Allan Tsung

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (171)789.33 Total impact

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    ABSTRACT: Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of damage associated molecular patterns (DAMPs), which trigger innate immune and inflammatory cascade via pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to the organ damage, innate immune and inflammatory responses. Formation of neutrophil extracellular trap (NET) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase (MPO)-DNA complexes and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase (PAD) 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. DAMPs, such as HMGB1 and histones, released by injured hepatocytes stimulate NET formation through Toll-like receptor (TLR4)- and TLR9-MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout (KO) or TLR9 KO neutrophils confers significant protection from liver I/R injury with significant decrease in NET formation. In addition, we found inhibition of NET formation by PAD4 inhibitor or DNase I reduces HMGB1 and histone-mediated liver I/R injury.Conclusion: DAMPs released during liver I/R promotes NET formation through TLRs signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R. This article is protected by copyright. All rights reserved.
    Hepatology 04/2015; DOI:10.1002/hep.27841 · 11.19 Impact Factor
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    ABSTRACT: The use of laparoscopy for liver surgery is increasing rapidly. The Second International Consensus Conference on Laparoscopic Liver Resections (LLR) was held in Morioka, Japan, from October 4 to 6, 2014 to evaluate the current status of laparoscopic liver surgery and to provide recommendations to aid its future development. Seventeen questions were addressed. The first 7 questions focused on outcomes that reflect the benefits and risks of LLR. These questions were addressed using the Zurich-Danish consensus conference model in which the literature and expert opinion were weighed by a 9-member jury, who evaluated LLR outcomes using GRADE and a list of comparators. The jury also graded LLRs by the Balliol Classification of IDEAL. The jury concluded that MINOR LLRs had become standard practice (IDEAL 3) and that MAJOR liver resections were still innovative procedures in the exploration phase (IDEAL 2b). Continued cautious introduction of MAJOR LLRs was recommended. All of the evidence available for scrutiny was of LOW quality by GRADE, which prompted the recommendation for higher quality evaluative studies. The last 10 questions focused on technical questions and the recommendations were based on literature review and expert panel opinion. Recommendations were made regarding preoperative evaluation, bleeding controls, transection methods, anatomic approaches, and equipment. Both experts and jury recognized the need for a formal structure of education for those interested in performing major laparoscopic LLR because of the steep learning curve.
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    ABSTRACT: To assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with unresectable intermediate- or advanced-stage hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization (RE). Retrospective chart review was performed for 176 patients with intermediate- or advanced-stage HCC treated with RE between August 2000 and November 2012. The appropriate NLR cutoff was determined by receiver operating characteristic curves. Demographic, clinical, radiographic, and pathologic parameters were compared between patients with a normal NLR (< 5) and those with an elevated NLR (≥ 5) before RE. Barcelona Clinic Liver Cancer (BCLC) stage-stratified univariate and multivariate analyses were conducted to determine variables associated with overall survival. Under univariate analyses, patients with a normal NLR were found to have longer survival than individuals with a high NLR in intermediate/advanced-disease and advanced-disease cohorts. A multivariate Cox proportional-hazards model in the advanced-disease group confirmed that elevated NLR, high α-fetoprotein level, and low albumin level were independent predictors of worse survival. This study provides stage-dependent evidence for the prognostic role of NLR in the radioembolized HCC cohort. Patients with BCLC stage C disease with elevated NLR may not derive benefit from RE, and other intervening modalities should be explored in this subpopulation. Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.
    Journal of vascular and interventional radiology: JVIR 03/2015; DOI:10.1016/j.jvir.2015.01.038 · 2.15 Impact Factor
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    ABSTRACT: Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage associated molecular patterns (DAMPs), such as high mobility group box-1 (HMGB1), and dysregulated microRNAs (miRNAs) involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in over-expression of miR-21. These changes were found to be dependent on the IL-6/Stat3 signaling axis. Invasion and migration of HCC cells in vitro was inhibited by both Stat3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a post-transcriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL-6/Stat3-miR-21 axis. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 02/2015; 75(8). DOI:10.1158/0008-5472.CAN-14-2147 · 9.28 Impact Factor
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    ABSTRACT: The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. Huh7 and Hepa1-6 cancer cells were investigated in vitro to investigate how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR-9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, knockdown of either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo after injection in mice. Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth. Copyright © 2015. Published by Elsevier B.V.
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    ABSTRACT: Pre-operative simulation using three-dimensional (3D) reconstructions have been suggested to enhance surgical planning of hepatectomy. Evidence on its benefits for hepatectomy patients remains limited. This systematic review examined the use and impact of pre-operative simulation and intraoperative navigation on hepatectomy outcomes. A systematical searched electronic databases for studies reporting on the use and results of simulation and navigation for hepatectomy was performed. The primary outcome was change in operative plan based on simulation. Secondary outcomes included operating time (min), estimated blood loss, surgical margins, 30-day postoperative morbidity and mortality, and study-specific outcomes. From 222 citations, we included 11 studies including 497 patients. All were observational cohort studies. No study compared hepatectomy with and without simulation. All studies performed 3D reconstruction and segmentation, most commonly with volumetrics measurements. In six studies reporting intraoperative navigation, five relied on ultrasound, and one on a resection map. Of two studies reporting on it, the resection line was changed intraoperatively in one third of patients, based on simulation. Virtually predicted liver volumes (Pearson correlation r = 0.917 to 0.995) and surgical margins (r = 0.84 to 0.967) correlated highly with actual ones in eight studies. Heterogeneity of the included studies precluded meta-analysis.Pre-operative simulation seems accurate in measuring volumetrics and surgical margins. Current studies lack intraoperative transposition of simulation for direct navigation. Simulation appears useful planning of hepatectomies, but further work is warranted focusing on the development of improved tools and appraisal of their clinical impact compared to traditional resection. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
    02/2015; DOI:10.1002/jhbp.220
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    ABSTRACT: Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via the LPA receptors 1-6. We and others have previously described proinflammatory and profibrotic activities of LPA signaling in bleomycin- or lipopolysaccharide (LPS)-induced pulmonary fibrosis or lung injury models. In this study, we investigated if LPA signaling plays a role in the pathogenesis of systemic sepsis from an abdominal source. We report here that antagonism of the LPA receptor LPA1 with the small molecule ki16425 reduces the severity of abdominal inflammation and organ damage in the setting of peritoneal endotoxin exposure. Pretreatment of mice with intraperitoneal ki16425 eliminates LPS-induced peritoneal neutrophil chemokine and cytokine production, liver oxidative stress, liver injury, and cellular apoptosis in visceral organs. Mice pretreated with ki16425 are also protected from LPS-induced mortality. Tissue myeloperoxidase activity is not affected by LPA1 antagonism. We have shown that LPA1 is associated with LPS coreceptor CD14 and the association is suppressed by ki16425. LPS-induced phosphorylation of PKCδ and p38 MAPK in liver cells and interleukin 6 production in Raw264 cells are likewise blunted by LPA1 antagonism. These studies indicate that the small molecule inhibitor of LPA1, ki16425, suppresses cytokine responses and inflammation in a peritoneal sepsis model by blunting downstream signaling through the LPA1-CD14-toll-like receptor 4 receptor complex. This anti-inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: To determine whether sociodemographic and geographic factors are associated with referral for surgery and receipt of recommended surgical intervention. Surgical interventions confer survival advantages compared with palliative therapies for hepatocellular carcinoma (HCC), but disparities exist in use of surgical intervention. Few have investigated referral for surgery as a potential barrier to surgical intervention, and little is known about the effects of patient geographic factors, including proximity to surgical centers. Data were abstracted from the Pennsylvania Cancer Registry for patients with a diagnosis of HCC from 2006 to 2011. Using hospital procedure volume data from the Pennsylvania Health Care Cost Containment Council, we calculated proximity to a surgical center. We used multivariable logistic regression to determine whether geographic, racial, socioeconomic, and clinical factors were associated with referral for surgery and receipt of a recommended surgical intervention. Of 3576 patients with HCC, 41.0% were referred for surgery. Patients who lived closer to a surgical center were less likely to be referred for surgery (adjusted odds ratio = 0.79; 95% confidence interval, 0.68-0.92). Surgical referral was less likely among older, male patients with Medicaid insurance and advanced tumor stage at diagnosis. Of those referred, 1276 (87.0%) underwent surgical intervention. Proximity to a surgical center was not associated with receipt of surgical intervention (P = 0.27). Patients with distant tumor stage at diagnosis were less likely to receive recommended surgical intervention (adjusted odds ratio = 0.27; 95% confidence interval, 0.15-0.50). Geographic and sociodemographic disparities in referral for surgery may be major barriers to surgical intervention for patients with HCC.
    Annals of Surgery 01/2015; DOI:10.1097/SLA.0000000000001111 · 7.19 Impact Factor
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    ABSTRACT: BACKGROUND Evidence continues to accumulate regarding the association between health-related quality of life (HRQoL) and survival across chronic diseases. The objectives of the current study were to investigate the prognostic value of HRQoL in patients with hepatocellular carcinoma and cholangiocarcinoma after adjusting for sociodemographics, disease-related factors, and treatment-related factors.METHODSA total of 321 patients diagnosed with hepatocellular or cholangiocarcinoma were administered the Functional Assessment of Cancer Therapy-Hepatobiliary instrument. Cox regression and Kaplan-Meier survival analyses were performed to test the association between the 5 domains of HRQoL and survival.RESULTSUsing Cox regression, overall HRQoL was found to be significantly associated with survival (P = .003) after adjusting for demographics, disease-specific factors, and treatment. Subscales of the Functional Assessment of Cancer Therapy-Hepatobiliary, including the Physical Well-Being (P = .02) and the Symptoms and Side Effects subscales (P = .05), were also found to be significantly associated with survival after adjusting for demographics, disease-specific factors, and treatment.CONCLUSIONSHRQoL was found to be prognostic of survival in patients with hepatocellular and cholangiocarcinoma while covarying for demographics, disease-specific factors, and treatment. Stratifying patients based on HRQoL when testing novel treatments may be recommended.Health-related quality of life was found to be prognostic of survival in patients with hepatocellular and cholangiocarcinoma while controlling for demographics, disease-specific factors, and treatment-related factors. Cancer 2014. © 2014 American Cancer Society.
    Cancer 12/2014; 120(23). DOI:10.1002/cncr.28902 · 4.90 Impact Factor
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    ABSTRACT: Purpose: Novel therapies for hepatitis C (HCV) are highly effective and very costly. Current guidelines recommend sofosbuvir, a recently approved RNA polymerase inhibitor, with or without injectable interferon. Trials suggest that more effective all-oral regimens will become available in 2015. We compare the cost-effectiveness of treating HCV with current sofosbuvir-based regimens versus waiting to treat with future all-oral regimens. Method: We developed a Markov model with 1-year cycle length for a cohort of 50-year old treatment-naïve Veterans with genotype 1, 2, or 3 HCV to compare: (1) treating all with current sofosbuvir regimens, (2) treating advanced disease with sofosbuvir and treating less advanced disease in one year with future all-oral regimens, and (3) treating all in one year with future all-oral regimens. For comparison, we included the previous standard-of-care (interferon-based regimen with telaprevir/boceprevir) and no treatment. Patients could progress through stages of HCV and cirrhosis, develop hepatocellular carcinoma, undergo transplantation, or die. Patients with sustained virologic response (SVR) had lower rates of progression, complications and mortality. Analyses were performed from the VA healthcare system perspective, using a lifetime time horizon and discounting 3%/year. We performed one-way and probabilistic sensitivity analyses. Result: In the base case, treating all genotype 1 patients with current sofosbuvir-based regimens was more costly but more effective ($105,151, 15.4 QALYs) than waiting to treat all patients with future all-oral regimens ($95,894, 15.1 QALYs), costing $36,234/QALY gained. These strategies dominated all other strategies. Treating all had an incremental cost-effectiveness ratio of $3,922/QALY for patients with genotype 2 and $23,813/QALY for genotype 3. In sensitivity analysis, if sofosbuvir/simeprevir combination therapy’s SVR was <84%, treating now was no longer favorable at a $100,000/QALY threshold. In probabilistic sensitivity analysis for genotype 1, waiting to treat with all-oral regimens was favored in 56% of iterations at $50,000/QALY; treating all patients with current sofosbuvir-based regimens was preferred in 44%. Treating with sofosbuvir-based regimens was preferred above $75,000/QALY. Conclusion: Treating patients with genotype 1, 2, or 3 HCV with currently available sofosbuvir-based regimens is more costly, but more effective than waiting one year to treat with future all-oral therapies. This strategy is preferred above a willingness-to-pay threshold of $75,000/QALY.
    The 36th Annual Meeting of the Society for Medical Decision Making; 10/2014
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    ABSTRACT: Laparoscopic liver resection (LLR) for metastatic colorectal cancer (mCRC) remains controversial. The objective of this manuscript was to perform a metaanalysis comparing outcomes of LLR with open liver resection (OLR) in patients with hepatic mCRC, and to identify which patients were suitable candidates for LLR.
    Surgery 10/2014; DOI:10.1016/j.surg.2014.08.036 · 3.11 Impact Factor
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    ABSTRACT: Purpose Previous studies have reported that an elevated preoperative Neutrophil-Lymphocyte Ratio (NLR) is associated with poor prognosis in patients with various solid tumors including colorectal cancer (CRC). Here, we examine whether NLR predicts survival in patients with unresectable CRC metastases undergoing hepatic radioembolization. Methods A retrospective review of 104 consecutive patients with unresectable metastatic CRC who were treated with radioembolization after failing first and second-line chemotherapy. Results Between 2002 and 2012, the median NLR for all patients was 4.6. Using receiver operating curve analysis, there was no difference between using an NLR cut-off of 4.6 or 5. Forty-eight patients had a high NLR of ≥5 and 56 patients had an NLR of p = 0.001). Other factors associated with risk of death were extrahepatic spread of disease, presence of pulmonary nodules, previous liver-targeted intervention, and radiographic response. On multivariate analysis, high NLR, progressive radiographic response, and presence of extrahepatic disease remained independently associated with increased risk of death. Conclusions NLR is a simply attainable, inexpensive, and useful biomarker to predict outcome in patients with metastatic colorectal cancer receiving radioembolization.
    Annals of Surgical Oncology 09/2014; 22(5). DOI:10.1245/s10434-014-4050-6 · 3.94 Impact Factor
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    ABSTRACT: AimTo evaluate the outcomes among elderly (≥70 years) and younger patients (<70 years) with liver-dominant metastatic colorectal cancer (mCRC) who received radioembolization (RE) as salvage therapy.MethodsA retrospective review of 107 consecutive patients with unresectable mCRC treated with RE after failing first- and second-line chemotherapy.ResultsFrom 2002 to 2012, 44 elderly and 63 younger (<70 years) patients received RE. Patients had similar previous extensive chemotherapy and liver-directed interventions. Using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, either a stable or a partial radiographical response was seen in 65.8% of the younger compared with 76.5% of the elderly patients. RE was equally well tolerated in both groups and common procedure-related adverse events were predominantly grade 1–2 and of short duration. No significant difference was found with regard to overall median survival between younger [8.4 months; 95% confidence interval (CI) = 6.2–10.6] or elderly patients (8.2 months; 95% CI = 5.9–10.5, P = 0.667). The presence of extrahepatic disease at the time of RE was associated with a significantly worse median survival in both groups.Conclusion Radioembolization appears to be as well tolerated and effective for the elderly as it is for younger patients with mCRC. Age alone should not be a discriminating factor for the use of radioembolization in the management of mCRC patients.
    HPB 09/2014; DOI:10.1111/hpb.12307 · 2.05 Impact Factor
  • Journal of the American College of Surgeons 09/2014; 219(3):S142-S143. DOI:10.1016/j.jamcollsurg.2014.07.343 · 4.45 Impact Factor
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    ABSTRACT: Background and Rationale. Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in industrialized countries. Understanding the mechanisms of APAP-induced liver injury as well as other forms of sterile liver injury is critical to improve the care of patients. Recent studies demonstrate that danger signaling and inflammasome activation play a role in APAP-induced injury. The purpose of these investigations was to test the hypothesis that benzyl alcohol (BA) is a therapeutic that protects against APAP-induced liver injury via modulation of danger signaling. Main Results. APAP-induced liver injury was dependent in part on TLR-9 and receptor for advanced glycation endproducts (RAGE) signaling. BA limited liver injury over a dose range of 135-540 µg/g body weight or when delivered as a pre-, concurrent, or post-APAP therapeutic. Furthermore, BA abrogated APAP-induced cytokines and chemokines as well as high mobility group box-1 release. Moreover, BA prevented APAP-induced inflammasome signaling as determined by IL-1β, IL-18 and caspase-1 cleavage in liver tissues. Interestingly, the protective effects of BA on limiting liver injury and inflammasome activation were dependent on TLR4 signaling, but not TLR2 or Cluster of differentiation 14 (CD14). Cell type specific knockouts of TLR4 were utilized in order to further determine the protective mechanisms of BA. These studies found that TLR4 expression specifically in myeloid cells (LyzCre-tlr4-/-) were necessary for the protective effects of BA. Conclusion: BA protects against APAP-induced acute liver injury and reduced inflammasome activation in a TLR4-dependent manner. BA may prove to be a useful adjunct in the treatment of APAP and other forms of sterile liver injury. (Hepatology 2014)
    Hepatology 09/2014; 60(3). DOI:10.1002/hep.27201 · 11.19 Impact Factor
  • Journal of the American College of Surgeons 09/2014; 219(3):S122-S123. DOI:10.1016/j.jamcollsurg.2014.07.290 · 4.45 Impact Factor
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    ABSTRACT: Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
    Molecular Aspects of Medicine 07/2014; DOI:10.1016/j.mam.2014.05.001 · 10.30 Impact Factor
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    ABSTRACT: Background: The management of hepatic hemangiomas remains ill defined. This study sought to investigate the indications, surgical management and outcomes of patients who underwent a resection for hepatic hemangiomas. Methods: A retrospective review from six major liver centres in the United States identifying patients who underwent surgery for hepatic hemangiomas was performed. Clinico-pathological, treatment and peri-operative data were evaluated. Results: Of the 241patients who underwent a resection, the median age was 46 years [interquartile range (IQR): 39-53] and 85.5% were female. The median hemangioma size was 8.5 cm (IQR: 6-12.1). Surgery was performed for abdominal symptoms (85%), increasing hemangioma size (11.3%) and patient anxiety (3.7%). Life-threatening complications necessitating a hemangioma resection occurred in three patients (1.2%). Clavien Grade 3 or higher complications occurred in 14 patients (5.7%). The 30- and 90-day mortality was 0.8% (n = 2). Of patients with abdominal symptoms, 63.2% reported improvement of symptoms post-operatively. Conclusion: A hemangioma resection can be safely performed at high-volume institutions. The primary indication for surgery remains for intractable symptoms. The development of severe complications associated with non-operative management remains a rare event, ultimately challenging the necessity of additional surgical indications for a hemangioma resection.
    HPB 06/2014; 16(10). DOI:10.1111/hpb.12291 · 2.05 Impact Factor
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    ABSTRACT: Purpose: Management guidelines for pancreatic IPMNs and MCNs are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA) remains unclear. Experimental Design: GNAS and KRAS testing was performed on EUS-FNA obtained fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNETs), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts and 1 lymphoepithelial cyst. Results: Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity (95% confidence interval [CI], 0.83-1.00), but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had a 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92). Conclusions: The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms.
    Clinical Cancer Research 06/2014; 20(16). DOI:10.1158/1078-0432.CCR-14-0513 · 8.19 Impact Factor
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    ABSTRACT: High mobility group box 1 (HMGB1) was originally defined as a ubiquitous nuclear protein, but it was later determined that the protein has different roles both inside and outside of cells. Nuclear HMGB1 regulates chromatin structure and gene transcription, whereas cytosolic HMGB1 is involved in inflammasome activation and autophagy. Extracellular HMGB1 has drawn attention because it can bind to related cell signalling transduction receptors, such as the receptor for advanced glycation end-products, toll-like receptor (TLR)2, TLR4 and TLR9. It also participates in the development and progression of a variety of diseases. HMGB1 is actively secreted by stimulation of the innate immune system, and it is passively released by ischaemia or cell injury. This review focuses on the important role of HMGB1 in the pathogenesis of acute and chronic sterile inflammatory conditions. Strategies that target HMGB1 have been shown to significantly decrease inflammation in several disease models of sterile inflammation, and this may represent a promising clinical approach for treatment of certain conditions associated with sterile inflammation. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 06/2014; 276(5). DOI:10.1111/joim.12276 · 5.79 Impact Factor

Publication Stats

5k Citations
789.33 Total Impact Points


  • 2004–2015
    • University of Pittsburgh
      • • Department of Surgery
      • • Division of Transplantation
      • • Thomas E. Starzl Transplantation Institute
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Central South University
      Ch’ang-sha-shih, Hunan, China
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
    • Montefiore Medical Center
      New York City, New York, United States
  • 1998
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States