Publications by authors named "Richard M Green"

121 Publications

Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1.

PLoS One 2022 14;17(1):e0261789. Epub 2022 Jan 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261789PLOS
January 2022

Hepatic X-Box Binding Protein 1 and Unfolded Protein Response Is Impaired in Weanling Mice With Resultant Hepatic Injury.

Hepatology 2021 12 9;74(6):3362-3375. Epub 2021 Sep 9.

Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Background And Aims: The unfolded protein response (UPR) is a coordinated cellular response to endoplasmic reticulum (ER) stress that functions to maintain cellular homeostasis. When ER stress is unresolved, the UPR can trigger apoptosis. Pathways within the UPR influence bile acid metabolism in adult animal models and adult human liver diseases, however, the UPR has not been studied in young animal models or pediatric liver diseases. In this study we sought to determine whether weanling age mice had altered UPR activation compared with adult mice, which could lead to increased bile acid-induced hepatic injury.

Approach And Results: We demonstrate that after 7 days of cholic acid (CA) feeding to wild-type animals, weanling age mice have a 2-fold greater serum alanine aminotransferase (ALT) levels compared with adult mice, with increased hepatic apoptosis. Weanling mice fed CA have increased hepatic nuclear X-box binding protein 1 spliced (XBP1s) expression, but cannot increase expression of its protective downstream target's ER DNA J domain-containing protein 4 and ER degradation enhancing α-mannoside. In response to tunicamycin induced ER stress, young mice have blunted expression of several UPR pathways compared with adult mice. CA feeding to adult liver-specific XBP1 knockout (LS-XBP1 ) mice, which are unable to resolve hepatic ER stress, leads to increased serum ALT and CCAAT/enhancer binding homologous protein, a proapoptotic UPR molecule, expression to levels similar to CA-fed LS-XBP1 weanlings.

Conclusions: Weanling mice have attenuated hepatic XBP1 signaling and impaired UPR activation with resultant increased susceptibility to bile acid-induced injury.
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http://dx.doi.org/10.1002/hep.32031DOI Listing
December 2021

Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.

PLoS One 2021 7;16(1):e0244743. Epub 2021 Jan 7.

Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Background & Aims: Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease.

Methods: We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages.

Results: We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver.

Conclusions: We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790256PMC
May 2021

A Fibrosis-Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis.

Hepatology 2021 03 28;73(3):1105-1116. Epub 2021 Feb 28.

Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.

Background And Aims: Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n = 74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events.

Approach And Results: The effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ = -0.80; P < 0.001). After removing the effect of fibrosis-related genes, the first principle component was not associated with fibrosis (ρ = -0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P < 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α-smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL-8 (all P > 0.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (ATF6) and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold changes of -0.18 [P = 0.02] and -0.16 [P = 0.02], respectively). Clinical events were enriched in the high-risk versus low-risk group (38% [12/32] vs. 2.4% [1/42], P < 0.0001).

Conclusions: Removing the contribution of fibrosis-related pathways uncovered alterations in the unfolded protein response, which were associated with liver-related complications in PSC.
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http://dx.doi.org/10.1002/hep.31488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048608PMC
March 2021

Telomeres, p53, Hepatocyte Nuclear Factor 4α, and Liver Disease.

Hepatology 2020 10 5;72(4):1166-1168. Epub 2020 Oct 5.

Feinberg School of Medicine, Northwestern University, Chicago, IL.

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http://dx.doi.org/10.1002/hep.31454DOI Listing
October 2020

A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury.

Physiol Rep 2020 05;8(10):e14446

Department of Surgery, Northwestern University, Chicago, IL, USA.

There are limited murine models of cholestatic liver diseases characterized by chronic biliary obstruction and resumption of bile flow. While murine bile duct ligation (BDL) is a well-established model of obstructive cholestasis, current models of BDL reversal (BDLR) alter biliary anatomy. We aimed to develop a more physiologic model of BDLR to evaluate the time course and mechanism for resolution of hepatic injury after biliary obstruction. In the present study, we restored bile flow into the duodenum without disruption of the gall bladder after murine BDL using biocompatible PE-50 tubing. After establishing the technique, overall survival for BDLR at 7 or 14 days after BDL was 88%. Sham laparotomy was performed in control mice. Laboratory data, liver histology, and hepatic gene expression were compared among BDL, BDLR, and controls. Laboratory evidence of cholestatic liver injury was observed at day 7 after BDL and rapid improvement occurred within 48 hr of BDLR. After BDLR there was also enhanced gene expression for the bile acid transporter Abcb11, however, bile duct proliferation persisted. Assessment of the immune response showed increased gene and protein expression for the general immune cell marker Cd45 in BDLR versus BDL mice suggesting a reparative immune response after BDLR. In summary, we have established a novel murine model of BDLR that allows for the investigation into bile acid and immune pathways responsible for hepatic repair following obstructive cholestasis. Future studies with our model may identify targets for new therapies to improve outcome in pediatric and adult cholestatic liver disease.
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http://dx.doi.org/10.14814/phy2.14446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243199PMC
May 2020

Correlation of commercially available quantitative (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival.

Neurooncol Pract 2019 May 8;6(3):194-202. Epub 2018 Aug 8.

University of California Los Angeles (UCLA) Department of Neurology, Los Angeles.

Background: Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase () promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome.

Methods: We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase () wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative scores obtained on pretreatment tissue samples. Using LabCorp's threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS).

Results: We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for methylated patients vs unmethylated patients. Cox regression analysis confirmed that (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 ( = .053) and 2.463 ( = .023), respectively, when compared to the (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of methylation and improved survival.

Conclusions: The unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival. These findings will require validation in additional independent clinical data sets.
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http://dx.doi.org/10.1093/nop/npy028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656311PMC
May 2019

Patterns of long-term survivorship following bevacizumab treatment for recurrent glioma: a case series.

CNS Oncol 2019 06 11;8(2):CNS35. Epub 2019 Jul 11.

Department of Neurology, University of California, Los Angeles, 710 Westwood Plaza RNRC #1-230, Los Angeles, CA 90095, USA.

Long-term survivors (LTS) after glioma recurrence while on bevacizumab (Bev) therapy are rarely reported in the current literature. The purpose of this case series is to confirm the existence of and describe a large cohort of recurrent glioma LTS treated with Bev (Bev-LTS). We identified Bev-LTS as patients with post-Bev initiation survival times of ≥3 years among 1397 Bev treated recurrent glioma patients. Among 962 grade-IV, 221 grade III, and 214 grade II Bev-treated glioma patients, we identified 28 (2.9%), 14 (6.3%) and 8 (3.7%) Bev-LTS patients, respectively. 45 Bev-LTS patients recurred on Bev, with 36 of those patients continuing therapy.  Our study shows that a small portion of grade-IV, -III, and -II glioma patients can have long-term survival on Bev therapy even after Bev recurrence.
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http://dx.doi.org/10.2217/cns-2019-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713025PMC
June 2019

Endoplasmic reticulum stress and liver diseases.

Liver Res 2019 Mar 30;3(1):55-64. Epub 2019 Jan 30.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tarry Building 15-709, 303 East Superior Street, Chicago, IL 60611, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Endoplasmic reticulum (ER) stress occurs when ER homeostasis is perturbed with accumulation of unfolded/misfolded protein or calcium depletion. The unfolded protein response (UPR), comprising of inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6) signaling pathways, is a protective cellular response activated by ER stress. However, UPR activation can also induce cell death upon persistent ER stress. The liver is susceptible to ER stress given its synthetic and other biological functions. Numerous studies from human liver samples and animal disease models have indicated a crucial role of ER stress and UPR signaling pathways in the pathogenesis of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, alpha-1 antitrypsin deficiency, cholestatic liver disease, drug-induced liver injury, ischemia/reperfusion injury, viral hepatitis and hepatocellular carcinoma. Extensive investigations have demonstrated the potential underlying mechanisms of the induction of ER stress and the contribution of UPR pathways during the development of the diseases. Moreover ER stress and the UPR proteins and genes have become emerging therapeutic targets to treat liver diseases.
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http://dx.doi.org/10.1016/j.livres.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363397PMC
March 2019

Somatostatin Receptor Ligand Therapy-A Potential Therapy for Neurocytoma.

J Clin Endocrinol Metab 2019 06;104(6):2395-2402

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.

Context: Neurocytoma (NC) is a rare, low-grade tumor of the central nervous system, with a 10-year survival rate of 90% and local control rate of 74%. However, 25% of NCs will be atypical, with an elevated Ki-67 labeling index >2%, and will exhibit a more aggressive course, with a high propensity for local recurrence and/or craniospinal dissemination. Although no standard treatment regimen exists for these atypical cases, adjuvant stereotactic or conventional radiotherapy and/or chemotherapy have been typically offered but have yielded inconsistent results.

Case Description: We have described the case of a patient with a vasopressin-secreting atypical NC of the sellar and cavernous sinus region. After subtotal resection via endoscopic transsphenoidal surgery, the residual tumor showed increased fluorodeoxyglucose uptake and high somatostatin receptor (SSTR) expression on a 68Ga-DOTA-TATE positron emission tomography/CT scan. Somatostatin receptor ligand (SRL) therapy with lanreotide (120 mg every 28 days) was initiated. Four years later, the residual tumor was stable with decreased fluorodeoxyglucose tumor uptake. Immunocytochemical SSTR2 and SSTR5 expression >80% was further confirmed in a series of NC tissues.

Conclusions: To the best of our knowledge, we have described the first use of SRL therapy for an atypical NC. Our results support consideration of adjuvant SRL therapy for NC refractory to surgical removal. Our findings further raise the possibility of SSTR-directed peptide receptor radionuclide therapy as NC therapy.
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http://dx.doi.org/10.1210/jc.2018-02419DOI Listing
June 2019

Open Versus Fenestrated Endovascular Repair of Complex Abdominal Aortic Aneurysms.

Ann Surg 2020 05;271(5):969-977

Division of Cardiac, Thoracic, and Vascular Surgery, New York-Presbyterian/Columbia University Irving Medical Center/Columbia University Vagelos College of Physicians and Surgeons, New York, NY.

Objective: To compare outcomes of fenestrated (FEVAR) and open repairs of complex abdominal aortic aneurysms (cAAA).

Background: FEVAR has emerged as an alternative to open surgery for treating cAAA, but direct comparisons are limited.

Methods: We studied all repairs of intact or symptomatic cAAA in the Vascular Quality Initiative between 2012 and 2018, excluding chimney/snorkels and any devices implanted under Investigational Device Exemption studies. We compared open repairs, commercially available FEVAR devices and physician-modified endografts (PMEG) using inverse probability weighting. As a secondary analysis, we compared PMEG separately.

Results: We identified 3253 cAAA repairs: 2125 open (65%), 877 FEVAR (27%), and 251 PMEG (8%). Patients undergoing FEVAR were older, with larger aneurysms, and more comorbidities. Propensity-weighted perioperative mortality was similar between open repair and FEVAR (4.7% vs 3.3%, respectively, P = 0.17), but open repair was associated with higher rates of myocardial infarction (5.0% vs 3.0%, P = 0.03), acute kidney injury (25% vs 16%, P < 0.001), and new dialysis (4.3% vs 2.1%, P = 0.003). However, propensity-weighted long-term mortality was higher following FEVAR [Hazard Ratio (HR) 1.7 (1.1-2.6), P = 0.02]. Although outcomes of commercially available FEVAR and PMEG were similar, there was a trend toward higher long-term mortality with PMEG compared to FEVAR [HR 1.7 (0.9-3.1), P = 0.09).

Conclusions: In patients undergoing cAAA repair, open surgery was associated with higher overall survival than FEVAR and similar perioperative mortality, but longer lengths of stay, and higher rates of postoperative renal dysfunction and MI. PMEG were associated with similar perioperative results as commercially available FEVAR, but further study is needed to establish their long-term durability.
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http://dx.doi.org/10.1097/SLA.0000000000003094DOI Listing
May 2020

MicroRNAs: Unfolding the Link Between Inositol-Requiring Enzyme 1α and Fatty Liver.

Hepatology 2019 06 7;69(6):2696-2698. Epub 2019 Mar 7.

Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1002/hep.30427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315223PMC
June 2019

HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination.

EMBO J 2018 11 2;37(22). Epub 2018 Nov 2.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

The endoplasmic reticulum-associated protein degradation (ERAD) is responsible for recognizing and retro-translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG-CoA Reductase (HMGCR) Degradation protein-HRD1-was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver-specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding condition and phenocopy the FGF21 gain-of-function mice showing growth retardation, female infertility, and diurnal circadian behavior disruption. HRD1-ERAD facilitates the degradation of the liver-specific ER-tethered transcription factor CREBH to downregulate FGF21 expression. HRD1-ERAD catalyzes polyubiquitin conjugation onto CREBH at lysine 294 for its proteasomal degradation, bridging a multi-organ crosstalk in regulating growth, circadian behavior, and female fertility through regulating the CREBH-FGF21 regulatory axis.
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http://dx.doi.org/10.15252/embj.201898942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236336PMC
November 2018

Complex bile duct network formation within liver decellularized extracellular matrix hydrogels.

Sci Rep 2018 08 15;8(1):12220. Epub 2018 Aug 15.

Simpson Querrey Institute, Northwestern University, Chicago, IL, USA.

The biliary tree is an essential component of transplantable human liver tissue. Despite recent advances in liver tissue engineering, attempts at re-creating the intrahepatic biliary tree have not progressed significantly. The finer branches of the biliary tree are structurally and functionally complex and heterogeneous and require harnessing innate developmental processes for their regrowth. Here we demonstrate the ability of decellularized liver extracellular matrix (dECM) hydrogels to induce the in vitro formation of complex biliary networks using encapsulated immortalized mouse small biliary epithelial cells (cholangiocytes). This phenomenon is not observed using immortalized mouse large cholangiocytes, or with purified collagen 1 gels or Matrigel. We also show phenotypic stability via immunostaining for specific cholangiocyte markers. Moreover, tight junction formation and maturation was observed to occur between cholangiocytes, exhibiting polarization and transporter activity. To better define the mechanism of duct formation, we utilized three fluorescently labeled, but otherwise identical populations of cholangiocytes. The cells, in a proximity dependent manner, either branch out clonally, radiating from a single nucleation point, or assemble into multi-colored structures arising from separate populations. These findings present liver dECM as a promising biomaterial for intrahepatic bile duct tissue engineering and as a tool to study duct remodeling in vitro.
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http://dx.doi.org/10.1038/s41598-018-30433-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093899PMC
August 2018

Endocrine Disruption: Current approaches for regulatory testing and assessment of plant protection products are fit for purpose.

Toxicol Lett 2018 Oct 11;296:10-22. Epub 2018 Jul 11.

Dow AgroSciences, 3b, Milton Park, Milton, Abingdon, OX14 4RN, UK.

The ongoing debate concerning the regulation of endocrine disruptors, has increasingly led to questions concerning the current testing of chemicals and whether this is adequate for the assessment of potential endocrine disrupting effects. This paper describes the current testing approaches for plant protection product (PPP) active substances in the European Union and the United States and how they relate to the assessment of endocrine disrupting properties for human and environmental health. This includes a discussion of whether the current testing approaches cover modalities other than the estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, sensitive windows of exposure, adequate assessment of human endocrine disorders and wildlife species, and the determination of thresholds for endocrine disruption. It is concluded, that the scope and nature of the core and triggered data requirements for PPP active substances are scientifically robust to address adverse effects mediated through endocrine mode(s) of action and to characterise these effects in terms of dose response.
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http://dx.doi.org/10.1016/j.toxlet.2018.07.011DOI Listing
October 2018

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

J Transl Med 2018 06 29;16(1):179. Epub 2018 Jun 29.

University of North Carolina, Chapel Hill, NC, USA.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
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http://dx.doi.org/10.1186/s12967-018-1552-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026340PMC
June 2018

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

J Transl Med 2018 05 29;16(1):142. Epub 2018 May 29.

University of North Carolina, Chapel Hill, NC, USA.

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax-L) to standard therapy for newly diagnosed glioblastoma.

Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.

Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.
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http://dx.doi.org/10.1186/s12967-018-1507-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975654PMC
May 2018

Bile Acids, Microbiota, and Metabolism.

Hepatology 2018 10;68(4):1229-1231

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1002/hep.30078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173626PMC
October 2018

Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment.

Int J Radiat Oncol Biol Phys 2018 04 6;100(5):1195-1203. Epub 2018 Jan 6.

Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM).

Methods And Materials: Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m on days 1, 4, 8, and 11 every 4 weeks.

Results: No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.

Conclusions: The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277207PMC
April 2018

Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.

Hepatology 2018 07 10;68(1):304-316. Epub 2018 May 10.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α (p-IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1α protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression.

Conclusion: FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).
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http://dx.doi.org/10.1002/hep.29815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033648PMC
July 2018

3D-printed gelatin scaffolds of differing pore geometry modulate hepatocyte function and gene expression.

Acta Biomater 2018 03 6;69:63-70. Epub 2018 Jan 6.

Department of Biomedical Engineering, Northwestern University, Evanston, IL, United States; Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, IL, United States; Department of Materials Science and Engineering, Northwestern University, Evanston, IL, United States; Department of Surgery - Organ Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States. Electronic address:

Three dimensional (3D) printing is highly amenable to the fabrication of tissue-engineered organs of a repetitive microstructure such as the liver. The creation of uniform and geometrically repetitive tissue scaffolds can also allow for the control over cellular aggregation and nutrient diffusion. However, the effect of differing geometries, while controlling for pore size, has yet to be investigated in the context of hepatocyte function. In this study, we show the ability to precisely control pore geometry of 3D-printed gelatin scaffolds. An undifferentiated hepatocyte cell line (HUH7) demonstrated high viability and proliferation when seeded on 3D-printed scaffolds of two different geometries. However, hepatocyte specific functions (albumin secretion, CYP activity, and bile transport) increases in more interconnected 3D-printed gelatin cultures compared to a less interconnected geometry and to 2D controls. Additionally, we also illustrate the disparity between gene expression and protein function in simple 2D culture modes, and that recreation of a physiologically mimetic 3D environment is necessary to induce both expression and function of cultured hepatocytes.

Statement Of Significance: Three dimensional (3D) printing provides tissue engineers the ability spatially pattern cells and materials in precise geometries, however the biological effects of scaffold geometry on soft tissues such as the liver have not been rigorously investigated. In this manuscript, we describe a method to 3D print gelatin into well-defined repetitive geometries that show clear differences in biological effects on seeded hepatocytes. We show that a relatively simple and widely used biomaterial, such as gelatin, can significantly modulate biological processes when fabricated into specific 3D geometries. Furthermore, this study expands upon past research into hepatocyte aggregation by demonstrating how it can be manipulated to enhance protein function, and how function and expression may not precisely correlate in 2D models.
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http://dx.doi.org/10.1016/j.actbio.2017.12.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831494PMC
March 2018

Weight of evidence approaches for the identification of endocrine disrupting properties of chemicals: Review and recommendations for EU regulatory application.

Regul Toxicol Pharmacol 2017 Dec 4;91:20-28. Epub 2017 Oct 4.

Dow AgroSciences, 3b, Milton Park, Abingdon, Oxfordshire, OX14 4RN, UK.

A Weight-of-evidence (WoE) evaluation should be applied in assessing all the available data for the identification of endocrine disrupting (ED) properties of chemicals. The European Commission draft acts specifying criteria under the biocidal products and plant protection products regulations require that WoE is implemented for the assessment of such products. However, only some general considerations and principles of how a WoE should be conducted are provided. This paper reviews WoE approaches to distil key recommendations specifically for the evaluation of potential ED properties of chemicals. In a manner, which is consistent with existing, published WoE frameworks, the WoE evaluation of ED properties can be divided into four phases: 1) Definition of causal questions and data gathering and selection, 2) Review of individual studies, 3) Data integration and evaluation, and 4) Drawing conclusions based on inferences. Recommendations are made on how to conduct each phase robustly and transparently to help guide the WoE evaluation of potential endocrine disrupting properties of chemicals within a European regulatory context.
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http://dx.doi.org/10.1016/j.yrtph.2017.10.004DOI Listing
December 2017

Beyond Farnesoid X receptor to target new therapies for NAFLD.

Hepatology 2017 12 30;66(6):1724-1726. Epub 2017 Oct 30.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1002/hep.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032979PMC
December 2017

Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in Mice.

Cell Mol Gastroenterol Hepatol 2017 Mar 10;3(2):261-271. Epub 2016 Dec 10.

Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Background & Aims: Cholestasis promotes endoplasmic reticulum (ER) stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice.

Methods: ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2) cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma.

Results: Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette []) and a bile salt efflux pump (). The observed regulation of , , and occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice.

Conclusions: Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism.
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http://dx.doi.org/10.1016/j.jcmgh.2016.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331781PMC
March 2017

Autoimmune hepatitis in patients with human immunodeficiency virus (HIV): Case reports of a rare, but important diagnosis with therapeutic implications.

Medicine (Baltimore) 2017 Feb;96(7):e6011

Division of Gastroenterology and Hepatology, Department of Medicine Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL.

Rationale: Chronic liver disease is a major cause of morbidity and mortality in patients with HIV. However, autoimmune hepatitis (AIH) in patients with HIV has rarely been reported. Our aim was to evaluate a cohort of patients with HIV and AIH and identify clinical presentations and outcomes.

Patient Concerns: Management of autoimmune hepatitis in context of human immunodeficiency virus, long-term outcomes, and safety in setting of underlying immunocompromised state.

Diagnoses: Autoimmune Hepatitis, Human Immunodeficiency Virus, Hepatotoxicity, Liver Injury, Liver Transplantation.

Interventions: We retrospectively reviewed the charts of patients with HIV and AIH based on histological, serologic, biochemical demographic, and clinical data.

Outcomes: Five patients were identified with autoimmune hepatitis; 4 of 5 were women, and all were African or African-American. The age at the time of AIH diagnosis was 46.6 ± 13.4 years. All patients acquired HIV sexually and all had CD4 counts >250 cells/uL (456-1011 cells/uL) and undetectable HIV viral loads at the time of AIH diagnosis. One patient presented with acute liver failure necessitating liver transplantation and developed AIH posttransplantation. At the time of diagnosis, the AST were 350 ± 448 U/L, ALT 247 ± 190 U/L, bilirubin 7 ± 12 mg/dL, and alkaline phosphatase 126 ± 53 U/L. All patients had histologic evidence of AIH on liver biopsies. Patients were successfully treated with prednisone and azathioprine, without a decrease in CD4 <250 cells/uL, infectious complications or significant side effects.

Lessons: AIH occurs in patients with well-controlled HIV. In our patient cohort, immunosuppressive therapy with prednisone and azathioprine was safe and effective in inducing remission, without significant complications or development of opportunistic infections.
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http://dx.doi.org/10.1097/MD.0000000000006011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319500PMC
February 2017

Endovascular Repair of Type A Aortic Dissection: Current Experience and Technical Considerations.

Semin Thorac Cardiovasc Surg 2016 Summer;28(2):312-317. Epub 2015 Dec 14.

Department of Surgery, Columbia University Medical Center Surgery, New York, New York. Electronic address:

Dissection of the ascending aorta, type A aortic dissection (TAAD), represents a surgical emergency with high morbidity and mortality. Current open surgical techniques, although state-of-the-art procedures and having improved outcomes for patients with TAAD over the last decades, confer significant risk of complications and death. Recently, endovascular techniques for repair of both the abdominal and thoracic aorta have gained acceptance within the vascular and cardiovascular surgical communities as a useful tool in select pathologies and patient populations. As development of endovascular technology proceeds ever closer to the aortic valve, thoracic endovascular repair for TAAD deserves special investigation. A comprehensive literature search for studies reporting outcomes of endovascular repair in the ascending aorta was performed. In this review, we compile the worldwide experience of thoracic endovascular repair for TAAD as well as imaging studies for patient selection and the use of hybrid (open plus endovascular) techniques. The authors discuss the remaining challenges that preclude its broader adoption in this role, namely patient selection and device specificity.
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http://dx.doi.org/10.1053/j.semtcvs.2015.12.004DOI Listing
June 2017

Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice.

J Lipid Res 2017 03 30;58(3):504-511. Epub 2016 Dec 30.

Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611

The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the UPR is important in lipid metabolism. However, its role in bile acid metabolism remains unknown. We demonstrate that liver-specific knockout (LS-) mice had a 45% reduction in total bile acid pool. LS- mice had lower serum 7α-hydroxy-4-cholesten-3-one (C4) levels compared with mice, indicating reduced cholesterol 7α-hydroxylase (CYP7A1) synthetic activity. This occurred without reductions of hepatic CYP7A1 protein expression. Feeding LS- mice cholestyramine increased hepatic CYP7A1 protein expression to levels 2-fold and 8-fold greater than cholestyramine-fed and chow-fed mice, respectively. However, serum C4 levels remained unchanged and were lower than both groups of mice. In contrast, although feeding LS- mice cholesterol did not increase CYP7A1 expression, serum C4 levels increased significantly up to levels similar to chow-fed mice and the total bile acid pool normalized. In conclusion, loss of hepatic XBP1 decreased the bile acid pool and CYP7A1 synthetic activity. Cholesterol feeding, but not induction of CYP7A1 with cholestyramine, increased CYP7A1 synthetic activity and corrected the genotype-specific total bile acid pools. These data demonstrate a novel role of IRE1α/XBP1 regulating bile acid metabolism.
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http://dx.doi.org/10.1194/jlr.M071266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335580PMC
March 2017

Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.

Neuro Oncol 2017 03;19(3):394-404

Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.

Background: Promoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear.

Methods: We performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression.

Results: We detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P < .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P < .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA.

Conclusion: The prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
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http://dx.doi.org/10.1093/neuonc/now189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464302PMC
March 2017

Multimodal Imaging of Nanocomposite Microspheres for Transcatheter Intra-Arterial Drug Delivery to Liver Tumors.

Sci Rep 2016 07 13;6:29653. Epub 2016 Jul 13.

Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

A modern multi-functional drug carrier is critically needed to improve the efficacy of image-guided catheter-directed approaches for the treatment of hepatic malignancies. For this purpose, a nanocomposite microsphere platform was developed for selective intra-arterial transcatheter drug delivery to liver tumors. In our study, continuous microfluidic methods were used to fabricate drug-loaded multimodal MRI/CT visible microspheres that included both gold nanorods and magnetic clusters. The resulting hydrophilic, deformable, and non-aggregated microspheres were mono-disperse and roughly 25 um in size. Sustained drug release and strong MRI T2 and CT contrast effects were achieved with the embedded magnetic nano-clusters and radiopaque gold nanorods. The microspheres were successfully infused through catheters selectively placed within the hepatic artery in rodent models and subsequent distribution in the targeted liver tissues and hepatic tumors confirmed with MRI and CT imaging. These multimodal nanocomposite drug carriers should be ideal for selective intra-arterial catheter-directed administration to liver tumors while permitting MRI/CT visualization for patient-specific confirmation of tumor-targeted delivery.
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http://dx.doi.org/10.1038/srep29653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942792PMC
July 2016

Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet.

Am J Physiol Gastrointest Liver Physiol 2015 Dec 15;309(12):G965-74. Epub 2015 Oct 15.

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient (Xbp1(-/-)) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1(-/-) mice exhibited higher serum alanine aminotransferase levels compared with Xbp1(fl/fl) controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1(-/-) mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1(-/-) mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1(-/-) compared with Xbp1(fl/fl) mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.
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http://dx.doi.org/10.1152/ajpgi.00132.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683298PMC
December 2015
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