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Influence of Blood Pressure and Calcineurin Inhibitors on Kidney Function After Heart or Liver Transplantation.

Fri, 12/08/2017 - 13:45

Influence of Blood Pressure and Calcineurin Inhibitors on Kidney Function After Heart or Liver Transplantation.

Transplantation. 2017 Dec 05;:

Authors: Morath C, Opelz G, Döhler B, Zeier M, Süsal C

Abstract
BACKGROUND: Chronic kidney disease is common after heart or liver transplantation, with calcineurin inhibitors (CNI) considered the key contributor. A possible influence of posttransplant blood pressure has not been extensively examined.
METHODS: Data from adult recipients of a first heart or liver transplant were analyzed regarding the relationship between blood pressure at year 1, renal function at year 5, and CNI therapy.
RESULTS: Whereas we confirmed the well-known detrimental effect of increased 1-year systolic blood pressure on 5-year kidney graft survival, heart or liver graft survival were not affected. However, among 2,534 heart transplant recipients with good renal function at year 1, increasing systolic blood pressure at year 1 was associated with higher rates of poor renal function at year 5 posttransplant. This association was confirmed on multivariate analysis overall (odds ratio [OR] 1.25 per 20 mmHg increment, P<0.001) and within subgroups. Similar results were observed in 1,822 liver transplant recipients (OR 1.35, P<0.001). Neither the type of CNI nor CNI dose or trough level at year 1 showed a significant association with kidney function at year 5.
CONCLUSIONS: One-year blood pressure was identified as the major modifiable risk factor associated with deteriorating kidney function between years 1 to 5 after heart or liver transplantation.

PMID: 29215461 [PubMed - as supplied by publisher]

Comparison of Preemptive Therapy and Antiviral Prophylaxis for Prevention of Cytomegalovirus in Seropositive Liver Transplant Recipients.

Fri, 12/08/2017 - 13:45

Comparison of Preemptive Therapy and Antiviral Prophylaxis for Prevention of Cytomegalovirus in Seropositive Liver Transplant Recipients.

Transplantation. 2017 Dec 05;:

Authors: Liu AW, Jutivorakool K, Fisher CE, Rakita RM, Reyes JD, Bhattacharya RB, Jerome KR, Limaye AP

Abstract
BACKGROUND: Few studies have directly compared preemptive therapy (PET) and antiviral prophylaxis (AP) for prevention of cytomegalovirus disease in CMV seropositive (R+) orthotopic liver transplant (OLT) recipients.
METHODS: We prospectively assessed CMV disease and clinical outcomes among 160 consecutive R+ OLT recipients who received PET (weekly plasma CMV PCR for 3 months, oral valganciclovir 900 mg twice daily for CMV viremia >250 IU/mL, until 2 consecutive negative weekly PCR results) and compared them to a historical cohort of 156 R+ recipients who received AP (valganciclovir 900 mg daily for 3 months).
RESULTS: Patient characteristics were similar between PET and AP cohorts (p>0.05 all comparisons). In the PET group, 24% (39/160) developed CMV viremia >250 IU/mL at a median of 42 (range 7-93) days post-OLT. CMV monitoring adherence in the PET cohort was 85% (1488/1760 required tests) and 86% (30/36) initiated PET within 3 days of the CMV result. By 12 months post-OLT, the incidence of CMV disease, acute allograft rejection, major infection, or death in the PET and AP cohorts was not significantly different: 2% vs 2%, 19% vs 16%, 10.5% vs 10.8%, and 5% vs 8%, respectively (p > 0.05 all comparisons). The estimated proportion of drug-exposed patients and average antiviral drug exposure were significantly lower with PET vs AP: 24% vs 100%, p<0.001, and 15.8 vs 81g per patient, p<0.001, respectively.
CONCLUSIONS: Preemptive therapy is feasible in a nonresearch setting and is associated with similar CMV disease rates and other clinically-relevant outcomes to antiviral prophylaxis in CMV seropositive liver transplant recipients.

PMID: 29215460 [PubMed - as supplied by publisher]

Low ascitic fluid total protein levels is not associated to the development of spontaneous bacterial peritonitis in a cohort of 274 patients with cirrhosis.

Fri, 12/08/2017 - 13:45

Low ascitic fluid total protein levels is not associated to the development of spontaneous bacterial peritonitis in a cohort of 274 patients with cirrhosis.

Scand J Gastroenterol. 2017 Dec 07;:1-6

Authors: Mo S, Bendtsen F, Wiese SS, Kimer N

Abstract
BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a complication to decompensated cirrhosis. Fluoroquinolones may prevent SBP. However, predictive markers for SBP are wanted. Guidelines suggest that patients with ascitic fluid protein below 15 g/l receive fluoroquinolones to prevent SBP. This study aimed to assess the clinical utility of low ascitic fluid protein in predicting SBP in patients with cirrhosis and ascites.
METHODS: A total of 274 patients with cirrhosis and ascites underwent paracentesis between January 2010 and June 2015. Patients were followed until two years, development of SBP, initiation of ciprofloxacin, death or liver transplantation. Data were compared between groups of patients with 'high' or 'low' ascitic protein.
RESULTS: SBP developed in 31 patients (11.3%). No difference in mean ascitic fluid protein levels were found (SBP, mean: 8.5 g/l and no SBP 8.2 g/l, p = .825). SBP developed at equal rates in patients with 'high' or 'low' ascitic protein (10.8% (≤15 g/l) and 14.0% (>15 g/l), p = .599). The same trend was observed when adjusting the threshold below 10 g/l (11.9% (≤10 g/l) and 10.2% (>10 g/l), p = .697).
CONCLUSIONS: Low ascitic fluid protein does not predict SBP in patients with cirrhosis and ascites. Better markers are needed.

PMID: 29214880 [PubMed - as supplied by publisher]

Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region.

Fri, 12/08/2017 - 13:45

Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region.

Ann Lab Med. 2018 Mar;38(2):85-94

Authors: Qin X, Rui J, Xia Y, Mu H, Song SH, Raja Aziddin RE, Miles G, Sun Y, Chun S

Abstract
BACKGROUND: The immunosuppressant drugs (ISDs), tacrolimus and cyclosporine, are vital for solid organ transplant patients to prevent rejection. However, toxicity is a concern, and absorption is highly variable across patients; therefore, ISD levels need to be precisely monitored. In the Asia-Pacific (APAC) region, tacrolimus and cyclosporine concentrations are typically measured using immunoassays. The objective of this study was to assess the analytical performance of Roche Elecsystacrolimus and cyclosporinee electrochemiluminescence immunoassays (ECLIAs).
METHODS: This evaluation was performed in seven centers across China, South Korea, and Malaysia. Imprecision (repeatability and reproducibility), assay accuracy, and lot-to-lot reagent variability were tested. The Elecsys ECLIAs were compared with commercially available immunoassays (Architect, Dimension, and Viva-E systems) using whole blood samples from patients with various transplant types (kidney, liver, heart, and bone marrow).
RESULTS: Coefficients of variation for repeatability and reproducibility were ≤5.4% and ≤12.4%, respectively, for the tacrolimus ECLIA, and ≤5.1% and ≤7.3%, respectively, for the cyclosporine ECLIA. Method comparisons of the tacrolimus ECLIA with Architect, Dimension, and Viva-E systems yielded slope values of 1.01, 1.14, and 0.897, respectively. The cyclosporine ECLIA showed even closer agreements with the Architect, Dimension, and Viva-E systems (slope values of 1.04, 1.04, and 1.09, respectively). No major differences were observed among the different transplant types.
CONCLUSIONS: The tacrolimus and cyclosporine ECLIAs demonstrated excellent precision and close agreement with other immunoassays tested. These results show that both assays are suitable for ISD monitoring in an APAC population across a range of different transplant types.

PMID: 29214751 [PubMed - in process]

PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease.

Fri, 12/08/2017 - 13:45

PD-L1 Prevents the Development of Autoimmune Heart Disease in Graft-versus-Host Disease.

J Immunol. 2017 Dec 06;:

Authors: Juchem KW, Sacirbegovic F, Zhang C, Sharpe AH, Russell K, McNiff JM, Demetris AJ, Shlomchik MJ, Shlomchik WD

Abstract
Effector memory T cells (TEM) are less capable of inducing graft-versus-host disease (GVHD) compared with naive T cells (TN). Previously, in the TS1 TCR transgenic model of GVHD, wherein TS1 CD4 cells specific for a model minor histocompatibility Ag (miHA) induce GVHD in miHA-positive recipients, we found that cell-intrinsic properties of TS1 TEM reduced their GVHD potency relative to TS1 TN Posttransplant, TS1 TEM progeny expressed higher levels of PD-1 than did TS1 TN progeny, leading us to test the hypothesis that TEM induce less GVHD because of increased sensitivity to PD-ligands. In this study, we tested this hypothesis and found that indeed TS1 TEM induced more severe skin and liver GVHD in the absence of PD-ligands. However, lack of PD-ligands did not result in early weight loss and colon GVHD comparable to that induced by TS1 TN, indicating that additional pathways restrain alloreactive TEM TS1 TN also caused more severe GVHD without PD-ligands. The absence of PD-ligands on donor bone marrow was sufficient to augment GVHD caused by either TEM or TN, indicating that donor PD-ligand-expressing APCs critically regulate GVHD. In the absence of PD-ligands, both TS1 TEM and TN induced late-onset myocarditis. Surprisingly, this was an autoimmune manifestation, because its development required non-TS1 polyclonal CD8+ T cells. Myocarditis development also required donor bone marrow to be PD-ligand deficient, demonstrating the importance of donor APC regulatory function. In summary, PD-ligands suppress both miHA-directed GVHD and the development of alloimmunity-induced autoimmunity after allogeneic hematopoietic transplantation.

PMID: 29212909 [PubMed - as supplied by publisher]

Is hematoxylin-eosin staining in rectal mucosal and submucosal biopsies still useful for the diagnosis of Hirschsprung disease?

Fri, 12/08/2017 - 13:45

Is hematoxylin-eosin staining in rectal mucosal and submucosal biopsies still useful for the diagnosis of Hirschsprung disease?

Diagn Pathol. 2017 Dec 06;12(1):84

Authors: Serafini S, Santos MM, Aoun Tannuri AC, Zerbini MCN, de Mendonça Coelho MC, de Oliveira Gonçalves J, Tannuri U

Abstract
BACKGROUND: Hematoxylin-eosin (HE) staining of a full-thickness rectal wall fragment is classically used for the diagnosis of Hirschsprung disease (HD). However, this technique requires large fragments for a better diagnosis. Additionally, the histochemical and immunohistochemical methods of staining small fragments of rectal mucosal and submucosal biopsies are not available in all centers. Therefore, the possibility of diagnosing HD through HE staining in these biopsies could be a valuable alternative for centers that do not have more specific techniques. The objectives of the current investigation were to evaluate the concordance of the results obtained by HE staining and the calretinin method with acetylcholinesterase (AChE) activity in fragments of mucosa and submucosa in the diagnosis of HD.
METHODS: For this study, 50 cases from our laboratory were selected. The tissue material was embedded in paraffin. Sixty levels of each fragment were utilized for HE, and the other 3 levels were used for calretinin. These slides were analyzed under the microscope, photographed and classified as either positive for HD when no ganglion cells were found with nerve trunks present or as negative when ganglion cells were found. The results from reading the slides were compared with those of AChE.
RESULTS: Of the 50 cases evaluated by the HE technique, only 5 contradicted the diagnosis based on AChE, with a Kappa value of 0.800 and an accuracy of 90%. In the comparison between calretinin and AChE, 8 cases were discordant, with a Kappa value of 0.676 and an accuracy of 84%.
CONCLUSIONS: The concordance of results from AChE and HE methods was satisfactory, allowing for the potential use of the HE method for fragments of mucosa and submucosa as a valid alternative in the diagnosis of HD. The immunohistochemical technique of calretinin did not show good agreement with the AChE activity in our study.

PMID: 29212517 [PubMed - in process]

The role of endoscopic ultrasound in children with Pancreatobiliary and gastrointestinal disorders: a single center series and review of the literature.

Fri, 12/08/2017 - 13:45

The role of endoscopic ultrasound in children with Pancreatobiliary and gastrointestinal disorders: a single center series and review of the literature.

BMC Pediatr. 2017 Dec 06;17(1):203

Authors: Fugazza A, Bizzarri B, Gaiani F, Manfredi M, Ghiselli A, Crafa P, Carra MC, de'Angelis N, de'Angelis GL

Abstract
BACKGROUND: The role of endoscopic ultrasound (EUS) in the management of pancreatobiliary and digestive diseases is well established in adults, but it remains limited in children. The aim of this study was to evaluate the feasibility, safety, and clinical impact of EUS use in children.
METHODS: This is a retrospective analysis of a prospectively acquired database of consecutive pediatric (< 18 years) patients presenting an indication for EUS for pancreatobiliary and gastrointestinal disorders.
RESULTS: Between January 2010 and January 2016, 47 procedures were performed in 40 children (mean age of 15.1 ± 4.7 years; range 3-18). The majority of EUS (n = 32; 68.1%) were performed for pancreatobiliary and upper gastrointestinal pathologies, including suspected common bile duct stones (CBDs), acute biliary pancreatitis, recurrent/chronic pancreatitis, cystic pancreatic mass, recurrent hypoglycemia, duodenal polyp, gastric submucosal lesion, and perigastric abscess. In only 2 out of 18 children with suspected CBDs or acute biliary pancreatitis, EUS confirmed CBDs. EUS-guided fine needle aspiration was performed in 3 (6.4%) patients. Fifteen (31.9%) procedures were performed for lower gastrointestinal tract disorders, including suspected anal Crohn's disease, fecal incontinence, and encopresis. Overall, EUS had a significant impact on the subsequent clinical management in 87.2% of patients.
CONCLUSION: The present findings were consistent with results observed in the current relevant literature and support EUS as a safe and feasible diagnostic and therapeutic tool, which yields a significant clinical impact in children with pancreatobiliary and gastrointestinal disorders.

PMID: 29212476 [PubMed - in process]

Autophagy-dependent generation of Axin2+ cancer stem-like cells promotes hepatocarcinogenesis in liver cirrhosis.

Fri, 12/08/2017 - 13:45
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Autophagy-dependent generation of Axin2+ cancer stem-like cells promotes hepatocarcinogenesis in liver cirrhosis.

Oncogene. 2017 Nov 30;36(48):6725-6737

Authors: Li J, Hu SB, Wang LY, Zhang X, Zhou X, Yang B, Li JH, Xiong J, Liu N, Li Y, Wu YZ, Zheng QC

Abstract
Autophagy is a pathophysiological phenomenon in liver cirrhosis that can further progress into hepatocarcinoma. Liver cancer stem cells (CSCs) are believed to initiate hepatocarcinogenesis. To investigate the precise mechanism related to the origin of CSCs in liver cirrhosis and hepatocarcinogenesis, we labeled Axin2+ hepatic cells with EGFP in Axin2Cre;Rosa26EGFP transgenic rats, and then stratified clinical and rat liver cirrhosis samples by autophagy flux. Clinical follow-up and lineage tracing in transgenic rat liver cirrhosis revealed that while Axin2/EGFP+ hepatic cells were present in normal livers and cirrhotic livers without aberrant autophagy, hepatic Axin2/EGFP+CD90+ cells were generated exclusively in cirrhotic livers with aberrant autophagy and promoted hepatocarcinogenesis. Aberrant autophagy in liver cirrhosis resulted in hepatocyte growth factor (HGF) expression, leading to activation of Met/JNK and Met/STAT3 signaling in sorted hepatic Axin2/EGFP+ cells and their transition into Axin2/EGFP+CD90+ cells that possess CSC properties. In a transgenic rat liver cirrhosis model, induction or inhibition of autophagy in cirrhotic livers by systemic administration of rapamycin or chloroquine or transfection with Atg3- and Atg7-shRNAs significantly induced or suppressed HGF expression, which in turn increased or reduced generation of EGFP+CD90+ hepatic cells by activating or inactivating Met/JNK and Met/STAT3 signaling, thereby promoting or preventing hepatocarcinogenesis. Systemic treatment with HGF-shRNA, SP600125 or stattic also reduced generation of EGFP(Axin2)+ hepatic cell-originated CD90+ CSCs in aberrant autophagic cirrhotic livers by inactivating HGF/Met/JNK or HGF/Met/STAT3 signaling, further preventing hepatocarcinogenesis. These data suggest that activation of Met/JNK and Met/STAT3 signaling in Axin2+ hepatic cells via autophagy-dependent HGF expression and the resultant generation of Axin2+CD90+ CSCs is a major mechanism of hepatocarcinogenesis in cirrhotic livers.

PMID: 28783177 [PubMed - indexed for MEDLINE]

Reticulocalbin-2 enhances hepatocellular carcinoma proliferation via modulating the EGFR-ERK pathway.

Fri, 12/08/2017 - 13:45
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Reticulocalbin-2 enhances hepatocellular carcinoma proliferation via modulating the EGFR-ERK pathway.

Oncogene. 2017 Nov 30;36(48):6691-6700

Authors: Ding D, Huang H, Jiang W, Yu W, Zhu H, Liu J, Saiyin H, Wu J, Huang H, Jiang S, Yu L

Abstract
Hepatocellular carcinoma (HCC) is a major health threat worldwide. Although the involvement of reticulocalbin-2 (RCN2) in cell differentiation has been reported, its function in oncogenesis is poorly understood. Here, we showed that RCN2 was upregulated in tumors compared with adjacent non-tumorous tissues in HCC patients and RCN2 expression clinically correlated with tumor size, disease recurrence and survival rate. Both knockdown and knockout of RCN2 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest and downregulating cyclin D1 expression, while the proliferative ability was restored in knockout HCC cells with exogenously expressed RCN2. Mechanistically, we demonstrated that RCN2 interacted with the epidermal growth factor receptor (EGFR). Knockout of RCN2 in HCC cells not only inhibited activation of the EGFR-ERK pathway by blocking EGF-mediated EGFR dimerization and internalization but also suppressed cell proliferation and EGFR phosphorylation under long exposure to EGF. We further showed that knockout of RCN2 inhibited EGFR phosphorylation, Ki-67 expression and tumor growth in nude mice. Moreover, we demonstrated that RCN2 knockout sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib, lapatinib and sunitinib. Taken together, our results indicate that RCN2 plays a pivotal role in HCC cell proliferation and tumor growth presumably through regulating activation of the EGFR-ERK pathway. Our work also suggests that RCN2 is a potential therapeutic target of HCC.

PMID: 28745317 [PubMed - indexed for MEDLINE]

X-linked Inhibitor of Apoptosis Complicated by Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) and Granulomatous Hepatitis.

Fri, 12/08/2017 - 13:45
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X-linked Inhibitor of Apoptosis Complicated by Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) and Granulomatous Hepatitis.

J Clin Immunol. 2016 Oct;36(7):733-8

Authors: Steele CL, Doré M, Ammann S, Loughrey M, Montero A, Burns SO, Morris EC, Gaspar B, Gilmour K, Bibi S, Shendi H, Devlin L, Speckmann C, Edgar DM

Abstract
The X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency characterized by Epstein-Barr virus (EBV)-driven hemophagocytic lymphohistiocytosis (HLH), splenomegaly, and colitis. Here, we present, for the first time, granulomatous hepatitis and granulomatous and lymphocytic interstitial lung disease (GLILD) as manifestations of XIAP deficiency. We report successful treatment of GLILD in XIAP deficiency with rituximab and azathioprine and discuss the role of XIAP deficiency in immune dysregulation.

PMID: 27492372 [PubMed - indexed for MEDLINE]

Catabolism of (64)Cu and Cy5.5-labeled human serum albumin in a tumor xenograft model.

Fri, 12/08/2017 - 13:45
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Catabolism of (64)Cu and Cy5.5-labeled human serum albumin in a tumor xenograft model.

Amino Acids. 2016 Jul;48(7):1667-75

Authors: Kang CM, Kim H, Koo HJ, Park JW, An GI, Choi JY, Lee KH, Kim BT, Choe YS

Abstract
Human serum albumin (HSA), the most abundant protein in blood plasma, has been used as a drug carrier for the last few decades. Residualizingly radiolabeled serum albumin has been reported to be avidly taken up by tumors of sarcoma-bearing mice and to most likely undergo lysosomal degradation. In this study, we prepared (64)Cu-1,4,7,10-tetraazacyclododecane-N,N',N″,N'″-tetraacetic acid (DOTA) and Cy5.5-conjugated HSA (dual probe), and evaluated its tumor uptake and catabolism. Two dual probes were prepared using different DOTA conjugation sites of HSA (one via Lys residues and the other via the Cys residue). (64)Cu-DOTA-Lys-HSA-Cy5.5 (dual probe-Lys) exhibited higher uptake by RR1022 sarcoma cells in vitro than (64)Cu-DOTA-Cys-HSA-Cy5.5 (dual probe-Cys). In RR1022 tumor-bearing mice, the two dual probes showed a similar level of tumor uptake, but uptake of dual probe-Lys was reduced in the liver and spleen compared to dual probe-Cys, probably because of the presence of a higher number of DOTA molecules in the former. At 24 and 48 h after injection, dual probe-Lys was intact or partially degraded in blood, liver, kidney, and tumor samples, but (64)Cu-DOTA-Lys was observed in the urine using radioactivity detection. Similarly, Cy5.5-Lys was observed in the urine using fluorescence detection. These results indicate that dual probe-Lys may be useful for predicting the catabolic fate of drug-HSA conjugates.

PMID: 27098932 [PubMed - indexed for MEDLINE]

Immunosuppression following liver transplantation and the course of inflammatory bowel disease - a case control study.

Thu, 12/07/2017 - 13:45

Immunosuppression following liver transplantation and the course of inflammatory bowel disease - a case control study.

Z Gastroenterol. 2017 Dec 06;:

Authors: Mogl MT, Baumgart DC, Fischer A, Pratschke J, Pascher A

Abstract
Aim The aim of this study was to investigate the influence of immunosuppression following orthotopic liver transplantation (OLT) on course of inflammatory bowel disease (IBD) including disease activity and complications. Methods Out of 1168 patients undergoing liver transplantation between 1988 and 2000 at our center, we identified those with IBD (n = 67). In a comparative cohort study, IBD patients after OLT were compared to controls without OLT. All drugs including immunosuppressive and anti-inflammatory medication and complications during follow-up were recorded in 6-month intervals. Also, surgical interventions before and after OLT as well as endoscopic interventions with macroscopic and microscopic findings were collected and analyzed. Additionally, development of malignant neoplasias was recorded. Results Of the 67 individuals with IBD and OLT, 41 were available for analyses and compared with 42 controls. The mean follow-up was 7.4 (range: 3 - 15) years. Short-term therapy with calcineurin inhibitors or mycophenolate mofetil led to short-term remission, yet sustained remission could only be achieved in patients receiving mycophenolate mofetil. At 14.5 years, clinical remission was reached by significantly more patients in the transplant group (54 %) than in the control group (33 %, p = 0.0295). Patients in the control group required nearly 2 times as many surgical interventions related to IBD than patients in the transplant group. Neoplasias were more common in the OLT (n = 8) compared with 4 solid organ cancers in the control group, respectively. Conclusions Our data demonstrate an overall positive impact of immunosuppression following OLT on the course of IBD, especially with mycophenolate mofetil, but an increased rate of malignancies.

PMID: 29212098 [PubMed - as supplied by publisher]

Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells.

Thu, 12/07/2017 - 13:45

Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells.

Cell Rep. 2017 Dec 05;21(10):2661-2670

Authors: Takebe T, Sekine K, Kimura M, Yoshizawa E, Ayano S, Koido M, Funayama S, Nakanishi N, Hisai T, Kobayashi T, Kasai T, Kitada R, Mori A, Ayabe H, Ejiri Y, Amimoto N, Yamazaki Y, Ogawa S, Ishikawa M, Kiyota Y, Sato Y, Nozawa K, Okamoto S, Ueno Y, Taniguchi H

Abstract
Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive "reverse" screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations.

PMID: 29212014 [PubMed - in process]

Impact of aberrant left hepatic artery ligation on the outcome of liver transplantation.

Thu, 12/07/2017 - 13:45

Impact of aberrant left hepatic artery ligation on the outcome of liver transplantation.

Liver Transpl. 2017 Dec 06;:

Authors: Montalti R, Benedetti Cacciaguerra A, Nicolini D, Alì Ahmed E, Coletta M, De Pietri L, Risaliti A, Troisi RI, Mocchegiani F, Vivarelli M

Abstract
BACKGROUND: The preservation of a graft's aberrant left hepatic artery (LHA) during liver transplantation (LT) ensures optimal vascularization of the left liver but can also be considered a risk factor for hepatic artery thrombosis. In contrast, ligation of an aberrant LHA may lead to hepatic ischaemia with the potential risk of graft dysfunction and biliary complications. The aim of this study was to prospectively analyse the impact on the surgical strategy for LT of 5 tests performed to establish whether an aberrant LHA was an accessory or a replaced artery, thus leading to the design of a decisional algorithm.
METHODS: From 8/2005 to 12/2016, 395 whole LTs were performed in 376 patients. Five parameters were evaluated to determine whether an aberrant LHA was an accessory or a replaced artery. Based on our decision algorithm, an aberrant LHA was ligated during surgery when assessed as accessory and preserved when assessed as replaced.
RESULTS: A total of 138 anatomical variants of hepatic arterial vascularization occurred in 120/395 (30.4%) grafts. Overall, the incidence of an aberrant LHA was 63/395 (15.9%). The LHA was ligated in 33 patients (52.4%) and preserved in 30 patients (47.6%). After a mean follow-up period of 46.2±35.9 months, the incidence of hepatic artery thrombosis, primary non-function, early allograft dysfunction, biliary stricture or leaks and overall survival was similar in the two groups.
CONCLUSIONS: Once shown to be an accessory, an LHA can be safely ligated without clinical consequences on the outcome of LT. This article is protected by copyright. All rights reserved.

PMID: 29211941 [PubMed - as supplied by publisher]

Liver fibrosis scores in the general population: Better risk indices are needed!

Thu, 12/07/2017 - 13:45

Liver fibrosis scores in the general population: Better risk indices are needed!

Hepatology. 2017 Dec 06;:

Authors: Åberg F

PMID: 29211940 [PubMed - as supplied by publisher]

Artificial Neural Networks and liver transplantation: Are we ready for self-driving cars?

Thu, 12/07/2017 - 13:45

Artificial Neural Networks and liver transplantation: Are we ready for self-driving cars?

Liver Transpl. 2017 Dec 06;:

Authors: Kwong AJ, Asrani SK

PMID: 29211925 [PubMed - as supplied by publisher]

Decellularized human placenta supports hepatic tissue and allows rescue in acute liver failure.

Thu, 12/07/2017 - 13:45

Decellularized human placenta supports hepatic tissue and allows rescue in acute liver failure.

Hepatology. 2017 Dec 06;:

Authors: Kakabadze Z, Kakabadze A, Chakhunashvili D, Karalashvili L, Berishvili E, Sharma Y, Gupta S

Abstract
Tissue engineering with scaffolds to form transplantable organs is of wide interest. Decellularized tissues have been tested for this purpose, although supplies of healthy donor tissues, vascular recellularization for perfusion and tissue homeostasis in engineered organs pose challenges. We hypothesized decellularized human placenta will be suitable for tissue engineering. The universal availability and unique structures of placenta for accommodating tissue, including presence of embedded vessels, were major attractions. We found decellularized placental vessels were re-endothelialized by adjacent native cells and bridged vessel defects in rats. Also, implantation of liver fragments containing all cell types successfully hepatized placenta with maintenance of albumin and urea synthesis, as well as hepatobiliary transport of 99mTc-mebrofenin, over up to three days in vitro. After hepatized placenta containing autologous liver was transplanted into sheep, tissue units were well-perfused and self-assembled. Histological examination indicated transplanted tissue retained hepatic cord structures with characteristic hepatic organelles, such as gap junctions, and hepatic sinusoids lined by endothelial, Kupffer, and other cell types. Hepatocytes in this neo-organ expressed albumin and contained glycogen. Moreover, transplantation of hepatized placenta containing autologous tissue rescued sheep in extended partial hepatectomy-induced acute liver failure. This rescue concerned amelioration of injury and induction of regeneration in native liver. The grafted hepatized placenta was intact with healthy tissue that neither proliferated nor was otherwise altered.
CONCLUSIONS: The unique anatomic structure and matrix of human placenta were effective for hepatic tissue engineering. This will advance applications ranging from biological studies, drug development and toxicology to therapies in people. This article is protected by copyright. All rights reserved.

PMID: 29211918 [PubMed - as supplied by publisher]

Towards Standardizing the Alcoholism Evaluation Of Potential Liver Transplant Recipients.

Thu, 12/07/2017 - 13:45

Towards Standardizing the Alcoholism Evaluation Of Potential Liver Transplant Recipients.

Alcohol Alcohol. 2017 Dec 04;:1-10

Authors: Beresford TP, Lucey MR

Abstract
Aims: For teams around the world, alcoholic liver disease patients comprise the largest, and clinically most controversial, group applying for liver transplant. And yet evaluation decisions for them remain highly variable by locale.
Methods: Targeting standardized assessment, we provide guidelines on what information the transplant team should seek, from what sources, and how best to make use of it. This report focuses on 'what to do and how to do it' in providing appropriate assessments for this complex patient group.
Results: Proper evaluation includes (a) taking the clinical history from the patient and a required, corroborating third person, (b) assessing patient cognition, (c) establishing alcohol/substance use diagnosis to differentiate alcohol dependence, abuse and polysubstance dependence, (d) assessing ambivalence in primary alcohol addiction, (e) measuring social stability and (f) using Vaillant's factors for abstinence prognosis.
Conclusions: Properly applied, these six factors will allow standardized selection in most cases taken across programs despite differences in resources, available expertise and decision practices.
Short Summary: This report focuses on the essentials of the psychiatric/behavioral evaluation for 'alcoholic' persons referred for liver transplant. Attention to those essentials offers clinical standardization across transplant programs in different locales.

PMID: 29211831 [PubMed - as supplied by publisher]

Delayed revascularization of islets after transplantation by IL-6 blockade in pig to non-human primate islet xenotransplantation model.

Thu, 12/07/2017 - 13:45

Delayed revascularization of islets after transplantation by IL-6 blockade in pig to non-human primate islet xenotransplantation model.

Xenotransplantation. 2017 Dec 06;:

Authors: Min BH, Shin JS, Kim JM, Kang SJ, Kim HJ, Yoon IH, Park SK, Choi JW, Lee MS, Park CG

Abstract
BACKGROUND: Pancreatic islet transplantation is currently proven as a promising treatment for type 1 diabetes patients with labile glycemic control and severe hypoglycemia unawareness. Upon islet transplantation, revascularization is essential for proper functioning of the transplanted islets. As IL-6 is important for endothelial cell survival and systemic inflammation related to xenograft, the effect of IL-6 receptor antagonist, tocilizumab, on revascularization of the transplanted islets was examined in pig to non-human primate islet xenotransplantation model. Also, the endothelial cell origin in a new vessel of the transplanted pig islets was determined.
METHODS: Pig islets were isolated from designated pathogen-free (DPF) SNU miniature pigs and transplanted via portal vein into five streptozotocin-induced diabetic monkeys. One group (n = 2, basal group) was treated with anti-thymoglobulin (ATG), anti-CD40 antibody (2C10R4), sirolimus, and tacrolimus, and the other group was additionally given tocilizumab on top of basal immunosuppression (n = 3, Tocilizumab group). To confirm IL-6 blocking effect, C-reactive protein (CRP) levels and serum IL-6 concentration were measured. Scheduled biopsy of the margin of the posterior segment right lobe inferior of the liver was performed at 3 weeks after transplantation to assess the degree of revascularization of the transplanted islets. Immunohistochemical staining using anti-insulin, anti-CD31 antibodies, and lectin IB4 was conducted to find the origin of endothelial cells in the islet graft.
RESULTS: CRP significantly increased at 1~2 days after transplantation in Basal group, but not in Tocilizumab group, and higher serum IL-6 concentration was measured in latter group, showing the biological potency of tocilizumab. In Basal group, well-developed endothelial cells were observed on the peri- and intraislet area, whereas the number of CD31+ cells in the intraislet space was significantly reduced in Tocilizumab group. Finally, new endothelial cells in the pig islet graft were positive for CD31, but not for lectin IB4, suggesting that they are originated from the recipient monkey.
CONCLUSIONS: Our results demonstrated that tocilizumab can delay revascularization of the transplanted islet, although this effect had no significant correlation to the overall islet graft survival. In the pig to NHP islet xenotransplantation model, the endothelial cells from recipient monkey form new blood vessels in and around pig islets.

PMID: 29210476 [PubMed - as supplied by publisher]

Current management of refractory ascites in patients with cirrhosis.

Thu, 12/07/2017 - 13:45

Current management of refractory ascites in patients with cirrhosis.

J Int Med Res. 2017 Jan 01;:300060517735231

Authors: Zhao R, Lu J, Shi Y, Zhao H, Xu K, Sheng J

Abstract
Liver cirrhosis is a health problem worldwide, and ascites is its principal symptom. Refractory ascites is intractable and occurs in 5%-10% of all patients with ascites due to cirrhosis. Refractory ascites leads to a poor quality of life and high mortality rate. Ascites develops as a result of portal hypertension, which leads to water-sodium retention and renal failure. Various therapeutic measures can be used for refractory ascites, including large-volume paracentesis, transjugular intrahepatic portosystemic shunt, vasoconstrictive drugs, and an automated low-flow ascites pump system. However, ascites generally can be resolved only by liver transplantation. Because not all patients can undergo liver transplantation, traditional approaches are still used to treat refractory ascites. The choice of treatment modality for refractory ascites depends, among other factors, on the condition of the patient.

PMID: 29210304 [PubMed - as supplied by publisher]

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