Allan Tsung

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you Allan Tsung?

Claim your profile

Publications (208)995.89 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tumor cells produce vascular endothelial growth factor (VEGF) which can interact with membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth. We aimed to investigate the role of extracellular/intracellular autocrine VEGF signaling and Apatinib, a highly selective VEGFR2 inhibitor, in extrahepatic bile duct cancer (EBDC). We found conditioned medium or recombinant human VEGF treatment promoted EBDC cell proliferation through a phospholipase C-γ1-dependent pathway. This pro-proliferative effect was diminished by VEGF, VEGFR1 or VEGFR2 neutralizing antibodies, but more significantly suppressed by intracellular VEGFR inhibitor. The rhVEGF induced intracellular VEGF signaling by promoting nuclear accumulation of pVEGFR1/2 and enhancing VEGF promoter activity, mRNA and protein expression. Internal VEGFR2 inhibitor Apatinib significantly inhibited intracellular VEGF signaling, suppressed cell proliferation in vitro and delayed xenograft tumor growth in vivo, while anti-VEGF antibody Bevacizumab showed no effect. Clinically, overexpression of pVEGFR1 and pVEGFR2 was significantly correlated with poorer overall survival (P = .007 and P = .020, respectively). In conclusion, the intracellular autocrine VEGF loop plays a predominant role in VEGF-induced cell proliferation. Apatinib is an effective intracellular VEGF pathway blocker that presents a great therapeutic potential in EBDC.
    No preview · Article · Jan 2016 · Cancer letters
  • [Show abstract] [Hide abstract]
    ABSTRACT: Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether as a result of its ability to ensnare moving cells NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice, through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase (PAD4), which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil-derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse.
    No preview · Article · Jan 2016 · Cancer Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aims: The American Gastroenterological Association (AGA) recently reported evidence-based guidelines for the management of asymptomatic neoplastic pancreatic cysts. These guidelines advocate a higher threshold for surgical resection than prior guidelines and imaging surveillance for a considerable number of patients with pancreatic cysts. The aims of this study were to assess the accuracy of the AGA guidelines in detecting advanced neoplasia and present an alternative approach to pancreatic cysts. Methods: The study population consisted of 225 patients that underwent EUS-guided fine-needle aspiration (EUS-FNA) for a pancreatic cyst between January 2014 and May 2015. For each patient, clinical findings, EUS features, cytopathology results, carcinoembryonic antigen (CEA) analysis and molecular testing of pancreatic cyst fluid were reviewed. Molecular testing included the assessment of hotspot mutations and deletions for KRAS, GNAS, VHL, TP53, PIK3CA, and PTEN. Results: Diagnostic pathology was available for 41 (18%) patients with 13 (6%) harboring advanced neoplasia. Among these cases, the AGA guidelines identified advanced neoplasia with 62% sensitivity, 79% specificity, 57% positive predictive value, and 82% negative predictive value. Moreover, the AGA guidelines missed 45% of IPMNs with adenocarcinoma or high-grade dysplasia. For cases without confirmatory pathology, 27 of 184 (15%) patients with serous cystadenomas (SCAs) based on EUS findings and/or VHL alterations would continue MRI surveillance. In comparison, a novel algorithmic pathway using molecular testing of pancreatic cyst fluid detected advanced neoplasia with 100% sensitivity, 90% specificity, 79% positive predictive value, and 100% negative predictive value. Conclusions: The AGA guidelines were inaccurate in detecting pancreatic cysts with advanced neoplasia. Further, because the AGA guidelines manage all neoplastic cysts similarly, patients with SCAs will continue unnecessary MRI surveillance. The results of an alternative approach with integrative molecular testing are encouraging, but require further validation.
    No preview · Article · Dec 2015 · Gastrointestinal endoscopy
  • [Show abstract] [Hide abstract]
    ABSTRACT: Conclusion: Managing any treatment-naïve genotype 1 hepatitis C patient with ombitasvir-based therapy is the most economically efficient strategy, although price and efficacy can impact cost-effectiveness. It is economically unfavorable to restrict treatment to patients with advanced disease or use a staged treatment strategy. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Hepatology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Preoperative anaemia is associated with adverse outcomes after surgery but outcomes after liver surgery specifically are not well established. We aimed to analyze the incidence of and effects of preoperative anemia on morbidity and mortality in patients undergoing liver resection.
    Preview · Article · Nov 2015 · HPB
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Previous studies have shown benefit not only from postoperative chemotherapy but also from a short interval to initiation of treatment after resection of primary colorectal cancer. The aim of this study was to determine difference in timing to postoperative chemotherapy for minimally invasive resection (MIR) vs. open resection (OR) of colorectal cancer liver metastases (CRCLM). Methods: This is a retrospective review of 1:1 matched patients undergoing MIR (n = 66) and OR (n = 66) for CRCLM at a single institution. Results: Patients undergoing MIR of CRCLM had significantly shorter length of hospital stay, fewer major complications, and shorter interval to postoperative chemotherapy (median 42 vs. 63 days, p < 0.001). Univariable analysis showed that surgical approach, postoperative complications, blood loss, number of lesions, and length of stay were associated with timing to chemotherapy. On multivariable analysis, surgical approach was still associated with timing to chemotherapy, and postoperative complications resulted in a delay of chemotherapy among patients who underwent OR but not among those who underwent MIR. In addition, worse disease-free survival was seen among patients who received postoperative chemotherapy more than 60 days after surgery. Conclusion: By modifying the deleterious effects of postoperative complications on timing of postoperative chemotherapy, patients undergoing MIR for CRCLM are treated with chemotherapy sooner after surgery compared to those undergoing OR.
    No preview · Article · Oct 2015 · Journal of Gastrointestinal Surgery
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatobiliary and pancreatic (HPB) operations have a high incidence of post-operative nosocomial infections. The aim of the present study was to determine whether hospitalization up to 1 year before HPB surgery is associated with an increased risk of post-operative infection, surgical-site infection (SSI) and infection resistant to surgical chemoprophylaxis. A retrospective cohort study of patients undergoing HPB surgeries between January 2008 and June 2013 was conducted. A multivariable logistic regression model was used for controlling for potential confounders to determine the association between pre-operative admission and post-operative infection. Of the 1384 patients who met eligibility criteria, 127 (9.18%) experienced a post-operative infection. Pre-operative hospitalization was independently associated with an increased risk of a post-operative infection [adjusted odds ratio (aOR): 1.61, 95% confidence interval [CI]: 1.06-2.46] and SSI (aOR: 1.79, 95% CI: 1.07-2.97). Pre-operative hospitalization was also associated with an increased risk of post-operative infections resistant to standard pre-operative antibiotics (OR: 2.64, 95% CI: 1.06-6.59) and an increased risk of resistant SSIs (OR: 3.99, 95% CI: 1.25-12.73). Pre-operative hospitalization is associated with an increased incidence of post-operative infections, often with organisms that are resistant to surgical chemoprophylaxis. Patients hospitalized up to 1 year before HPB surgery may benefit from extended spectrum chemoprophylaxis. © 2015 International Hepato-Pancreato-Biliary Association.
    No preview · Article · Sep 2015 · HPB
  • David A Geller · Allan Tsung
    [Show abstract] [Hide abstract]
    ABSTRACT: Two recent multi-institutional Japanese studies used propensity score matching to compare the perioperative and long-term outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma or colorectal liver metastases. They found no difference in oncologic outcomes between the two groups, while the laparoscopic liver resection group had less blood loss and shorter hospital stay.
    No preview · Article · Jun 2015 · Journal of Hepato-Biliary-Pancreatic Sciences
  • Lee M Ocuin · Allan Tsung
    [Show abstract] [Hide abstract]
    ABSTRACT: Utilization of robotic techniques for resection of the liver is slowly gaining acceptance in specific situations and is now being applied to more challenging endeavors, such as major hepatectomy for cancer. This review provides a summary of robotic applications in liver surgery, with specific attention perioperative outcomes, oncologic outcomes, cost, and comparison to conventional laparoscopic techniques of liver resection. We also discuss future applications of robotic-assisted liver surgery. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Jun 2015 · Journal of Surgical Oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fatty acid binding protein 4 (FABP4) has been known as a mediator of inflammatory response in the macrophages and adipose tissue, but its hepatic function is poorly understood. The goal of this study is to investigate the role of FABP4 in liver ischemia/reperfusion (I/R), a clinical condition involves both hypoxia and inflammation. To examine the I/R regulation of FABP4, mice were subjected to I/R surgery before being measured for FABP4 gene expression. Both loss-of-function (by using a pharmacological FABP4 inhibitor) and gain-of-function (by adenoviral overexpression of FABP4) were used to determine the functional relevance of FABP4 expression and its regulation during I/R. To determine the hypoxia responsive regulation of FABP4, primary mouse hepatocytes were exposed to hypoxia. The FABP4 gene promoter was cloned and its regulation by hypoxia inducible factor 1α (HIF-1α) was characterized by luciferase reporter gene, electrophoretic mobility shift, and chromatin immunoprecipitation assays. We found that the hepatic expression of FABP4 was markedly induced by I/R. At the functional level, pharmacological inhibition of FABP4 alleviated the I/R injury, whereas adenoviral overexpression of FABP4 sensitized mice to I/R injury. We also showed that exposure of primary hepatocytes to hypoxia or transgenic overexpression of HIF-1α in the mouse liver was sufficient to induce the expression of FABP4. Our promoter analysis established FABP4 as a novel transcriptional target of HIF-1α. FABP4 is a hypoxia inducible gene that sensitizes mice to liver I/R injury. FABP4 may represent a novel therapeutic target, and FABP4 inhibitors may be used as therapeutic agents to manage hepatic I/R injury. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jun 2015 · Journal of Hepatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Estrogen sulfotransferase (EST) regulates estrogen homeostasis by sulfonating and deactivating estrogens. Liver ischemia and reperfusion (I/R) involves both hypoxia during the ischemic phase and oxidative damage during the reperfusion phase. In this report, we showed that the expression of EST was markedly induced by I/R. Mechanistically, oxidative stress-induced activation of Nrf2 was responsible for the EST induction, which was abolished in Nrf2-/- mice. EST is a direct transcriptional target of Nrf2. In the female mice, the I/R responsive induction of EST compromised estrogen activity. EST ablation attenuated the I/R injury as a result of decreased estrogen deprivation, whereas this benefit was abolished upon ovariectomy. The effect of EST ablation was sex-specific, because the EST-/- males showed heightened I/R injury. Reciprocally, both estrogens and EST regulate the expression and activity of Nrf2. Estrogen deprivation by ovariectomy abolished the I/R responsive Nrf2 accumulation, whereas the compromised estrogen deprivation in EST-/- mice was associated with an increased Nrf2 accumulation. Our results suggested a novel I/R responsive feedback mechanism to limit the activity of Nrf2, in which Nrf2 induces the expression of EST, which subsequently increases estrogen deactivation and limits the estrogen responsive activation of Nrf2. Inhibition of EST, at least in females, may represent an effective approach to manage hepatic I/R injury. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Apr 2015 · Journal of Biological Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Robotic distal pancreatectomy (RDP) is performed increasingly, but knowledge of the number of cases required to attain procedural proficiency is lacking. The aim of this study was to identify the learning curve associated with RDP at a high-volume pancreatic centre. Metrics of perioperative safety and efficiency for all consecutive RDPs were evaluated. Outcomes were followed to 90 days. Cumulative sum (CUSUM) analysis was used to identify inflexion points corresponding to the learning curve. Between 2008 and 2013, 100 patients underwent RDP. There was no 90-day mortality. In two patients (2.0%), surgery was converted to laparotomy. Thirty procedures were performed for pancreatic adenocarcinoma. Precipitous operative time reductions from an initial operative time of 331 min were observed after the first 20 and 40 cases to 266 min and 210 min, respectively (P < 0.0001). The likelihood of readmission was significantly lower after the first 40 cases (P = 0.04), and non-significant reductions were observed in incidences of major (Clavien-Dindo Grade II or higher) morbidity and Grade B and C leaks, and length of stay. In this experience, RDP outcomes were optimized after 40 cases. Familiarity with the platform and dedicated training are likely to contribute to significantly shorter learning curves in future adopters. © 2015 International Hepato-Pancreato-Biliary Association.
    No preview · Article · Apr 2015 · HPB
  • [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: 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, which trigger an innate immune and inflammatory cascade through pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to organ damage and innate immune and inflammatory responses. Formation of neutrophil extracellular traps (NETs) 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-DNA complexes, and tissue level of citrullinated-histone H3 compared to control mice. Treatment with peptidyl-arginine-deiminase 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. Damage-associated molecular patterns, such as High Mobility Group Box 1 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 or TLR9 knockout neutrophils confers significant protection from liver I/R injury with a significant decrease in NET formation. In addition, we found inhibition of NET formation by the peptidyl-arginine-deiminase 4 inhibitor and that DNase I reduces High Mobility Group Box 1 and histone-mediated liver I/R injury. Conclusion: Damage-associated molecular patterns released during liver I/R promote NET formation through the TLR signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R. (Hepatology 2015;62:600-614.
    No preview · Article · Apr 2015 · Hepatology
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Apr 2015 · Annals of Surgery
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Mar 2015 · Journal of vascular and interventional radiology: JVIR
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Feb 2015 · Cancer Research
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Feb 2015 · Journal of Hepatology
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2015 · Journal of Hepato-Biliary-Pancreatic Sciences
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Jan 2015 · Translational Research
  • [Show abstract] [Hide abstract]
    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.
    No preview · Article · Jan 2015 · Annals of Surgery

Publication Stats

7k Citations
995.89 Total Impact Points

Institutions

  • 2004-2016
    • University of Pittsburgh
      • • Department of Surgery
      • • Division of Transplantation
      Pittsburgh, Pennsylvania, United States
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
    • Montefiore Medical Center
      New York City, New York, United States
  • 2010
    • Duke University
      Durham, North Carolina, United States