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1.  Current surgical treatment strategies for hepatocellular carcinoma in North America 
World Journal of Gastroenterology : WJG  2014;20(41):15007-15017.
Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease. Many patients do not initially manifest any symptoms of HCC and present late when cure with surgical resection or transplantation is no longer possible. For this reason, patients at high risk for developing HCC are subjected to frequent screening processes. The surgical management of HCC is complex and requires an inter-disciplinary approach. Hepatic resection is the treatment of choice for HCC in patients without cirrhosis and is indicated in some patients with early cirrhosis (Child-Pugh A). Liver transplantation has emerged in the past decade as the standard of care for patients with cirrhosis and HCC meeting Milan criteria and in select patients with HCC beyond Milan criteria. Loco-regional therapy with transarterial chemoembolization, transarterial embolization, radiofrequency ablation and other similar local treatments can be used as neo-adjuvant therapy to downstage HCC to within Milan criteria or as a bridge to transplantation in patients on transplant wait list.
PMCID: PMC4223234  PMID: 25386049
Hepatocellular carcinoma; Liver transplantation; Liver resection; Transarterial chemoembolization; Radiofrequency ablation
2.  Novel In Vitro Model for Studying Hepatic Ischemia-Reperfusion Injury Using Liver Cubes 
Surgery  2012;152(2):247-253.
While inflow occlusion techniques have given surgeons the ability to carry out increasingly complex liver resections, ischemia-reperfusion (IR) injury continues to be a source of morbidity. Efforts to ameliorate IR injury have been hindered in absence of adequate pre-clinical models. The goal of the present study was to develop a simple, efficient, and cost-effective means of studying hepatic IR injury.
Liver cubes were procured from normal (C57BL/6) mice. Following hepatectomy, 4 mm punch biopsies were taken for individual placement in culture wells containing hepatocyte media. Experimental cubes underwent hypoxia for 60 minutes, while controls remained normoxic. Supernatants were collected from individual wells following 0, 6 and 12 hours of rediffusion for transaminase and cytokine measurement. Histologic examination was performed on individual cubes.
Extensive histologic injury was seen in the experimental cubes compared to controls with greater staining for activated caspase-3 and TUNEL at 6 and 24 hours, respectively. Changes consistent with ischemic injury occurred more centrally in liver cubes whereas markers for rediffusion injury were appreciated along the periphery. Transaminases were significantly higher at 6 hours following rediffusion in experimental cubes compared to controls, p = 0.02. TNF-α and IL-1β were significantly higher in the media of experimental cubes compared to controls at 12 hours rediffusion, p = 0.05 and 0.03 respectively.
In vitro IR of cubes produces a significant injury whose pattern is reflective of hepatic lobular architecture. This novel technique may open new avenues for uncoupling the mechanisms of IR while facilitating rapid screening of potential therapies.
PMCID: PMC4258692  PMID: 22698934
3.  Aortic Balloon Valvuloplasty Prior to Orthotopic Liver Transplantation: A Novel Approach to Aortic Stenosis and End-Stage Liver Disease 
Case Reports in Cardiology  2014;2014:325136.
The combination of severe aortic stenosis and end-stage liver disease increases the morbidity and mortality of surgical aortic valve replacement or orthotopic liver transplantation resulting in a prohibitive operative risk. We propose a staged approach of balloon aortic valvuloplasty prior to orthotopic liver transplantation as a bridge to definitive aortic valve replacement. Between 2010 and 2012, four patients with severe aortic stenosis and end-stage liver disease underwent staged balloon aortic valvuloplasty followed by orthotopic liver transplantation. All patients had been deemed to be inappropriate candidates for liver transplantation or aortic valve surgery due to their comorbidity. One patient died of complications from a perivalvular abscess. Three patients went on to successful graft implantation and function and surgical recovery. Two of the three patients proceeded to definitive surgical aortic valve replacement with the remainder currently undergoing evaluation. In this case series, we present a novel approach of balloon aortic valvuloplasty prior to liver transplantation as a potential bridge to definitive treatment of severe aortic stenosis in the end-stage liver patient.
PMCID: PMC4241694  PMID: 25431682
4.  Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection 
Human immunology  2013;74(11):10.1016/j.humimm.2013.07.002.
Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.
PMCID: PMC3813452  PMID: 23876679
Alloimmunity; Autoimmunity; Transplant rejection; Antigen presentation; Interleukin-17
5.  Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis 
Journal of Virology  2014;88(7):3733-3743.
Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBPα, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBPα, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBPα. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA-449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis.
IMPORTANCE Hepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.
PMCID: PMC3993535  PMID: 24429361
6.  Temporal association between increased virus-specific Th17 response and spontaneous recovery from recurrent hepatitis C in a liver transplant recipient 
Transplantation  2011;92(12):1364-1370.
Spontaneous clearance of Hepatitis C virus (HCV) following liver transplantation (OLT) is a rare occurrence. Here we present detailed immunological analysis of an interferon naive OLT recipient receiving uninterrupted immunosuppression who cleared HCV spontaneously two years after transplantation.
Enzyme linked immunospot assay (ELISpot) analysis of peripheral T-cell IFNγ, IL-10, and IL-17 response to HCV core and non-structural antigen 4 (NS4) and enzyme linked immunosorbent assay (ELISAs) to collagen (Col) subtypes I, II, IV, and V were performed in the index patient at the time of viral clearance and compared to an OLT cohort with persistent viremia matched for time from OLT, immunosuppression, and histology. ELISpot and ELISA analysis were repeated on the patient 4 years after OLT. Transcription-mediated amplification assays were used to confirm viral clearance.
Compared to a cohort of post-OLT and non-transplanted viremic HCV patients, the index patient with HCV clearance demonstrated higher IL-17, IL-10 and lower IFN-γ response to NS4 and core antigen and a higher titer of Abs to Col subtypes I, II, and V during clearance. On follow-up 2 years later, HCV specific IFN-γ was increased in the index patient, with a decline in IL-17 and IL-10 response as well as Col I, II, and V Ab titer.
Virus induced activation of Th-17 cells may contribute to HCV clearance post- OLT. Maintenance of viral suppression may be facilitated by restoration of Th1 (IFNγ) responses. Modulation of Th17 immunity deserves further attention as a therapeutic strategy in the treatment of HCV recurrence post-OLT.
PMCID: PMC3697051  PMID: 22082818
Transplant immunology  2012;26(4):201-206.
Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to increased primary graft nonfunction following transplantation. Activation of nuclear factor kappa-B (NFκB) following I/R injury plays a crucial role in activation of pro-inflammatory responses leading to injury.
We evaluated the role of NFκB in steatotic liver injury by using an orthotopic liver transplant (OLT) model in Zucker rats (lean to lean or obese to lean) to define the mechanisms of steatotic liver injury. Obese donors were treated with bortezomib to assess the role of NF-κB in steatotic liver I/R injury. Hepatic levels of NF-κB and pro-inflammatory cytokines were analyzed by ELISA. Serum transaminase levels and histopathological analysis were performed to assess associated graft injury.
I/R injury in steatotic liver results in significant increases in activation of NF-κB (40%, p<0.003), specifically the p65 subunit following transplantation. Steatotic donor pretreatment with proteasome inhibitor bortezomib (0.1 mg/kg) resulted in significant reduction in levels of activated NF-κB (0.58±0.18 vs. 1.37±0.06 O.D./min/10μg protein, p<0.003). Bortezomib treatment also reduced expression of pro-inflammatory cytokines MIP-2 compared with control treated steatotic and lean liver transplants respectively (106±17.5 vs. 443.3±49.9 vs. 176±10.6 pg/mL, p=0.02), TNF-α (223.8±29.9 vs. 518.5±66.5 vs 264.5±30.1 pg/2μg protein, p=0.003) and IL-1β (6.0±0.91 vs. 19.8±5.2 vs 5±1.7 pg/10μg protein, p= 0.02) along with a significant reduction in ALT levels (715±71 vs 3712.5±437.5 vs 606±286 U/L, p=0.01).
These results suggest that I/R injury in steatotic liver transplantation are associated with exaggerated activation of NFκB subunit p65, leading to an inflammatory mechanism of reperfusion injury and necrosis. Proteasome inhibition in steatotic liver donor reduces NFκB p65 activation and inflammatory I/R injury, improving transplant outcomes of steatotic grafts in a rat model.
PMCID: PMC3675789  PMID: 22286145
hepatic steatosis; I/R injury; liver transplantation; NFκB; PS-341; bortezomib; obese; marginal graft
8.  Donor Graft Steatosis Influences Immunity to Hepatitis C Virus and Allograft Outcome After Liver Transplantation 
Transplantation  2011;92(11):1259-1268.
Hepatitis C (HCV) recurrence following orthotopic liver transplantation (OLT) is universal, often with accelerated allograft fibrosis. Donor liver steatosis is frequently encountered and often associated with poor early post-operative outcome. The study’s aim was to test the hypothesis that allograft steatosis alters immune responses to HCV and self-antigens promoting allograft fibrosis.
Forty-eight HCV OLT recipients (OLTr) were enrolled and classified based on amount of allograft macrovesicular steatosis at time of OLT. Group 1-No Steatosis (0–5% steatosis, n=21), Group 2 – Mild (5–35% - n=16), Group 3 – moderate (>35%, n=11). Cells secreting IL-17, IL-10, IFN-γ in response to HCV antigens were enumerated by ELISpot. Serum cytokines were measured by Luminex, antibodies (Abs) to Collagen (Col) I, II, III, IV, V by ELISA.
OLTr of moderate steatotic grafts had the highest incidence of advanced fibrosis in protocol one-year post-OLT biopsy (10.8% vs. 15.8% vs. 36.6%, r = 0.157, p<0.05). OLTr from Groups 2 and 3 had increased HCV specific IL-17 (p<0.05) and IL-10 (p<0.05) with reduced IFN-γ (p<0.05) secreting cells when compared to group 1. This was associated with increase in serum IL-17, IL-10, IL-1β, IL-6, IL-5 and decreased IFN-γ. In addition, there was development of Abs to Col I, II, III and V in OLTr with increased steatosis (p<0.05).
The results demonstrate that allograft steatosis influences post-OLT HCV specific immune responses leading to a IL-17 T-helper response and activation of humoral immune responses to liver associated self antigens which may contribute to allograft fibrosis and poor outcome.
PMCID: PMC3223266  PMID: 22011763
Allograft Steatosis; Hepatitis C; Recurrence; Fibrosis; Liver Transplantation
9.  Efficacy of Neoadjuvant Chemoradiation followed by Liver Transplantation for Perihilar Cholangiocarcinoma at 12 US Centers 
Gastroenterology  2012;143(1):10.1053/j.gastro.2012.04.008.
Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation (LT) for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing (UNOS) to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception.
We collected and analyzed data from 12 large-volume transplant centers in the US who met the inclusion criteria of treating three or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy followed by liver transplantation from 1993–2010 (n=287 total patients). Center-specific protocols and medical charts were reviewed on-site.
The patients completed external radiation (99%), brachytherapy (75%), radio-sensitizing (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate of 11.5% in 3 months). Intent-to-treat survival was 68% and 53%, 2 and 5 years after therapy, respectively; post-transplantation, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the UNOS criteria (those with tumor mass >3 cm, trans-peritoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P<.001). There were no differences in outcomes among patients based on differences in operative staging or brachytherapy. Although most patients came from 1 center (n=193), the other 11 centers had similar survival times after therapy.
Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, demonstrating this therapy to be highly effective. An 11.5% dropout rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.
PMCID: PMC3846443  PMID: 22504095
liver cancer; biliary; hepatic; treatment efficacy
10.  Concepts and Preliminary Data Toward the Realization of Image-guided Liver Surgery 
Image-guided surgery provides navigational assistance to the surgeon by displaying the surgical probe position on a set of preoperative tomograms in real time. In this study, the feasibility of implementing image-guided surgery concepts into liver surgery was examined during eight hepatic resection procedures. Preoperative tomographic image data were acquired and processed. Accompanying intraoperative data on liver shape and position were obtained through optically tracked probes and laser range scanning technology. The preoperative and intraoperative representations of the liver surface were aligned using the iterative closest point surface matching algorithm. Surface registrations resulted in mean residual errors from 2 to 6 mm, with errors of target surface regions being below a stated goal of 1 cm. Issues affecting registration accuracy include liver motion due to respiration, the quality of the intraoperative surface data, and intraoperative organ deformation. Respiratory motion was quantified during the procedures as cyclical, primarily along the cranial–caudal direction. The resulting registrations were more robust and accurate when using laser range scanning to rapidly acquire thousands of points on the liver surface and when capturing unique geometric regions on the liver surface, such as the inferior edge. Finally, finite element models recovered much of the observed intraoperative deformation, further decreasing errors in the registration. Image-guided liver surgery has shown the potential to provide surgeons with important navigation aids that could increase the accuracy of targeting lesions and the number of patients eligible for surgical resection.
PMCID: PMC3839065  PMID: 17458587
Image-guided surgery; Liver resection; Surface registration; Laser range scanning; Finite element
11.  Organ Surface Deformation Measurement and Analysis in Open Hepatic Surgery: Method and Preliminary Results From 12 Clinical Cases 
IEEE transactions on bio-medical engineering  2011;58(8):10.1109/TBME.2011.2146782.
The incidence of soft tissue deformation has been well documented in neurosurgical procedures and is known to compromise the spatial accuracy of image-guided surgery systems. Within the context of image-guided liver surgery (IGLS), no detailed method to study and analyze the observed organ shape change between preoperative imaging and the intraoperative presentation has been developed. Contrary to the studies of deformation in neurosurgical procedures, the majority of deformation in IGLS is imposed prior to resection and due to laparotomy and mobilization. As such, methods of analyzing the organ shape change must be developed to use the intraoperative data [e.g., laser range scan (LRS) surfaces] acquired with the organ in its fully deformed shape. To achieve this end we use a signed closest point distance deformation metric computed after rigid alignment of the intraoperative LRS data with organ surfaces generated from the preoperative tomograms. The rigid alignment between the intraoperative LRS surfaces and preoperative image data was computed with a feature weighted surface registration algorithm. In order to compare the deformation metrics across patients, an interpatient nonrigid registration of the preoperative CT images was performed. Given the interpatient liver registrations, an analysis was performed to determine the potential similarities in the distribution of measured deformation between patients for which similar procedures had been performed. The results of the deformation measurement and analysis indicate the potential for soft tissue deformation to compromise surgical guidance information and suggests a similarity in imposed deformation among similar procedure types.
PMCID: PMC3819167  PMID: 21521662
Image-guided surgery (IGS); laser range scanning; open hepatic surgery; soft tissue deformation
12.  Hepatitis C Virus Induced miR200c Down Modulates FAP-1, a Negative Regulator of Src Signaling and Promotes Hepatic Fibrosis 
PLoS ONE  2013;8(8):e70744.
Hepatitis C virus (HCV) induced liver disease is the leading indication for liver transplantation (LTx). Reinfection and accelerated development of fibrosis is a universal phenomenon following LTx. The molecular events that lead to fibrosis following HCV infection still remains poorly defined. In this study, we determined microRNA (miRNA) and mRNA expression profiles in livers from chronic HCV patients and normals using microarrays. Using Genego software and pathway finder we performed an interactive analysis to identify target genes that are modulated by miRNAs. 22 miRNAs were up regulated (>2 fold) and 35 miRNAs were down regulated (>2fold) compared to controls. Liver from HCV patients demonstrated increased expression of 306 genes (>3 fold) and reduced expression of 133 genes (>3 fold). Combinatorial analysis of the networks modulated by the miRNAs identified regulation of the phospholipase C pathway (miR200c, miR20b, and miR31through cellular proto-oncogene tyrosine-protein kinase Src (cSrc)), response to growth factors and hormones (miR141, miR107 and miR200c through peroxisome proliferator-activated receptor alpha and extracellular-signal-regulated kinases, and regulation of cellular proliferation (miR20b, miR10b, and miR141 through cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 p21). Real time PCR (RT-PCR) validation of the miRNA in HCV infected livers demonstrated a 3.3 ±0.9 fold increase in miR200c. In vitro transfection of fibroblasts with miR200c resulted in a 2.2 fold reduction in expression of tyrosine-protein phosphatase non-receptor type 13 or FAS associated phosphatase 1 (FAP-1) and 2.3 fold increase in expression of cSrc. miR200c transfection resulted in significant increases in expression of collagen and fibroblast growth factor (2.8 and 3.4 fold, p<0.05). Therefore, we propose that HCV induced increased expression of miR200c can down modulate the expression of FAP1, a critical regulator of Src and MAP kinase pathway that play an important role in the production of fibrogenic growth factors and development of fibrosis.
PMCID: PMC3741284  PMID: 23950995
Hepatitis C Virus (HCV) infection and recurrence post-transplant (OLT) is associated with extracellular matrix (ECM) components remodeling, particularly collagen (Col), leading to fibrosis. Our aim was to determine whether development of antibodies (Abs) to self antigen Col in HCV infection correlates with fibrosis stage and peripheral cytokine response. Chronic HCV patients, those with recurrence after OLT undergoing biopsy and healthy control subjects were enrolled. HCV subjects (n=70) were stratified: 1) Non OLT No Fibrosis (Scheuer Stage 0–2) 2) Non OLT Fibrosis (Scheuer Stage 3–4) 3) Post OLT No Fibrosis (Scheuer 0–2) and 4) Post OLT Fibrosis (Scheuer 3–4). Serum was analyzed for Abs against Col-1, 2, 4, 5 and vimentin using ELISA. Serum levels of cytokines were measured using Multiplex Bead immunoassays. Levels of Abs to Col 1 were higher in fibrosis groups compared with no fibrosis groups and control both Non OLT (p<0.0001) and Post OLT (P=0.01). There were increased levels of Abs to Col 2, 4, 5 and vimentin, in fibrotic groups Non OLT (Col 2: p=0.0001, Col 4: p =0.09, Col 5: p<0.0001, vimentin: p=0.36) and Post OLT (Col 2: p=0.006, Col 4: p = 0.1, Col 5: p<0.0001, vimentin: p=0.24) compared with non fibrotic groups. Fibrotic groups non-OLT and post OLT demonstrated significantly higher Th2, Th17 cytokines and lower Th1 cytokines compared to non fibrotic groups. Our results demonstrate that in HCV infection, Abs to ECM Collagen 1, 2, 5 positively correlate with liver fibrosis which is associated with a predominant Th2 and Th17 cytokine profile.
PMCID: PMC3700355  PMID: 21425431
Autoantibodies; IL-17; Fibrosis; HCV Recurrence
14.  Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway 
PLoS ONE  2012;7(11):e50826.
Liver disease due to hepatitis C virus (HCV) infection is an important health problem worldwide. HCV induced changes in microRNAs (miRNA) are shown to mediate inflammation leading to liver fibrosis. Gene expression analyses identified dysregulation of miRNA-449a in HCV patients but not in alcoholic and non-alcoholic liver diseases. By sequence analysis of the promoter for YKL40, an inflammatory marker upregulated in patients with chronic liver diseases with fibrosis, adjacent binding sites for nuclear factor of Kappa B/P65 and CCAAT/enhancer-binding protein alpha (CEBPα) were identified. P65 interacted with CEBPα to co-operatively activate YKL40 expression through sequence specific DNA binding. In vitro analysis demonstrated that tumor necrosis factor alpha (TNFα) mediated YKL40 expression is regulated by miRNA-449a and its target NOTCH1 in human hepatocytes.NOTCH1 facilitated nuclear localization of P65 in response to TNFα. Further, HCV patients demonstrated upregulation of NOTCH1 along with downregulation of miRNA-449a. Taken together it is demonstrated that miRNA-449a plays an important role in modulating expression of YKL40 through targeting the components of the NOTCH signaling pathway following HCV infection. Therefore, defining transcriptional regulatory mechanisms which control inflammatory responses and fibrosis will be important towards developing strategies to prevent hepatic fibrosis especially following HCV recurrence in liver transplant recipients.
PMCID: PMC3511274  PMID: 23226395
15.  The role of molecular chaperonins in warm ischemia and reperfusion injury in the steatotic liver: A proteomic study 
BMC Biochemistry  2012;13:17.
The molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software.
The relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1was significantly upregulated in steatotic liver following I/R.
Down-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts.
PMCID: PMC3445822  PMID: 22962947
Ischemia repurfusion injury; Two dimensional gel electrophoresis; Mass spectrometry; Liver transplantation; Chaperonins; Endoplasmic reticulum (ER) stress
16.  Endoplasmic Reticulum Stress is a Mediator of Post-Transplant Injury in Severely Steatotic Liver Allografts 
Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have an increased susceptibility to cold ischemia and reperfusion (CIR) injury compared to otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance and the metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury following liver transplantation into strain-matched lean recipients. ER stress response components were decreased by the chemical chaperone, TUDCA, resulting in improvement of the allograft injury. TUDCA treatment decreased NF-κB activation, and the pro-inflammatory cytokines IL-6 and IL-1β. However, the predominant response was decreased expression of the ER stress cell death mediator, CHOP. Further, activation of the inflammation-associated caspase 11 was decreased linking ER Stress/CHOP to pro-inflammatory cytokine production following steatotic liver transplantation. These data confirm ER stress in steatotic allografts, and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft.
PMCID: PMC3056557  PMID: 21280192
Liver Transplantation; Endoplasmic Reticulum Stress; Hepatic Steatosis; Ischemia-Reperfusion Injury
17.  Do adverse histopathologic findings in colorectal cancer patients explain disparate outcomes? 
We have previously reported reduced overall and disease-free survival in black patients from a 10-year retrospective review of 668 patients from tumor registry data. This study of 213 patients reports the analysis of available archived tissue from a city hospital (n=44 patients, 53% black) and from a university medical center (n=169, 10.6% black). Two senior pathologists independently reviewed slides for predetermined histologic criteria reported to correlate with survival: tumor type, stage at diagnosis, character of invasion, vascular or perineural invasion, the presence of residual adenoma, the presence of a Crohn's-like reaction and number of nodes resected. Differences in discrete variables were compared using the Chi-squared test. Differences in continuous variables were analyzed using independent t tests. No statistically significant differences were identified in tumor stage or type by institution or race. In patients treated at the city hospital, there was a higher incidence of infiltrating tumors (85% vs. 61%, p<0.001), vascular invasion (70% vs. 36%, p<0.05) and residual adenoma (84% vs. 39%, p<0.05); however, no differences by race were identified. Blacks at both hospitals had significantly more perineural invasion (81% vs. 30%, p<0.05) and Crohn's-like reaction (64% vs. 30%, p<0.05) when compared to white patients, although there was no difference between hospitals. The total number of lymph nodes resected was higher at the university hospital (17.0 vs. 8.9, p<0.001). There were no differences in number of nodes resected at either institution by race. Histopathologic findings did not explain the apparent disparity in survival. The differences in number of nodes harvested may suggest inadequate resection or insufficient recovery of nodes by the pathologist.
PMCID: PMC2576115  PMID: 16573297
18.  Water warming garment versus forced air warming system in prevention of intraoperative hypothermia during liver transplantation: a randomized controlled trial [ISRCTN32154832] 
BMC Anesthesiology  2002;2:7.
The authors compared two strategies for the maintenance of intraoperative normothermia during orthotopic liver transplantation (OLT): the routine forced-air warming system and the newly developed, whole body water garment.
In this prospective, randomized and open-labelled study, 24 adult patients were enrolled in one of two intraoperative temperature management groups during OLT. The water-garment group (N = 12) received warming with a body temperature (esophageal) set point of 36.8°C. The forced air-warmer group (N = 12) received routine warming therapy using upper- and lower-body forced-air warming system. Body core temperature (primary outcome) was recorded intraoperatively and during the two hours after surgery in both groups.
The mean core temperatures during incision, one hour after incision and during the skin closing were significantly higher (p < 0.05, t test with Bonferroni corrections for the individual tests) in the water warmer group compared to the control group (36.7 ± 0.1, 36.7 ± 0.2, 36.8 ± 0.1 vs 36.1 ± 0.4, 36.1 ± 0.4, 36.07 ± 0.4°C, respectively). Moreover, significantly higher core temperatures were observed in the water warmer group than in the control group during the placement of cold liver allograft (36.75 ± 0.17 vs 36.09 ± 0.38°C, respectively) and during the allograft reperfusion period (36.3 ± 0.26 vs 35.52 ± 0.42°C, respectively). In addition, the core temperatures immediately after admission to the SICU (36.75 ± 0.13 vs 36.22 ± 0.3°C, respectively) and at one hr (36.95 ± 0.13 vs 36.46 ± 0.2°C, respectively) were significantly higher in the water warmer group, compared to the control group, whereas the core temperature did not differ significantly afte two hours in ICU in both groups.
The investigated water warming system results in better maintenance of intraoperative normothermia than routine air forced warming applied to upper- and lower body.
PMCID: PMC137608  PMID: 12441007

Results 1-18 (18)