Medicine and Health Sciences Commons^™

The Generation Of An Engineered Interleukin-10 Protein With Improved Stability And Biological Function, Faisal Minshawi, Sebastian Lanvermann, Edward Mckenzie, Rebecca Jeffery, Kevin Couper, Stamatia Papoutsopoulou, Axel Roers, Werner Muller

Center for Translational Medicine Faculty Papers

Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a pivotal role in modulating inflammation. IL-10 has inhibitory effects on proinflammatory cytokine production and function in vitro and in vivo; as such, IL-10 is viewed as a potential treatment for various inflammatory diseases. However, a significant drawback of using IL-10 in clinical application is the fact that the biologically active form of IL-10 is an unstable homodimer, which has a short half-life and is easily degraded in vivo. Consequently, IL-10 therapy using recombinant native IL-10 has had only limited success in the treatment of human disease. To improve the therapeutic potential …

Hepatic Stellate Cells And Hepatocarcinogenesis, Anna E Barry, Rajkumar Baldeosingh, Ryan Lamm, Keyur Patel, Kai Zhang, Dana A Dominguez, Kayla J Kirton, Ashesh P. Shah, Hien Dang

Department of Surgery Faculty Papers

Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create …

Nk Cell-Derived Gm-Csf Potentiates Inflammatory Arthritis And Is Negatively Regulated By Cis, Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D'Silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa J Davis, Jeffrey J Babon, Bogoljub Ciric, Eric Vivier, Warren S Alexander, Nicholas D Huntington, Ian P Wicks

Department of Neurology Faculty Papers

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also …

Insights From Immuno-Oncology: The Society For Immunotherapy Of Cancer Statement On Access To Il-6-Targeting Therapies For Covid-19., Paolo Antonio Ascierto, Bernard Fox, Walter Urba, Ana Carrizosa Anderson, Michael B Atkins, Ernest C Borden, Julie Brahmer, Lisa H Butterfield, Alessandra Cesano, Daniel Chen, Tanja De Gruijl, Robert O Dillman, Charles G Drake, Leisha A Emens, Thomas F Gajewski, James L Gulley, F Stephen Hodi, Patrick Hwu, David Kaufman, Howard Kaufman, Michael Lotze, Douglas G Mcneel, Kim Margolin, Francesco Marincola, Michael J Mastrangelo, Marcela V Maus, David R Parkinson, Pedro J Romero, Paul M Sondel, Stefani Spranger, Mario Sznol, George J Weiner, Jon M Wiggington, Jeffrey S Weber

Department of Microbiology and Immunology Faculty Papers

No abstract provided.

The Histone Deacetylase Inhibitor Tubacin Mitigates Endothelial Dysfunction By Up-Regulating The Expression Of Endothelial Nitric Oxide Synthase., Jihui Chen, Jian Zhang, Noor F. Shaik, Bing Yi, Xin Wei, Xiao-Feng Yang, Ulhas P. Naik, Ross Summer, Guijun Yan, Xinyun Xu, Jianxin Sun

Center for Translational Medicine Faculty Papers

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo.Wefound that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found …

In Vivo Investigation Of The Tissue Response To Commercial Teflon Insulin Infusion Sets In Large Swine For 14 Days: The Effect Of Angle Of Insertion On Tissue Histology And Insulin Spread Within The Subcutaneous Tissue., Gabriella Eisler, Jasmin R. Kastner, Marc C. Torjman, Abdurizzagh Khalf, David Diaz, Alek R. Dinesen, Channy Loeum, Mathew L. Thakur, Paul Strasma, Jeffrey I. Joseph

Department of Anesthesiology Faculty Papers

Objective: This study investigated the effects of the inflammatory tissue response (ITR) to an insulin infusion set (IIS) on insulin bolus spread over wear time, as well as the effect of cannula insertion angle on the ITR, bolus shape, and pump tubing pressure.

Research design and methods: Angled or straight IISs were inserted every other day for 14 days into the subcutaneous tissue of 11 swine and insulin was delivered continuously. Prior to euthanasia, a 70 µL bolus of insulin/X-ray contrast agent was infused while recording a pressure profile (peak tubing pressure, p_max; area under the pressure curve, …

Aneurysm Formation, Growth, And Rupture: The Biology And Physics Of Cerebral Aneurysms., Pavlos Texakalidis, Ahmad Sweid, Nikolaos Mouchtouris, Eric C. Peterson, Chrissa Sioka, Leonardo Rangel-Castilla, John Reavey-Cantwell, Pascal Jabbour

Department of Neurosurgery Faculty Papers

Cerebral aneurysms (CAs) are characterized by a pathological wall structure with internal elastic lamina and media disruption, which leads to focal weakened pouches of the arterial wall. The prevalence of unruptured CAs has been estimated to be 2%-5% in the general population. During the past few decades, the pathophysiological mechanisms behind the formation, growth, and rupture of CAs have been the focus of numerous research studies. In the present review, we have summarized the inflammatory pathways, genetics, and risk factors for the formation, growth, and rupture of CAs. In addition, we have discussed the concepts of geometric indexes, flow patterns, …

Surgical Stress And Cancer Progression: The Twisted Tango., Zhiwei Chen, Peidong Zhang, Ya Xu, Jiahui Yan, Zixuan Liu, Wayne Bond Lau, Bonnie Lau, Ying Li, Xia Zhao, Yuquan Wei, Shengtao Zhou

Department of Emergency Medicine Faculty Papers

Surgical resection is an important avenue for cancer treatment, which, in most cases, can effectively alleviate the patient symptoms. However, accumulating evidence has documented that surgical resection potentially enhances metastatic seeding of tumor cells. In this review, we revisit the literature on surgical stress, and outline the mechanisms by which surgical stress, including ischemia/reperfusion injury, activation of sympathetic nervous system, inflammation, systemically hypercoagulable state, immune suppression and effects of anesthetic agents, promotes tumor metastasis. We also propose preventive strategies or resolution of tumor metastasis caused by surgical stress.

Single-Cell Glia And Neuron Gene Expression In The Central Amygdala In Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis, Sean J. O'Sullivan, Evangelia Malahias, James Park, Ankita Srivastava, Beverly A.S. Reyes, Jonathan Gorky, Rajanikanth Vadigepalli, Elisabeth J. Van Bockstaele, James S. Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Drug-seeking in opioid dependence is due in part to the severe negative emotion associated with the withdrawal syndrome. It is well-established that negative emotional states emerge from activity in the amygdala. More recently, gut microflora have been shown to contribute substantially to such emotions. We measured gene expression in single glia and neurons gathered from the amygdala using laser capture microdissection and simultaneously measured gut microflora in morphine-dependent and withdrawn rats to investigate drivers of negative emotion in opioid withdrawal. We found that neuroinflammatory genes, notably Tnf, were upregulated in the withdrawal condition and that astrocytes, in particular, were highly …

Roles Of Gm-Csf In The Pathogenesis Of Autoimmune Diseases: An Update., Noushin Lotfi, Rodolfo Thome, Nahid Rezaei, Guang-Xian Zhang, Abbas Rezaei, A. M. Rostami, Nafiseh Esmaeil

Department of Neurology Faculty Papers

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) …

Biomarkers In Patients With Mucopolysaccharidosis Type Ii And Iv., Honoka Fujitsuka, Kazuki Sawamoto, Hira Peracha, Robert W. Mason, William Mackenzie, Hironori Kobayashi, Seiji Yamaguchi, Yasuyuki Suzuki, Kenji Orii, Tadao Orii, Toshiyuki Fukao, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Glycosaminoglycans (GAGs), dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS), are the primary biomarkers in patients with mucopolysaccharidoses (MPS); however, little is known about other biomarkers. To explore potential biomarkers and their correlation with GAGs, blood samples were collected from 46 MPS II patients, 34 MPS IVA patients, and 5 MPS IVB patients. We evaluated the levels of 8 pro-inflammatory factors (EGF, IL-1β, IL-6, MIP-1α, TNF-α, MMP-1, MMP-2, and MMP-9), collagen type II, and DS, HS (HS0S, HSNS), and KS (mono-sulfated, di-sulfated) in blood. Eight biomarkers measured were significantly elevated in untreated MPS II patients, compared with those …

Intestinal Barrier Tightening By A Cell-Penetrating Antibody To Bin1, A Candidate Target For Immunotherapy Of Ulcerative Colitis., Sunil Thomas, Kevther Hoxha, Walker Alexander, John Gilligan, Rima Dilbarova, Kelly Whittaker, Andrew Kossenkov, George C. Prendergast, James M. Mullin

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) …

Lacrimal Gland Tumors In Turkey: Types, Frequency, And Outcomes., Yağmur Seda Yeşiltaş, Ahmet Kaan Gündüz, Esra Erden, Carol L. Shields

Wills Eye Hospital Papers

AIM: To evaluate the clinical, radiological, and treatment features of lacrimal gland tumors.

METHODS: Retrospective review of 99 eyes of 92 patients with lacrimal gland tumors diagnosed and managed in a single institution between January 1999 and March 2017. Clinical and radiological features, histopathology, treatment methods, and prognosis were evaluated.

RESULTS: The mean patient age was 40.3 (range: 7-80)y. The diagnosis was made histopathologically in 91 (91.9%) tumors and on a clinical and radiological basis in 8 (8.1%) tumors. Final diagnoses included idiopathic orbital inflammation (pseudotumor) in 46 (46.5%) lesions, pleomorphic adenoma in 14 (14.1%), adenoid cystic carcinoma in 12 …

The Guanylate Cyclase C-Cgmp Signaling Axis Opposes Intestinal Epithelial Injury And Neoplasia., Jeffrey A. Rappaport, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses …

Sclerosing Mesenteritis: Clinical Presentation, Imaging Findings, And Treatment, Jennifer Nauheim, Bsc, Rose Onyeali, Md

The Medicine Forum

CASE PRESENTATION

A 67-year old male with a history of myocardial infarction status post percutaneous coronary intervention and stage IV bladder cancer status post radical cystoprostatectomy with ileal neobladder reconstruction and chemotherapy (cisplatin and gemcitabine) presented with progressive, severe epigastric and lower abdominal pain associated with nausea. The pain had intensified over the previous week and was associated with a recent fifteen pound weight loss in the setting of poor oral intake. He denied nausea or diarrhea. His physical exam was notable for abdominal tympany and tenderness. His labs were notable for mild hyperkalemia (potassium 5.0 mmol/L), normal white blood …

A Case Of Secondary Hemophagocytic Lymphohistiocytosis In An Adult Patient Treated With Concurrent Dexamethasone And Interleukin-1 Receptor Blockade, Vikas Sunder, Md

The Medicine Forum

INTRODUCTION

Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of overwhelming inflammation caused by activation and proliferation of T-lymphocytes and hemophagocytic macrophages. This uncontrolled proliferation of macrophages creates a cytokine storm with resultant tissue damage. HLH is associated with clinical and laboratory findings which include fever, cytopenias, hepatic dysfunction, splenomegaly, and marked hyperferritinemia.1-3 There exists limited epidemiologic data on adult (age ≥ 18 years) cases of HLH, and its incidence is uncertain. HLH can be due to inherited mutations causing immune system dysregulation or secondary to underlying malignancy, infection, or rheumatologic condition. Macrophage activation syndrome (MAS) refers to HLH that …

Dna Checkpoint And Repair Factors Are Nuclear Sensors For Intracellular Organelle Stresses-Inflammations And Cancers Can Have High Genomic Risks., Huihong Zeng, Gayani K Nanayakkara, Ying Shao, Hangfei Fu, Yu Sun, Ramon Cueto, William Y Yang, Qian Yang, Haitao Sheng, Na Wu, Luqiao Wang, Wuping Yang, Hongping Chen, Lijian Shao, Jianxin Sun, Xuebin Qin, Joon Y. Park, Konstantinos Drosatos, Eric T. Choi, Qingxian Zhu, Hong Wang, Xiaofeng Yang

Department of Medicine Faculty Papers

Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA DD

Migraine And Vascular Disease Biomarkers: A Population-Based Case-Control Study., Gretchen E. Tietjen, Jagdish Khubchandani, Nabeel Herial, Inge H. Palm-Meinders, Hille Koppen, Gisela M. Terwindt, Mark A. Van Buchem, Lenore J. Launer, Michel D. Ferrari, Mark C. Kruit

Department of Neurosurgery Faculty Papers

Background The underpinnings of the migraine-stroke association remain uncertain, but endothelial activation is a potential mechanism. We evaluated the association of migraine and vascular disease biomarkers in a community-based population. Methods Participants (300 women, 117 men) were recruited as a part of the Dutch CAMERA 1 (Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis) study. Participants were aged 30-60 (mean 48) years, 155 migraine had with aura (MA), 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared …

Tnf-Α Promotes Nuclear Enrichment Of The Transcription Factor Tonebp/Nfat5 To Selectively Control Inflammatory But Not Osmoregulatory Responses In Nucleus Pulposus Cells., Zariel I. Johnson, Alexandra C. Doolittle, Joseph W. Snuggs, Irving M. Shapiro, Christine L. Le Maitre, Makarand V. Risbud

Department of Orthopaedic Surgery Faculty Papers

Intervertebral disc degeneration (IDD) causes chronic back pain and is linked to production of proinflammatory molecules by nucleus pulposus (NP) and other disc cells. Activation of tonicity-responsive enhancer-binding protein (TonEBP)/NFAT5 by non-osmotic stimuli, including proinflammatory molecules, occurs in cells involved in immune response. However, whether inflammatory stimuli activate TonEBP in NP cells and whether TonEBP controls inflammation during IDD is unknown. We show that TNF-α, but not IL-1β or LPS, promoted nuclear enrichment of TonEBP protein. However, TNF-α-mediated activation of TonEBP did not cause induction of osmoregulatory genes. RNA sequencing showed that 8.5% of TNF-α transcriptional responses were TonEBP-dependent and …

Sex Differential In 15-Hydroxyprostaglandin Dehydrogenase Levels In The Lumen Of Human Intracranial Aneurysms., Nohra Chalouhi, Pascal Jabbour, Mario Zanaty, Robert M. Starke, James Torner, Daichi Nakagawa, David M. Hasan

Department of Neurosurgery Faculty Papers

BACKGROUND: Aspirin is a promising medical therapy for the prevention of intracranial aneurysm (IA) rupture. Recently, we found that men have a better response to aspirin than women. The purpose of this study was to determine whether a sex differential exists in the level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in the lumen of human IAs.

METHODS AND RESULTS: Consecutive patients undergoing coiling or stent-assisted coiling for a saccular IA at our institution were enrolled. Two samples (A and B) were collected from IA lumens, and the plasma level of 15-PGDH was measured using an ELISA-based method. The study included 38 patients, …

An Investigation Of Human Beta-Defensins And Cathelicidin Expression In Patients With Pterygium., Remzi Karadag, Nurettin Bayram, Serpil Oguztuzun, Huseyin Bayramlar, Busra Bozer, Gulcin Simsek, Christopher J Rapuano

Wills Eye Hospital Papers

PURPOSE: To investigate human beta-defensins (HBDs) and cathelicidin LL-37 (LL-37) expressions in patients with pterygium.

METHODS: In this retrospective consecutive case series, 26 pterygium specimens and 15 normal conjunctival specimens of 15 control subjects were in vestigated. Expressions of HBD-1, HBD-2, HBD-3, and LL-37 were assessed using immuno histochemical staining. A brown color in the cytoplasm and/or nuclei of epithelial cells indicated positive staining for HBDs and LL-37. For each antibody, the intensity of the reaction (negative [-], weak [1+], moderate [2+], or strong [3+]) was determined to describe the immunoreactions.

RESULTS: The median age was 52 years in both …

Pathologic Evaluation Of Tumor-Associated Macrophage Density And Vessel Inflammation In Invasive Breast Carcinomas, Yoshihiro Morita, Roy Zhang, Macall Leslie, Smita Adhikari, Nafis Hasan, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor-associated macrophages (TAMs) are major constituents of the tumor microenvironment in solid tumors and have been implicated as mediators of tumor progression, invasion and metastasis. Correspondingly, accumulation of TAMs is associated with unfavorable clinical outcomes in numerous types of solid tumors. E-selectin is a hallmark of inflammation and a key adhesion molecule that accommodates the initial contact of circulating immune cells with the inflamed vessel surface. Currently, the association between E-selectin and TAMs is not fully elucidated; therefore, the present study investigated the association between vessel inflammation, TAM infiltration, and clinical outcome in breast cancer. A total of 53 procedure-naïve …

Danshen-Chuanxiong-Honghua Ameliorates Cerebral Impairment And Improves Spatial Cognitive Deficits After Transient Focal Ischemia And Identification Of Active Compounds., Xianhua Zhang, Wan Zheng, Tingrui Wang, Ping Ren, Fushun Wang, Xin-Liang Ma, Jian Wang, Xi Huang

Department of Emergency Medicine Faculty Papers

Previously, we only apply a traditional Chinese medicine (TCM) Danshen-Chuanxiong-Honghua (DCH) for cardioprotection via anti-inflammation in rats of acute myocardial infarction by occluding coronary artery. Presently, we select not only DCH but also its main absorbed compound ferulic acid (FA) for cerebra protection via similar action of mechanism above in animals of the transient middle cerebral artery occlusion (tMCAO). We investigated whether oral administration of DCH and FA could ameliorate MCAO-induced brain lesions in animals. By using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we analyzed four compounds, including tanshinol, salvianolic acid B, hydroxysafflor yellow A and especially FA as the putative …

T Cell Migration From Inflamed Skin To Draining Lymph Nodes Requires Intralymphatic Crawling Supported By Icam-1/Lfa-1 Interactions., Alvaro Teijeira, Morgan C. Hunter, Erica Russo, Steven T Proulx, Thomas Frei, Gudrun F. Debes, Marc Coles, Ignacio Melero, Michael Detmar, Ana Rouzaut, Cornelia Halin

Department of Microbiology and Immunology Faculty Papers

T cells are the most abundant cell type found in afferent lymph, but their migration through lymphatic vessels (LVs) remains poorly understood. Performing intravital microscopy in the murine skin, we imaged T cell migration through afferent LVs in vivo. T cells entered into and actively migrated within lymphatic capillaries but were passively transported in contractile collecting vessels. Intralymphatic T cell number and motility were increased during contact-hypersensitivity-induced inflammation and dependent on ICAM-1/LFA-1 interactions. In vitro, blockade of endothelial cell-expressed ICAM-1 reduced T cell adhesion, crawling, and transmigration across lymphatic endothelium and decreased T cell advancement from capillaries into lymphatic collectors …

Proteoglycan Neofunctions: Regulation Of Inflammation And Autophagy In Cancer Biology., Liliana Schaefer, Claudia Tredup, Maria A. Gubbiotti, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which …

Rna Sequencing Reveals A Role Of Tonebp Transcription Factor In Regulation Of Pro-Inflammatory Genes In Response To Hyperosmolarity In Healthy Nucleus Pulposus Cells: A Homeostatic Response?, Zariel I. Johnson, Irving M. Shapiro, Makarand V. Risbud

Department of Orthopaedic Surgery Faculty Papers

Transcription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown. RNA sequencing was performed on NP cells with TonEBP knockdown under hypertonic conditions. 1140 TonEBP-dependent genes were identified and categorized using Ingenuity Pathway Analysis. Bioinformatic analysis showed enrichment of matrix homeostasis and cytokine/chemokine signaling pathways. C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), tumor necrosis factor (TNF), and nitric oxide synthase 2 (NOS2) …

Ido1 Is An Integral Mediator Of Inflammatory Neovascularization., Arpita Mondal, Courtney Smith, James B. Duhadaway, Erika Sutanto-Ward, George C. Prendergast, Arturo Bravo-Nuevo, Alexander J. Muller

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects …

Repression Of Esophageal Neoplasia And Inflammatory Signaling By Anti-Mir-31 Delivery In Vivo., Cristian Taccioli, Michela Garofalo, Hongping Chen, Yubao Jiang, Guidantonio Malagoli Tagliazucchi, Gianpiero Di Leva, Hansjuerg Alder, Paolo Fadda, Justin Middleton, Karl J. Smalley, Tommaso Selmi, Srivatsava Naidu, John L. Farber, Carlo M. Croce, Louise Fong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.

METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter …

Prophylactic Methylprednisolone To Reduce Inflammation And Improve Outcomes From One Lung Ventilation In Children: A Randomized Clinical Trial., Mary C. Theroux, Alicia Olivant Fisher, Maria E. Rodriguez, Robert P. Brislin, Kirk W. Reichard, Suken A. Shah, Matt Mccoy, Melinda Brown, Kirk W. Dabney, William G. Mackenzie, Douglas A. Katz, Thomas H. Shaffer

Department of Anesthesiology Faculty Papers

BACKGROUND: One lung ventilation (OLV) results in inflammatory and mechanical injury, leading to intraoperative and postoperative complications in children. No interventions have been studied in children to minimize such injury.

OBJECTIVE: We hypothesized that a single 2-mg·kg(-1) dose of methylprednisolone given 45-60 min prior to lung collapse would minimize injury from OLV and improve physiological stability.

METHODS: Twenty-eight children scheduled to undergo OLV were randomly assigned to receive 2 mg·kg(-1) methylprednisolone (MP) or normal saline (placebo group) prior to OLV. Anesthetic management was standardized, and data were collected for physiological stability (bronchospasm, respiratory resistance, and compliance). Plasma was assayed for …

Compensatory Fetal Membrane Mechanisms Between Biglycan And Decorin In Inflammation., Luciana Batalha De Miranda De Araujo, Casie E Horgan, Abraham Aron, Renato V. Iozzo, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Preterm premature rupture of fetal membranes (PPROM) is associated with infection, and is one of the most common causes of preterm birth. Abnormal expression of biglycan and decorin, two extracellular matrix proteoglycans, leads to preterm birth and aberrant fetal membrane morphology and signaling in the mouse. In humans and mice, decorin dysregulation is associated with inflammation in PPROM. We therefore investigated the link between biglycan and decorin and inflammation in fetal membranes using mouse models of intraperitoneal Escherichia coli injections superimposed on genetic biglycan and decorin deficiencies. We assessed outcomes in vivo as well as in vitro using quantitative PCR, …