for peritoneal recurrence respectively) were identified (colorectal n=8 and appendicular cancer n=4). At second look a HIPEC was systematically proposed, even if there was no evidence of macroscopic recurrence. Results: Median follow-up from initial diagnosis was 24,8 months (range 9 -67). The mean PCI score was 1 (range 0 – 8). Only 2 patients out of 12 had PCI score other than 0 but histopathology showed peritoneal disease in 3 patients. Three patients were explored by laparoscopy and HIPEC was performed by mini laparotomy. One 90 days, Dindo-Clavien grade IIIb complication occurred (8%) and no mortality. Mean hospital stay was 14 days (range 8 -29). All patients are alive in the follow up but 5 of them presented recurrent disease (42%): 1 peritoneal with redo HIPEC, 1 hepatic with partial hepatectomy, 1 pulmonary resected, 1 multisite recurrence. Conclusions: In our series of 12 patients, with a theoretical risk of 50 to 70% of peritoneal relapse, we only identified 1 (8%) of peritoneal recurrence suggesting that this strategy can be considered as an essential weapon in the management of colorectal cancer and this with an acceptable morbidity.

In Situ Chemical Oxidation (ISCO) can be applied to soils contaminated by polyaromatic hydrocarbons (PAHs). PAH degradation yields are often rather low, because of different obstacles not clearly understood. These include the low availability of PAHs, the type and age of soil organic matter and the carbonate content of the soil. The aim of this work was to provide a better understanding of the influence of these limiting factors at a given oxidant dose. Batch experiments were performed on contrasted PAH-contaminated soils or matrices using permanganate, persulfate, modified Fenton’s reagent and activated persulfate. PAH availability was estimated by a cyclodextrin-enhanced extraction method. Moderate amounts of oxidant were used in order to lower costs whilst minimizing environmental impacts. Results showed that chemical oxidation efficiency was mainly affected by PAH availability, particularly with low persistent oxidant. With permanganate, a correlation was found between PAH availability and degradation yield. With low persistent oxidants, degradation yields were significantly increased by sequential addition. The negative impacts of a high content of soil organic matter and/or carbonate were highlighted. For the aged contaminated soils, PAH degradation yields remained below 30% after most treatments except with permanganate (40–60%) and sequential addition of Fenton’s reagent (40–70%). These results should have useful implications for the design of ISCO treatments. Fil: Lemaire, Julien. Université de Lorraine; Francia Fil: Mora, Veronica Cecilia. Université de Lorraine; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre National de la Recherche Scientifique; Francia Fil: Faure, Pierre. Université de Lorraine; Francia Fil: Hanna, Khalil. Centre National de la Recherche Scientifique; Francia. Ecole Nationale Supérieure de Chimie de Rennes; Francia Fil: Buès, Michel. Université de Lorraine; Francia. Centre National de la Recherche Scientifique; Francia Fil: Simonnot, Marie Odile. Université de Lorraine; Francia. Centre National de la Recherche Scientifique; Francia

International audience; Virtual reality videos are an important element in the range of immersive contents as they open new perspectives for story-telling, journalism or education. Accessing these immersive contents through Internet streaming is however much more difficult owing to the required data rates much higher than for regular videos. While current streaming strategies rely on video compression, in this paper we investigate a radically new stance: we posit that degrading the visual quality is not the only choice to reduce the required data rate, and not necessarily the best. Instead, we propose two new impairments, Virtual Walls (VWs) and Slow Downs (SDs), that change the way the user can interact with the 360 degree video in an environment with insufficient available bandwidth. User experiments with a double-stimulus approach show that, when triggered in proper time periods, these impairments are better perceived than visual quality degradation from video compression. We confirm with network simulations the usefulness of these new types of impairments: incorporated into a FoV-based adaptation, they can enable reduction in stalls and startup delay, and increase quality in FoV, even in the presence of substantial playback buffers.

The incidence of thyroid cancer has increased markedly in recent decades, but has been stable in terms of mortality rates. For the most part, these cancers are treated with surgery, which may or may not be followed by radioactive iodine depending on the tumor subtype. Still, many of these cancers will recur and may be treated with radioactive iodine or another surgery. It is unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. Chemotherapy has a very low response rate. However, in the past few years, several systemic therapies, primarily targeted, have emerged to improve the overall survival of these patients. Alternative treatments are also of interest, namely peptide receptor radionuclide therapy or immunotherapy.

The development of the large European biomethane potential is facing the challenge of the biogas upgrading technologies adaptation to the agricultural context (small and medium size anaerobic digestion units, rural environment). Membrane contactors are an opportunity to adapt the robust Water Scrubbing (WS) process and to decrease the high specific investment costs reported for available technologies. Microporous polypropylene (PP) hollow fiber membrane contactors were combined in an absorption/desorption closed-loop using water as the absorbent. A Design of Experiments methodology highlighted the gas and liquid flowrates, the inlet biogas composition and the absorption gas pressure to be the most significant parameters impacting biomethane quality with a low level of interactions. From the subsequent optimization, gas-grid quality biomethane (......4......=97.6%) was produced with a moderate recovery rate (......4=83.7%). The limited mass transfer efficiency may be compensated by a larger membrane area. Alternatively, the addition of a methane recycling loop, similarly to the conventional WS process, significantly improved the methane recovery rate (......4......=95.9% / ......4=93.5%). These experimental results were confirmed by on-site upgrading of raw farm biogas., Proceedings of the 25th European Biomass Conference and Exhibition, 12-15 June 2017, Stockholm, Sweden, pp. 1116-1125

International audience; The agro-industrial sector generates large amounts of coproducts such as lignocellulosic biomass which could be valorized into many chemicals and bio-based intermediates (sugars, paper pulp, surfactants, polymers or bioethanol). However, in the case of biomass hydrolysis by diluted sulfuric acid, current downstream processes involve a partial or complete neutralization which are not satisfactory for economic and environmental reasons. This work presents a purification process of pentoses from hemicellulosic hydrolysates without neutralization for sulfuric acid recovery. Compared to conventional processes, less energy, water and chemicals are required. Very promising results were obtained at pilot scale with 100 L of wheat bran hydrolysates. The process is based on the combination of ultrafiltration, Conventional electrodialysis and ion-exchange. Ultrafiltration with a 10 kDa organic membrane totally removed harmful macromolecules which precipitate during electrodialysis operation because of pH rise. Till a volumetric concentration factor 3.6, the average flux kept good for industrial application (27 L h(-1)m(-2)). However suspended materials have to be filtered before ultrafiltration. Besides, a 2.5 diafiltration is required to recover most of sugars (99%): Then conventional electrodialysis was performed to recover most of sulfuric acid (80%). The average faradic yield was quite good (80%) and the specific energy consumption of the electrodialysis stack was quite interesting (1.1 kW h per kg of H2SO4 recovered and 8.4 kW h per m(3) of hydrolysate). Finally, the complete demineralization (conductivity < 10 mu S cm(-1)) and discoloration (420 nm absorbance < 0.01) of the sugars solution was performed by ion-exchange and an activated carbon polishing treatment. The sugars purity was close to 100% meanwhile the overall sugars recovery rate reach about 90%. Finally we checked that the reused sulfuric acid solution was as efficient as a fresh one in a second hydrolysis operation of wheat bran. Recovery rates could be increased by a scale-up operation or a continuous mode of the process.

Highlights • During the nineties, laparoscopic adjustable gastric banding (LAGB) was considered the safest and most reversible procedure in bariatric surgery. • Long-term follow-up of gastric banding implantation shows an overall complication rate of 34%, with a rate of intragastric migration (IGM) of 0.3–11% according to series. • Jejunal obstruction caused by a band migration can only be treated properly by surgery. • Considering also better weight loss and comorbidities improvement with gastric bypass and sleeve gastrectomy than with gastric banding, this type of late complication invite to question the use of LAGB in current bariatric practice, Introduction We present a rare case of jejunal obstruction due to the migration of a laparoscopic adjustable gastric band (LAGB) that occurred 10 years after surgery and was successfully treated by laparoscopy. This report is compliant with the SCARE guidelines. Presentation of case A 42-year-old woman who underwent LAGB for morbid obesity 10 years ago was admitted with a small bowel obstruction due to the migration of a LAGB in the proximal small bowel. An attempt to endoscopic removal was unsuccessful and resulted in a laparoscopic extraction of the band. The post-operative course was uneventful. Discussion Formerly, LAGB was considered the safest technique in bariatric surgery. However, the rate of complication increases in long-term studies. When the IGM of the band is diagnosed, removal is the only issue. Small bowel obstruction caused by a migrated band appears to be a rare complication following IGM, and the only therapeutic option is surgery because an endoscopic procedure is not reliable. Furthermore, LAGB appears to be a less effective technique for weight loss than the sleeve gastrectomy and the gastric bypass. Conclusion Small bowel obstruction caused by LAGB migration is a rare but serious complication following IGM. In such cases, endoscopy has to be avoided because of the risk of jejunal disruption. The only way to treat it properly is surgery. This type of late complication reinforces the interest in the techniques currently used in bariatric surgery such as sleeve gastrectomy and gastric bypass, providing also a better weight loss than the LAGB.

International audience; Bio-based organic acids are promising renewable carbon sources for the chemical industry. However energy-consuming purification processes are used, like distillation or crystallization, to reach high purities required in some applications. That is why preparative chromatography was studied as an alternative separation technique. In a previous work dealing with the purification of lactic, succinic and citric acids, the Langmuir model was insufficient to explain the elution profiles obtained with a strong anionic resin.Consequently the Langmuir model was coupled with a usual ion-exchange model to take into account the retention of their conjugate bases (

International audience; The valorization of lignocellulosic biomass as a renewable carbon source is growing in chemical industries, particularly in the agro-industrial sector. Many chemicals compounds and bio-based intermediates can be produced but their production needs to be more cost-competitive. The valorization of pentoses in hemicellulosic hydrolysates, obtained by using dilute sulfuric acid, is of growing interest. However, current downstream processes which involve a partial or complete neutralization of the acid are not satisfactory for economic and environmental reasons.This work presents a method of purification of pentoses with sulfuric acid recovery which reduces water and chemicals consumptions. The results obtained at the laboratory scale with wheat bran hydrolysates are very promising. The process is based on the combination of ultrafiltration, conventional electrodialysis and ion-exchange. A special organic UF membrane (Alpha Laval - UFX10pHt), resistant to acidic conditions, removed totally macromolecules which can damage the electrodialysis unit by precipitation, with good mean permeate flow rate (24 L h−1 m−2 till VCF = 4.4). Then, conventional electrodialysis was performed to recover most of sulfuric acid (>80%) without losing sugars (

An industrial coating site in activity located on a chalky plateau, contaminated by BTEX (mainly xylenes, no benzene), is currently remediated by in situ chemical oxidation (ISCO). We present the bench scale study that was conducted to select the most appropriate oxidant. Ozone and catalyzed hydrogen peroxide (Fenton's reaction) were discarded since they were incompatible with plant activity. Permanganate, activated percarbonate and activated persulfate were tested. Batch experiments were run with groundwater and groundwater-chalk slurries with these three oxidants. Total BTEX degradation in groundwater was reached with all the oxidants. The molar ratios [oxidant]:[Fe(2+)]:[BTEX] were 100:0:1 with permanganate, 100:100:1 with persulfate and 25:100:1 with percarbonate. Precipitation of either manganese dioxide or iron carbonate (siderite) occurred. The best results with chalk slurries were obtained with permanganate at the molar ratio 110:0:1 and activated persulfate at the molar ratio 110:110:1. To avoid precipitation, persulfate was also used without activation at the molar ratio 140:1. Natural Oxidant Demand measured with both oxidants was lower than 5% of initial oxidant contents. Activated percarbonate was not appropriate because of radical scavenging by carbonated media. Permanganate and persulfate were both effective at oxidant concentrations of ca 1 g kg(-1) with permanganate and 1.8 g kg(-1) with persulfate and adapted to site conditions. Activation of persulfate was not mandatory. This bench scale study proved that ISCO remediation of a chalky aquifer contaminated by mainly xylenes was possible with permanganate and activated or unactivated persulfate.

It was recently demonstrated that the pathogen Brucella melitensis produces a polar sheathed flagellum under the control of the master regulator FtcR. However, the regulatory mechanism controlling the flagellar assembly remains unknown. In this work, we investigate the flagellar hierarchy of B. melitensis as well as the flagellin FliC regulation. We show that a mutation in fliF or flgE (coding for the basal body structure and the hook, respectively) does not affect FliC synthesis, suggesting that production of FliC does not depend on the flagellar assembly. We demonstrate that FlbT is a FliC activator since inactivation of flbT causes a decrease in fliC expression by using a fliC–lacZ translational reporter construct. Moreover, the quantitative real-time PCR and Western blot analysis show a marked decrease in fliC mRNA and FliC protein level, respectively. Conversely, the B. melitensis wild-type strain overexpressing flaF fails to produce FliC, suggesting an opposite function. Interestingly, the expression of the flbT gene in an ftcR or an flbT mutant restores FliC production, demonstrating that FlbT plays a regulatory checkpoint role in FliC synthesis. This mechanism could be conserved in the Rhizobiales since complementation of an flbT or an ftcR mutant with flbT from Sinorhizobium meliloti restores FliC synthesis.

The genome of Brucella melitensis contains genes coding for the sigma factors RpoD, RpoN, RpoH1, RpoH2, RpoE1 and RpoE2. Previously published data show that B. melitensis is flagellated and that an rpoE1 mutant overexpresses the flagellar protein FlgE. In this study, we demonstrate that mutation of rpoE1 causes an overexpression of the flagellar genes fliF, flgE, fliC, flaF and flbT, correlating with the production of a longer filament and thereby demonstrating that RpoE1 acts as a flagellar repressor. Moreover, mutation of rpoE1 increases the promoter activity of the flagellar master regulator ftcR, suggesting that RpoE1 acts upstream of ftcR. Together, these data show that RpoE1 represses the flagellar synthesis and filament length in B. melitensis.

Many pathogenic bacteria use a regulatory process termed quorum sensing (QS) to produce and detect small diffusible molecules to synchronize gene expression within a population. In Gram-negative bacteria, the detection of, and response to, these molecules depends on transcriptional regulators belonging to the LuxR family. Such a system has been discovered in the intracellular pathogen Brucella melitensis, a Gram-negative bacterium responsible for brucellosis, a worldwide zoonosis that remains a serious public health concern in countries were the disease is endemic. Genes encoding two LuxR-type regulators, VjbR and BabR, have been identified in the genome of B. melitensis 16 M. A ΔvjbR mutant is highly attenuated in all experimental models of infection tested, suggesting a crucial role for QS in the virulence of Brucella. At present, no function has been attributed to BabR. The experiments described in this report indicate that 5% of the genes in the B. melitensis 16 M genome are regulated by VjbR and/or BabR, suggesting that QS is a global regulatory system in this bacterium. The overlap between BabR and VjbR targets suggest a cross-talk between these two regulators. Our results also demonstrate that VjbR and BabR regulate many genes and/or proteins involved in stress response, metabolism, and virulence, including those potentially involved in the adaptation of Brucella to the oxidative, pH, and nutritional stresses encountered within the host. These findings highlight the involvement of QS as a major regulatory system in Brucella and lead us to suggest that this regulatory system could participate in the spatial and sequential adaptation of Brucella strains to the host environment., Some pathogens use the regulatory process termed Quorum Sensing (QS) to synchronize gene expression within bacterial population. We report here the first genome scale study of the Quorum Sensing system of the intracellular pathogen Brucella melitensis. Our combined proteomic and transcriptomic data suggest that Quorum Sensing is involved in the spatial and sequential adaptation of B. melitensis to the host environment.

Successful establishment of infection by bacterial pathogens requires fine-tuning of virulence-related genes. Quorum sensing (QS) is a global regulation process based on the synthesis of, detection of, and response to small diffusible molecules, called N -acyl-homoserine lactones (AHL), in gram-negative bacteria. In numerous species, QS has been shown to regulate genes involved in the establishment of pathogenic interactions with the host. Brucella melitensis produces N -dodecanoyl homoserine lactones (C 12 -HSL), which down regulate the expression of flagellar genes and of the virB operon (encoding a type IV secretion system), both of which encode surface virulence factors. A QS-related regulator, called VjbR, was identified as a transcriptional activator of these genes. We hypothesized that VjbR mediates the C 12 -HSL effects described above. vjbR alleles mutated in the region coding for the AHL binding domain were constructed to test this hypothesis. These alleles expressed in trans in a Δ vjbR background behave as constitutive regulators both in vitro and in a cellular model of infection. Interestingly, the resulting B. melitensis strains, unable to respond to AHLs, aggregate spontaneously in liquid culture. Preliminary characterization of these strains showed altered expression of some outer membrane proteins and overproduction of a matrix-forming exopolysaccharide, suggesting for the first time that B. melitensis could form biofilms. Together, these results indicate that QS through VjbR is a major regulatory system of important cell surface structures of Brucella and as such plays a key role in host-pathogen interactions.

International audience; This work is a part of the OXYSOL project aiming at the conception of a global treatment pathway including In Situ Chemical Oxidation to clean up soils of former metallurgical sites. It deals with the selection of the most adapted oxidants. Batch experiments were performed with aged contaminated soil samples of a former steel-making plant to degrade the 16 US EPA PAHs. In this research, hydrogen peroxide, modified Fenton's reaction, potassium permanganate, sodium percarbonate and sodium persulfate were compared at high and moderate doses. Hydrogen peroxide, modified Fenton's reagent, percarbonate and activated persulfate led to a maximum degradation ratio of 45%. A higher ratio (70%) was obtained with a high dose of permanganate. Except for permanganate, increasing oxidant dose did not improve degradation rates, especially with radical-based oxidative systems probably due to radical scavenging. Oxidant doses had an effect on pH that drastically increased or dropped in some cases, which was a drawback. Permanganate efficacy was mainly assigned to its persistence. In all cases, the low availability of PAHs, partly sequestrated in the aged soil, was identified as the most limiting factor for degradation performance. Oxidants were ranked according to their efficiency for PAH oxidation in soils. Efficiency was not correlated to the doses.

International audience; Soils of former steel-making or coking plants have been contaminated for decades by PAHs. These soils could be cleaned up by In situ chemical oxidation (ISCO) but the low PAH availability may be a drawback. The objective of the present contribution was to study the efficiency of PAH oxidation in two aged soils compared to a spiked soil in dynamic conditions. Column experiments were performed with two oxidants: hydrogen peroxide used in modified Fenton's reaction and activated persulfate. The oxidant doses were moderate to ensure the feasibility of process upscaling. Besides, the availability of PAHs in these soils was measured by extraction with a cyclodextrin. Our results showed that oxidation was limited: the higher PAH degradation rate was 30% with the aged soils and 55% with the spiked one. PAH availability was a parameter explaining these results but no direct correlation was found between PAH extractability by the cyclodextrin and oxidation efficiency. Other parameters were also involved, such as the organic carbon content, the calcite content and the pH. This study was a first achievement before studying the influence of a number of parameters on the efficiency of PAH oxidation in aged soils.

BACKGROUND:: Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction. MATERIAL AND METHODS:: Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12-84). RESULTS:: Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (

Graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). Chronic GVHD (cGVHD) may lead to irreversible liver failure. We report a case of successful liver transplantation (LT) for end-stage liver failure because of cGVHD that had developed 22 months after BMT in a 24-year-old male. Re-transplantation was necessary 6 months later because of intrahepatic ischaemic type biliary tract lesions. He is now in excellent condition 10 years after the first transplant. This experience and the review of literature indicate that LT can cure GVHD-related chronic liver failure. Recurrent GVHD in the allograft has not yet been reported.