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1.  Predictive Factors of Neurological Complications and One-Month Mortality after Liver Transplantation 
Background: Neurological complications are common after orthotopic liver transplantation (OLT). We aimed to characterize the risk factors associated with neurological complications and mortality among patients who underwent OLT in the post-model for end-stage liver disease (MELD) era.
Methods: In a retrospective review, we evaluated 227 consecutive patients at the Keck Hospital of the University of Southern California before and after OLT to define the type and frequency of and risk factors for neurological complications and mortality.
Results: Neurological complications were common (n = 98), with encephalopathy being most frequent (56.8%), followed by tremor (26.5%), hallucinations (11.2%), and seizure (8.2%). Factors associated with neurological complications after OLT included preoperative dialysis, hepatorenal syndrome, renal insufficiency, intra-operative dialysis, preoperative encephalopathy, preoperative mechanical ventilation, and infection. Preoperative infection was an independent predictor of neurological complications (OR 2.83, 1.47–5.44). One-month mortality was 8.8% and was independently associated with urgent re-transplant, preoperative intubation, and intra-operative arrhythmia.
Conclusion: Neurological complications are common in patients undergoing OLT in the post-MELD era, with encephalopathy being most frequent. An improved understanding of the risk factors related to both neurological complications and one-month mortality post-transplantation can better guide perioperative care and help improve outcomes among OLT patients.
PMCID: PMC4269112  PMID: 25566180
liver transplant; neurological complications; mortality
2.  Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells 
The Journal of Clinical Investigation  2013;123(7):2832-2849.
Tumor-initiating stem-like cells (TICs) are resistant to chemotherapy and associated with hepatocellular carcinoma (HCC) caused by HCV and/or alcohol-related chronic liver injury. Using HCV Tg mouse models and patients with HCC, we isolated CD133+ TICs and identified the pluripotency marker NANOG as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG–dependent TICs were defective in the TGF-β tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-β signaling. Mechanistically, we determined that YAP1 mediates cytoplasmic retention of phosphorylated SMAD3 and suppresses SMAD3 phosphorylation/activation by the IGF2BP3/AKT/mTOR pathway. Silencing of both YAP1 and IGF2BP3 restored TGF-β signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-β signaling (Spnb2+/– mice) exhibited enhanced liver TLR4 expression and developed HCC in a TLR4-dependent manner. Taken together, these results suggest that the activated TLR4/NANOG oncogenic pathway is linked to suppression of cytostatic TGF-β signaling and could potentially serve as a therapeutic target for HCV-related HCC.
PMCID: PMC3696549  PMID: 23921128
3.  Cancer stem cells generated by alcohol, diabetes, and HCV 
Cancer stem cells (Tumor-initiating stem-like cells: TISCs) are resistant to chemotherapy and are associated with metastatic hepatocellular carcinoma (HCC), which is commonly observed in hepatitis C virus (HCV)-infected patients with obesity or alcohol abuse. However, it is unknown whether the TLR4-NANOG pathway serves as a universal oncogenic signaling in the genesis of TISCs and HCC. We aimed to determine whether Tlr4 is a putative proto-oncogene for TISCs in liver oncogenesis due to different etiologies and how Tlr4 is regulated at the transcriptional and epigenetic levels. CD133+/CD49f+ TISCs were isolated using FACS from HCC developed in HCV Core Tg mice fed alcohol, diethylnitrosamine-treated mice, and alcoholic patients with or without HCV infection. CD133+/CD49f+ cells isolated from the animal models and patients are tumorigenic both in vitro and in a xenograft model, and Tlr4 or Nanog silencing with shRNA attenuates their tumor initiating property. Functional oncogene screening of a cDNA library identified the organ size control pathway targets Yap1 and AKT activator Igf2bp3 as NANOG-dependent genes that inhibit TGF-β signaling in TISCs. Tlr4 expression is higher in TISCs compared to CD133−/CD49f+ cells, and DNA hypomethylation, histone acetylation and de-methylation drive Tlr4 induction through NOTCH signaling or Hif-1α. Taken together, Tlr4 is induced by hypoxia and NOTCH signaling and is a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.
PMCID: PMC3306127  PMID: 22320911
Alcohol; HCV; HCC; Tumor-initiating stem-like cells; Obesity
4.  Surgical Technique of Orthotopic Liver Transplantation 
The results of orthotopic liver transplantation (OLTx) have improved dramatically over the last few years. One of the most important contributing factors to the overall success of this operation is the refinement and standardization of the surgical procedure. Although still a complex undertaking, these technical advances have transformed the operation into one that is within the capability of many competent general and vascular surgeons and one that is practical on a large-scale basis. This article will highlight various aspects of the surgical technique of orthotopic liver transplantation (OLTx) that have evolved over a 25-year period initially at the University of Colorado in Denver, and then it will cover from 1981 onward, as practiced at the University of Pittsburgh. These techniques, or modifications thereof, have been disseminated to and adopted throughout the majority of liver transplant centers across the world.
The complete transplant procedure is composed of four main stages: the donor hepatectomy, the recipient hepatectomy, the implantation of the graft (4 vascular anastomoses), followed by hemostasis and the bile duct reconstruction.
PMCID: PMC3228369  PMID: 3292430
6.  Improved Method of Porcine Renal Allografting for Transplantation Research 
This study presents a refined, reproducible, and clinically appropriate animal model of renal transplantation. A pair of kidneys are harvested from a donor pig and preserved in Euro-Collins’ solution (4°C). After a set period of preservation, the allografts are transplanted to two recipient pigs. The abdomen is entered through a midline incision. The right common iliac artery and vein are dissected and bilateral native nephrectomy is performed. Each allograft is then randomly assigned and transplanted to the recipients. Three minutes before unclamping, 100 mg of furosemide and 10 g of mannitol are given IV. Immediately after reperfusion, urine output is measured for 1 h. The allograft is biopsied and ureteroneocystostomy is created. Cystostomy is then placed using a 16F Foley catheter. The bladder neck is ligated to secure complete diversion of urine, and the abdomen is closed in layers. This kidney transplant model allows an absolutely paired study of the kidney allograft function from the same donor and also collection of pure urine at any time postoperatively, obviating the need for metabolic cages or sedation for urinary collection. This model and its unique modifications allow various transplant studies, including organ preservation, immunosuppressive protocol, and the prevention of reperfusion injury from oxygen free radicals.
PMCID: PMC2967356  PMID: 2069932
Transplantation; kidney; animal experiment
Surgery, gynecology & obstetrics  1989;168(5):394-396.
A tension mucocele was created in three hepatic homografts by ligating a low-lying cystic duct during transplant cholecystectomy and by incorporating its outflow end into the anastomosis of the common hepatic duct to the recipient common duct or Roux limb of jejunum. The consequent complication of obstruction of the biliary tract that necessitated reoperation and excision of the mucocele in all three patients can be avoided by the simple expedient of completely removing the cystic duct when feasible or providing egress to the secretion of the cystic duct as described.
PMCID: PMC2672429  PMID: 2652346

Results 1-8 (8)