Medicine and Health Sciences Commons^™

Wnt Signaling Exerts An Antiproliferative Effect On Adult Cardiac Progenitor Cells Through Igfbp3., Angelos Oikonomopoulos, Konstantina-Ioanna Sereti, Frank Conyers, Michael Bauer, Annette Liao, Jian Guan, Dylan Crapps, Jung-Kyu Han, Hanhua Dong, Ahmad F Bayomy, Gabriel C Fine, Karen Westerman, Travis L Biechele, Randall T Moon, Thomas Force, Ronglih Liao

Center for Translational Medicine Faculty Papers

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical …

A 2-Step Approach To Myeloablative Haploidentical Stem Cell Transplantation: A Phase 1/2 Trial Performed With Optimized T-Cell Dosing., Dolores Gross, Matthew Carabasi, Joanne Filicko-O'Hara, Margaret Kasner, John L Wagner, Beth Colombe, Patricia Cornett Farley, William O'Hara, Phyllis Flomenberg, Maria Werner-Wasik, Janet Brunner, Bijoyesh Mookerjee, Terry Hyslop, Mark Weiss, Neal Flomenberg

Department of Medical Oncology Faculty Papers

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg …

Human Glial-Restricted Progenitor Transplantation Into Cervical Spinal Cord Of The Sod1 Mouse Model Of Als., Angelo C Lepore, John O'Donnell, Andrew S Kim, Timothy Williams, Alicia Tuteja, Mahendra S Rao, Linda L Kelley, James T Campanelli, Nicholas J Maragakis

Department of Neuroscience Faculty Papers

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1(G93A) rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1(G93A) rat. Those findings demonstrated the feasibility and efficacy of transplantation-based …

Relationship Of Adipokines With Insulin Sensitivity In African Americans., Maria P Martinez Cantarin, Scott W Keith, Stephanie Deloach, Yonghong Huan, Bonita Falkner

Department of Medicine Faculty Papers

INTRODUCTION: Cytokines produced by adipose tissue, including adiponectin, have been associated with metabolic abnormalities. The purpose of this study was to examine the relationship of insulin sensitivity measured by euglycemic hyperinsulinemic insulin clamp with plasma adiponectin and other adipokines in young adult African Americans.

METHODS: Participants were healthy African Americans. Anthropometric measures, blood pressure, an oral glucose tolerance test and an euglycemic hyperinsulinemic insulin clamp were performed. Insulin sensitivity measurements were adjusted for percentage of fat mass. Plasma concentrations of adiponectin, plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6) were assayed on plasma from fasting blood samples. Pearson correlation coefficients and …

The Incidence Of Deep Vein Thrombosis Detected By Routine Surveillance Ultrasound In Neurosurgery Patients Receiving Dual Modality Prophylaxis., Patricia C Henwood, Thomas M Kennedy, Lynda Thomson, Taki Galanis, George L Tzanis, Geno J Merli, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The optimal method of thromboprophylaxis and the value of screening ultrasonography for detection of deep venous thrombosis (DVT) in neurosurgery patients remains unclear. The goal of this study was to determine the incidence of DVT in neurosurgical patients who, by hospital protocol, receive surveillance ultrasonography of the lower extremities twice weekly, in addition to prophylaxis with unfractionated heparin and external pneumatic compression sleeves. A retrospective review of 7,298 ultrasound studies carried out on 2,593 patients over 4 years at a university neurosurgical hospital was conducted. There was a 7.4% incidence of proximal lower extremity DVT and a 9.7% total incidence …

Tumor-Derived Interleukin-10 As A Prognostic Factor In Stage Iii Patients Undergoing Adjuvant Treatment With An Autologous Melanoma Cell Vaccine., Amit Mahipal, Mizue Terai, David Berd, Inna Chervoneva, Kashyap Patel, Michael Mastrangelo, Takami Sato

Department of Medical Oncology Faculty Papers

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP).

METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind …

The Variable Presentations Of Anaplastic Spindle Cell Squamous Carcinoma Associated With Tall Cell Variant Of Papillary Thyroid Carcinoma., Pallavi P Gopal, Kathleen T Montone, Zubair Baloch, Madalina Tuluc, Virginia Livolsi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: In 1976, Hawk and Hazard described the tall cell variant (TCV) of papillary thyroid carcinoma (PTC). While the lesions they described had cytologic features of papillary carcinoma, they showed more aggressive behavior with a greater propensity for extrathyroid extension and lymphovascular invasion than classic PTC. In 1991, Bronner and LiVolsi described a series of patients with TCV that progressed to spindle cell squamous carcinoma (SCSC), a unique form of anaplastic thyroid carcinoma. This study describes the variable clinical and pathologic presentations in 31 patients with anaplastic SCSC arising in association with TCV.

METHODS: The surgical pathology archives as well …

A Phase I/Iia Clinical Trial Of A Recombinant Rho Protein Antagonist In Acute Spinal Cord Injury., Michael G Fehlings, Nicholas Theodore, James Harrop, Gilles Maurais, Charles Kuntz, Chris I Shaffrey, Brian K Kwon, Jens Chapman, Albert Yee, Allyson Tighe, Lisa Mckerracher

Department of Neurosurgery Faculty Papers

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or …

Mitostatin Is Down-Regulated In Human Prostate Cancer And Suppresses The Invasive Phenotype Of Prostate Cancer Cells., Matteo Fassan, Domenico D'Arca, Juraj Letko, Andrea Vecchione, Marina P Gardiman, Peter Mccue, Bernadette Wildemore, Massimo Rugge, Dolores Shupp-Byrne, Leonard G Gomella, Andrea Morrione, Renato V Iozzo, Raffaele Baffa

Kimmel Cancer Center Faculty Papers

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in …

The Interplay Between Nf-Kappab And E2f1 Coordinately Regulates Inflammation And Metabolism In Human Cardiac Cells., Xavier Palomer, David Álvarez-Guardia, Mercy M Davidson, Tung O Chan, Arthur M Feldman, Manuel Vázquez-Carrera

Department of Medicine Faculty Papers

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, …

Tdp-43 Potentiates Alpha-Synuclein Toxicity To Dopaminergic Neurons In Transgenic Mice., Tian Tian, Cao Huang, Jianbin Tong, Ming Yang, Hongxia Zhou, Xugang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in …

The Effects Of Laropiprant, A Selective Prostaglandin D₂ Receptor 1 Antagonist, On The Antiplatelet Activity Of Clopidogrel Or Aspirin., Aimee Dallob, Wen-Lin Luo, Julie Mabalot Luk, Lisa Ratcliffe, Amy O Johnson-Levonas, Jules I Schwartz, Victor Dishy, Walter K. Kraft, Jan N De Hoon, Anne Van Hecken, Inge De Lepeleire, Waldemar Radziszewski, John A Wagner, Eseng Lai

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time …