DOCSLIB.ORG

Blockage of Neddylation Modification Stimulates Tumor Sphere Formation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Blockage of Neddylation Modification Stimulates Tumor Sphere Formation Blockage of neddylation modification stimulates tumor PNAS PLUS sphere formation in vitro and stem cell differentiation and wound healing in vivo Xiaochen Zhoua,b,1, Mingjia Tanb,1, Mukesh K. Nyatib, Yongchao Zhaoc,d, Gongxian Wanga,2, and Yi Sunb,c,e,2 aDepartment of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; bDivision of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109; cInstitute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; dKey Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; and eCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, China Edited by Vishva M. Dixit, Genentech, San Francisco, CA, and approved March 10, 2016 (received for review November 13, 2015) MLN4924, also known as pevonedistat, is the first-in-class inhibitor acting alone or in combination with current chemotherapy of NEDD8-activating enzyme, which blocks the entire neddylation and/or radiation (6, 11). One of the seven clinical trials of MLN4924 modification of proteins. Previous preclinical studies and current (NCT00911066) was published recently, concluding a modest effect clinical trials have been exclusively focused on its anticancer property. of MLN4924 against acute myeloid leukemia (AML) (12). Unexpectedly, we show here, to our knowledge for the first time, To further elucidate the role of blocking neddylation in cancer that MLN4924, when applied at nanomolar concentrations, signif- treatment, we thought to study the effect of MLN4924 on cancer icantly stimulates in vitro tumor sphere formation and in vivo stem cells (CSCs) or tumor-initiating cells (TICs), a small group tumorigenesis and differentiation of human cancer cells and mouse of tumor cells with stem cell properties that have been claimed to embryonic stem cells. These stimulatory effects are attributable to be responsible for cancer initiation and relapse (13). Meanwhile, (i) c-MYC accumulation via blocking its degradation and (ii)contin- a recent study showed that pharmacological inactivation of SKP2 SCF (SKP1–Cullins–F-box proteins) E3 ubiquitin ligase (also ued activation of EGFR (epidermal growth factor receptor) and its known as CRL1) by a small molecule inhibitor, compound 25, downstream pathways, including PI3K/AKT/mammalian target of could restrict CSC traits and cancer progression in prostate rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. cancer (14). Finally, MLN4924 accelerates EGF-mediated skin wound healing in To our utter surprise, we found that at low drug concentra- mouse and stimulates cell migration in an in vitro culture setting. tions (30–100 nM), MLN4924 stimulates in vitro tumor sphere Taking these data together, our study reveals that neddylation (TS) formation and in vivo tumorigenesis of both cancer cells modification could regulate stem cell proliferation and differenti- and embryonic stem cells. Mechanistic studies revealed the ation and that a low dose of MLN4924 might have a therapeutic involvement of accumulation of c-MYC, and dimerization and value for stem cell therapy and tissue regeneration. activation of EGFR (epidermal growth factor receptor). We also found that MLN4924 could accelerate the process of EGF- MLN4924 | neddylation | EGFR | stem cell | wound healing induced skin wound healing in mouse and cell migration in an in vitro culture setting. Thus, MLN4924, when applied at low n cells, homeostasis is reached by a fine balance between the Irates of protein synthesis and degradation. The process of Significance protein degradation by the ubiquitin-proteasome system (UPS) involves two sequential steps: (i) ubiquitylation catalyzed by the MLN4924, a potent small-molecule inhibitor of NEDD8-activating ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme enzyme, blocks cullin-RING ligase activity through inhibiting (E2), and a ubiquitin ligase (E3) and (ii) degradation catalyzed cullin neddylation. MLN4924 is widely used in both preclinical by 26S proteasome (1). Abnormal UPS activity abrogates the and clinical settings for an anticancer application. We report here homeostasis and is associated with many human diseases, an unexpected finding: MLN4924 at nanomolar concentra- including cancer (2, 3). Bortezomib, the first Food and Drug tion stimulates stem cell proliferation, self-renewal, and differ- Administration-approved proteasome inhibitor for the treatment entiation in both tumor and normal stem cell models and of multiple myeloma and mantle cell lymphoma (4), possesses promotes skin wound healing in a mouse model and cell mi- significant cytotoxicity against normal cells due to its universal gration in vitro. Mechanistic studies revealed that MLN4924 inhibition of the UPS (5). This stimulated an intensive search for causes c-MYC accumulation and promotes EGFR (epidermal inhibitors targeting the enzymes upstream of the proteasome for growth factor receptor) dimerization to activate the EGFR sig- improved specificity. naling pathway. Our study raises a concern in anticancer appli- Cullin-RING ligases (CRLs), consisting of scaffold cullins, adaptor cation of MLN4924, but at the same time provides an opportunity proteins, substrate-recognizing receptors, and RING finger proteins, for future development of MLN4924 as an agent for stem cell are the largest family of E3 ubiquitin ligases and are responsible for therapy and tissue regeneration. the ubiquitylation of about 20% of all cellular proteins (6, 7). The activity of CRLs requires neddylation of the cullin proteins (8, 9), a Author contributions: X.Z., M.K.N., G.W., and Y.S. designed research; X.Z., M.T., and Y.Z. ubiquitylation-like process, which is sequentially catalyzed by three performed research; X.Z. and Y.S. contributed new reagents/analytic tools; X.Z., M.K.N., CELL BIOLOGY enzymes: a NEDD8-activating enzyme (NAE or E1), NEDD8- and Y.S. analyzed data; and X.Z. and Y.S. wrote the paper. conjugating enzyme (E2), and NEDD8 ligase (E3). Abnormal el- The authors declare no conflict of interest. evation of CRL activity has been found in multiple human cancers, This article is a PNAS Direct Submission. which makes them favorable targets for cancer treatment (10, 11). Freely available online through the PNAS open access option. MLN4924 was descried in 2009 as the first-in-class NAE in- 1X.Z. and M.T. contributed equally to this work. hibitor exclusively in the application for cancer treatment by 2To whom correspondence may be addressed. Email: [email protected] or wanggx- inactivation of CRLs via blockage of cullin neddylation (7). Since [email protected]. the initial report, more than 150 papers (by PubMed search) This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. were published to show its preclinical anticancer activity, either 1073/pnas.1522367113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1522367113 PNAS | Published online May 9, 2016 | E2935–E2944 Downloaded by guest on September 27, 2021 concentrations, may have potential utility in the field of stem cell therapy and tissue regeneration. Results Bipolar Effects of MLN4924 on Proliferation of Cancer Cells. Sup- pression of cancer cell growth by MLN4924 has been well- documented in the literature (for a review, see ref. 11). Indeed, we found a dose-dependent growth inhibition in multiple human cancer cell lines, including H1299 (lung cancer), MCF7 and SUM159 (breast cancer), and HCT116 (colorectal cancer), when cultured in the media containing 10% (vol/vol) or 1% serum (Fig. S1 A and B). Unexpectedly, when cultured in serum-free medium, we observed various degrees of dose-dependent growth stimulation at low MLN4924 concentrations (30–300 nM) in H1299 [maximum effective concentration (ECmax), 0.1 μM, P < 0.0001 (Fig. S1A)], HCT116 (ECmax,0.3μM, P < 0.0001) (Fig. S1B), MCF7 (ECmax,0.1μM, P = 0.0001) (Fig. S1B), and SUM159 (ECmax,0.1μM, P = 0.0098) (Fig. S1B) cells, followed by growth suppression at higher concentrations. We confirmed via trypan blue exclusion assay that the number of living cells was indeed signif- icantly increased following treatment with a low dose of MLN4924 under serum-free conditions (Fig. S1C)(P < 0.0001). Collectively, we uncovered the bipolar effects of MLN4924 on cell proliferation, both stimulatory and inhibitory, on cancer cells depending on se- rum and drug concentrations. We then focused our study on the growth-stimulating effect of MLN4924. MLN4924 Stimulates TS Formation in Multiple Cancer Cell Lines. The observation that MLN4924 at low concentrations stimulated cell growth under serum-starved conditions triggered us to test whether MLN4924 would promote TS formation, an assay widely used to study the stem cell potential in a serum-free suspension culture (15). We first tested H1299 nonsmall cell lung cancer Fig. 1. MLN4924 stimulates TS formation and in vivo tumorigenesis. (A–C) H1299 (NSCLC) cells that formed typically spherical TSs in standard TS formation assay. H1299 cells were plated at clonal density in the TS me- conditioned TS medium (16). We found a significant dose- dium in 24-well ULA plates and treated with the indicated concentration dependent stimulation by MLN4924 on TS formation with an of MLN4924 for up to 16 d. Representative pictures were taken (A) and SSSs ECmax of 100 nM, followed by a dose-dependent inhibition of TS were documented at 4-d intervals. Fold-changes in SSSs were calculated by formation, with 1 μM MLN4924 completely disrupting TS for- arbitrarily setting the SSS of vehicle treated wells as 1 and were plotted mation (Fig. 1A). To quantify, we used our recently developed against dose (B) and time (C). (D) Ki67 staining of H1299 TS. H1299 TS cul- Standardized Sphere Score (SSS) (16) as the assessment pa- tured in DMSO (vehicle control) and 0.1 μM MLN4924 were harvested and rameter and found that 0.1 μM MLN4924 induced a greater than sectioned for Ki67 staining. (E) Effect of MLN4924 on TS formation in the 30-fold increase in SSS in H1299 cells (Fig.
Load more

Recommended publications
  • The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma
    International Journal of Molecular Sciences Article The Anti-Tumor Activity of the NEDD8 Inhibitor Pevonedistat in Neuroblastoma Jennifer H. Foster 1,* , Eveline Barbieri 1, Linna Zhang 1, Kathleen A. Scorsone 1, Myrthala Moreno-Smith 1, Peter Zage 2,3 and Terzah M. Horton 1,* 1 Texas Children’s Cancer and Hematology Centers, Department of Pediatrics, Section of Hematology and Oncology, Baylor College of Medicine, Houston, TX 77030, USA; [email protected] (E.B.); [email protected] (L.Z.); [email protected] (K.A.S.); [email protected] (M.M.-S.) 2 Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA 92024, USA; [email protected] 3 Peckham Center for Cancer and Blood Disorders, Rady Children’s Hospital, San Diego, CA 92123, USA * Correspondence: [email protected] (J.H.F.); [email protected] (T.M.H.); Tel.: +1-832-824-4646 (J.H.F.); +1-832-824-4269 (T.M.H.) Abstract: Pevonedistat is a neddylation inhibitor that blocks proteasomal degradation of cullin–RING ligase (CRL) proteins involved in the degradation of short-lived regulatory proteins, including those involved with cell-cycle regulation. We determined the sensitivity and mechanism of action of pevonedistat cytotoxicity in neuroblastoma. Pevonedistat cytotoxicity was assessed using cell viability assays and apoptosis. We examined mechanisms of action using flow cytometry, bromod- eoxyuridine (BrDU) and immunoblots. Orthotopic mouse xenografts of human neuroblastoma were generated to assess in vivo anti-tumor activity. Neuroblastoma cell lines were very sensitive to pevonedistat (IC50 136–400 nM). The mechanism of pevonedistat cytotoxicity depended on p53 Citation: Foster, J.H.; Barbieri, E.; status.
    [Show full text]
  • Medicare 2019 Part C & D Star Ratings Cut Point Trends
    Trends in Part C & D Star Rating Measure Cut Points Updated – 12/19/2018 (Last Updated 12/19/2018) Page 1 Document Change Log Previous Revision Version Description of Change Date - Final release of the 2019 Star Ratings Cut Point Trend document 12/19/2018 (Last Updated 12/19/2018) Page i Table of Contents DOCUMENT CHANGE LOG .............................................................................................................................. I TABLE OF CONTENTS .................................................................................................................................... II INTRODUCTION ............................................................................................................................................... 1 PART C MEASURES ........................................................................................................................................ 2 Measure: C01 - Breast Cancer Screening ........................................................................................................................ 2 Measure: C02 - Colorectal Cancer Screening .................................................................................................................. 3 Measure: C03 - Annual Flu Vaccine .................................................................................................................................. 4 Measure: C04 - Improving or Maintaining Physical Health ...........................................................................................
    [Show full text]
  • Neddylation: a Novel Modulator of the Tumor Microenvironment Lisha Zhou1,2*†, Yanyu Jiang3†, Qin Luo1, Lihui Li1 and Lijun Jia1*
    Zhou et al. Molecular Cancer (2019) 18:77 https://doi.org/10.1186/s12943-019-0979-1 REVIEW Open Access Neddylation: a novel modulator of the tumor microenvironment Lisha Zhou1,2*†, Yanyu Jiang3†, Qin Luo1, Lihui Li1 and Lijun Jia1* Abstract Neddylation, a post-translational modification that adds an ubiquitin-like protein NEDD8 to substrate proteins, modulates many important biological processes, including tumorigenesis. The process of protein neddylation is overactivated in multiple human cancers, providing a sound rationale for its targeting as an attractive anticancer therapeutic strategy, as evidence by the development of NEDD8-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Neddylation inhibition by MLN4924 exerts significantly anticancer effects mainly by triggering cell apoptosis, senescence and autophagy. Recently, intensive evidences reveal that inhibition of neddylation pathway, in addition to acting on tumor cells, also influences the functions of multiple important components of the tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs) and some factors, all of which are crucial for tumorigenesis. Here, we briefly summarize the latest progresses in this field to clarify the roles of neddylation in the TME, thus highlighting the overall anticancer efficacy of neddylaton inhibition. Keywords: Neddylation, Tumor microenvironment, Tumor-derived factors, Cancer-associated fibroblasts, Cancer- associated endothelial cells, Immune cells Introduction Overall, binding of NEDD8 molecules to target proteins Neddylation is a reversible covalent conjugation of an can affect their stability, subcellular localization, conform- ubiquitin-like molecule NEDD8 (neuronal precursor ation and function [4]. The best-characterized substrates cell-expressed developmentally down-regulated protein of neddylation are the cullin subunits of Cullin-RING li- 8) to a lysine residue of the substrate protein [1, 2].
    [Show full text]
  • Phase Ib Study of Pevonedistat, a NEDD8-Activating Enzyme Inhibitor
    Investigational New Drugs (2019) 37:87–97 https://doi.org/10.1007/s10637-018-0610-0 PHASE I STUDIES Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors A Craig Lockhart1 & Todd M. Bauer2 & Charu Aggarwal3 & Carrie B. Lee4 & RDonaldHarvey5 & Roger B. Cohen6 & Farhad Sedarati7 & Tsz Keung Nip8 & Hélène Faessel9 & Ajeeta B. Dash10 & Bruce J. Dezube7 & Douglas V. Faller7 & Afshin Dowlati11 Received: 1 March 2018 /Accepted: 11 May 2018 /Published online: 21 May 2018 # The Author(s) 2018 Summary Purpose This phase Ib study (NCT01862328) evaluated the maximum tolerated dose (MTD), safety, and efficacy of pevonedistat in combination with standard-of-care chemotherapies in patients with solid tumors. Methods Patients received pevonedistat with docetaxel (arm 1, n = 22), carboplatin plus paclitaxel (arm 2, n = 26), or gemcitabine (arm 3, n = 10) in 21-days (arms 1 and 2) or 28-days (arm 3) cycles. A lead-in cohort (arm 2a, n = 6) determined the arm 2 carboplatin dose. Dose escalation proceeded via continual modified reassessment. Results Pevonedistat MTD was 25 mg/m2 (arm 1) or 20 mg/m2 (arm 2); arm 3 was discontinued due to poor tolerability. Fifteen (23%) patients experienced dose-limiting toxicities during cycle 1 (grade ≥3 liver enzyme elevations, febrile neutropenia, and thrombocytopenia), managed with dose holds or reductions. Drug-related adverse events (AEs) occurred in 95% of patients. Most common AEs included fatigue (56%) and nausea (50%). One drug-related death occurred in arm 3 (febrile neutropenia). Pevonedistat exposure increased when co-administered with carboplatin plus paclitaxel; no obvious changes were observed when co-administered with docetaxel or gemcitabine.
    [Show full text]
  • Thermo-Responsive Poly(N-Isopropylacrylamide)- Cellulose Nanocrystals Hybrid Hydrogels for Wound Dressing
    Article Thermo-Responsive Poly(N-Isopropylacrylamide)- Cellulose Nanocrystals Hybrid Hydrogels for Wound Dressing Katarzyna Zubik 1, Pratyawadee Singhsa 1,2, Yinan Wang 1, Hathaikarn Manuspiya 2 and Ravin Narain 1,* 1 Department of Chemical and Materials Engineering, Donadeo Innovation Centre in Engineering, 116 Street and 85 Avenue, Edmonton, AB T6G 2G6, Canada; [email protected] (K.Z.); [email protected] (P.S.); [email protected] (Y.W.) 2 The Petroleum and Petrochemical College, Center of Excellence on Petrochemical and Materials Technology, Chulalongkorn University, Soi Chulalongkorn 12, Pathumwan, Bangkok 10330, Thailand; [email protected] * Correspondence: [email protected]; Tel.: +1-780-492-1736 Academic Editor: Shiyong Liu Received: 29 January 2017; Accepted: 21 March 2017; Published: 24 March 2017 Abstract: Thermo-responsive hydrogels containing poly(N-isopropylacrylamide) (PNIPAAm), reinforced both with covalent and non-covalent interactions with cellulose nanocrystals (CNC), were synthesized via free-radical polymerization in the absence of any additional cross-linkers. The properties of PNIPAAm-CNC hybrid hydrogels were dependent on the amounts of incorporated CNC. The thermal stability of the hydrogels decreased with increasing CNC content. The rheological measurement indicated that the elastic and viscous moduli of hydrogels increased with the higher amounts of CNC addition, representing stronger mechanical properties of the hydrogels. Moreover, the hydrogel injection also supported the hypothesis that CNC reinforced the hydrogels; the increased CNC content exhibited higher structural integrity upon injection. The PNIPAAm- CNC hybrid hydrogels exhibited clear thermo-responsive behavior; the volume phase transition temperature (VPTT) was in the range of 36 to 39 °C, which is close to normal human body temperature.
    [Show full text]
  • Pevonedistat (MLN4924), a First-In-Class NEDD8-Activating Enzyme Inhibitor, in Patients with Acute Myeloid Leukaemia and Myelodysplastic Syndromes: a Phase 1 Study
    research paper Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study Ronan T. Swords,1 Harry P. Erba,2 Summary Daniel J. DeAngelo,3 Dale L. Bixby,2 This trial was conducted to determine the dose-limiting toxicities (DLTs) Jessica K. Altman,4 Michael Maris,5 Zhaowei Hua,6 Stephen J. Blakemore,6 and maximum tolerated dose (MTD) of the first in class NEDD8-activating Helene Faessel,6 Farhad Sedarati,6 enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat Bruce J. Dezube,6 Francis J. Giles4 and pharmacokinetics and pharmacodynamics in patients with acute myeloid Bruno C. Medeiros7 leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was 1Leukemia Program, Sylvester Comprehensive administered via a 60-min intravenous infusion on days 1, 3 and 5 (sche- Cancer Center, Miami, FL, 2Division of Hema- dule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. tology/Oncology, University of Michigan, Ann Dose escalation proceeded using a standard ‘3 + 3’ design. Responses were 3 Arbor, MI, Department of Medical Oncology, assessed according to published guidelines. The MTD for schedules A and Dana-Farber Cancer Institute, Boston, MA, B were 59 and 83 mg/m2, respectively. On schedule A, hepatotoxicity was 4 Northwestern Medicine Developmental Thera- dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. peutics Institute, Northwestern University, The overall complete (CR) and partial (PR) response rate in patients trea- Chicago, IL, 5Colorado Blood Cancer Institute, ted at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A Denver, CO, 6Takeda Pharmaceuticals Interna- tional Co., Cambridge, MA, and 7Division of and 10% (2/19, 2 PRs) for schedule B.
    [Show full text]
  • High-Dose Chemotherapy Less Frequent Catheter Dressing Changes
    Bone Marrow Transplantation (2002) 29, 653–658 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt High-dose chemotherapy Less frequent catheter dressing changes decrease local cutaneous toxicity of high-dose chemotherapy in children, without increasing the rate of catheter-related infections: results of a randomised trial E Benhamou1, E Fessard2, C Com-Nougue´1,3, PS Beaussier2, G Nitenberg4, C Tancre`de5, S Dodeman2 and O Hartmann2 1Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France; 2Department of Pediatrics, Institut Gustave Roussy, Villejuif, France; 3Pierre et Marie Curie University, Paris, France; 4Intensive Care Unit, Institut Gustave Roussy, Villejuif, France; and 5Department of Microbiology, Institut Gustave Roussy, Villejuif, France Summary: In our hospital, patients treated with high-dose chemo/radiotherapy (HDC) regimens followed by bone Cutaneous lesions caused by catheter dressing changes marrow transplantation (BMT) are fitted with a central can be serious and generate local pain in children venous catheter which is usually inserted a few days before undergoing high-dose chemotherapy followed by bone hospitalisation in the transplantation unit. Usually, central marrow transplantation. One hundred and thirteen venous catheter dressings are changed, empirically, every children entered a randomised trial to compare two 3 or 4 days,1,2 whatever the state of the dressing and mostly catheter dressing change frequencies (15 days vs 4 days). because less frequent changes are suspected of promoting Skin toxicity was classified according to the following local infections likely to give rise to bacteraemia in granul- scale: grade 0: healthy skin, to grade 4: severe skin tox- ocytopenic patients.
    [Show full text]
  • Local Anesthetics in Cosmetic Dermatology
    COSMETIC DERMATOLOGY Local Anesthetics in Cosmetic Dermatology Peter W. Hashim, MD, MHS; John K. Nia, MD; Mark Taliercio, BS; Gary Goldenberg, MD PRACTICE POINTS • The proper delivery of local anesthesia is integral to successful cosmetic interventions. • Regional nerve blocks can provide effective analgesia while reducing the number of injections and preserving the architecture of the cosmetic field. copy Local anesthetics play an important role in cos- LOCAL ANESTHETICS metic dermatology. Techniques using topical and The sensation of pain is carried to the central ner- regional anesthesia provide numerous pain man- vousnot system by unmyelinated C nerve fibers. Local agement options for laser and injection treatments. anesthetics (LAs) act by blocking fast voltage-gated In this article, we review strategies to maximize sodium channels in the cell membrane of the nerve, patient comfort during cosmetic interventions. thereby inhibiting downstream propagation of an Cutis. 2017;99:393-397.Doaction potential and the transmission of painful stimuli.1 The chemical structure of LAs is funda- mental to their mechanism of action and metabo- ocal anesthesia is a central component of suc- lism. Local anesthetics contain a lipophilic aromatic cessful interventions in cosmetic dermatol- group, an intermediate chain, and a hydrophilic Logy. The number of anesthetic medications amine group. Broadly, agents are classified as amides and administration techniques has grown in recent or esters depending on the chemical group attached years as outpatient cosmetic procedures continue to the intermediate chain.2 Amides (eg, lidocaine, to expand. Pain is a commonCUTIS barrier to cosmetic bupivacaine, articaine, mepivacaine, prilocaine, procedures, and alleviating the fear of painful inter- levobupivacaine) are metabolized by the hepatic sys- ventions is critical to patient satisfaction and future tem; esters (eg, procaine, proparacaine, benzocaine, visits.
    [Show full text]
  • EMA/CVMP/508559/2019 Committee for Medicinal Products for Veterinary Use
    28 August 2020 EMA/CVMP/508559/2019 Committee for Medicinal Products for Veterinary Use Advice on implementing measures under Article 106 (6) of Regulation (EU) 2019/6 on veterinary medicinal products – scientific problem analysis and recommendations to ensure a safe and efficient administration of oral veterinary medicinal products via routes other than medicated feed Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Introduction On 1 July 2019 the European Commission requested the European Medicines Agency to provide a scientific problem analysis and recommendations to ensure the safe and efficient oral administration of veterinary medicinal products via routes other than medicated feed, by taking into account: - the effective and safe use of veterinary medicinal products authorised and prescribed for oral administration via routes other than medicated feed, such as mixing of water for drinking with a veterinary medicinal product, mixing of a veterinary medicinal product into the ordinary feed by the farmer or by use of top-dressing of the feed offered to the animal in a feeding device with a veterinary medicinal product (solid or as an emulsion); this issue should address the borderline between medication with medicated feed
    [Show full text]
  • A Field Guide to Common Wildlife Diseases and Parasites in the Northwest Territories
    A Field Guide to Common Wildlife Diseases and Parasites in the Northwest Territories 6TH EDITION (MARCH 2017) Introduction Although most wild animals in the NWT are healthy, diseases and parasites can occur in any wildlife population. Some of these diseases can infect people or domestic animals. It is important to regularly monitor and assess diseases in wildlife populations so we can take steps to reduce their impact on healthy animals and people. • recognize sickness in an animal before they shoot; •The identify information a disease in this or field parasite guide in should an animal help theyhunters have to: killed; • know how to protect themselves from infection; and • help wildlife agencies monitor wildlife disease and parasites. The diseases in this booklet are grouped according to where they are most often seen in the body of the Generalanimal: skin, precautions: head, liver, lungs, muscle, and general. Hunters should look for signs of sickness in animals • poor condition (weak, sluggish, thin or lame); •before swellings they shoot, or lumps, such hair as: loss, blood or discharges from the nose or mouth; or • abnormal behaviour (loss of fear of people, aggressiveness). If you shoot a sick animal: • Do not cut into diseased parts. • Wash your hands, knives and clothes in hot, soapy animal, and disinfect with a weak bleach solution. water after you finish cutting up and skinning the 2 • If meat from an infected animal can be eaten, cook meat thoroughly until it is no longer pink and juice from the meat is clear. • Do not feed parts of infected animals to dogs.
    [Show full text]
  • Instructions After Anorectal Surgery
    Instructions After Anorectal Surgery You are scheduled for ambulatory or same day admission surgery. Your colorectal attending surgeon, resident staff and the anesthesia staff will meet you in the preanesthesia area to answer any questions that you may have before your surgery. Your surgeon will talk with your family members in the waiting area after the procedure by telephone or in person. Any special instructions will be given to you or your family member at that time. If general or regional anesthesia is used, you will be monitored in the recovery room for 1-2 hours after your surgery. A responsible adult must accompany you home. You should not drive or operate machinery for the remainder of the day. You will be given any prescriptions or dressings needed for discharge. Wound Care You should remove your dressings on the morning after your procedure. If the dressing become soiled or soaked, you may change them on the evening of the procedures. Any packing within the anus or wounds should be removed gently from the anus before or during the first bath. It may be easier to remove the gauze after you get into the water once it is wet. Warm tub or sitz baths should be taken 3-4 times per day initially, especially after each bowel movement. After the first week you may decrease this to 2 times per day. You do not need to add anything to the water (no Epson salts, etc). You may notice slight ooze or bleeding for several days, usually with bowel movements. You do not need to apply or insert any packing after your first bath but you must place gauze pads to absorb any drainage and protect your undergarments.
    [Show full text]
  • Study Protocol and Statistical Analysis Plan
    STUDY00008815 Approval: 4/1/2019 Protocol Title: PSCI 17-056 A Phase II Study of Pevonedistat (MLN4924, TAK924) and Azacitidine as Maintenance Therapy after Allogeneic Stem Cell Transplantation for Non-Remission Acute Myelogenous Leukemia Principal Investigator: Shin Mineishi, M.D. Professor and Director, Blood and Marrow Transplant Program 500 University Drive, CH46 Hershey, PA 17111 717-531-8678 (Office) 717-531-4969 (Fax) Email:[email protected] Site PIs Additional sites may be added in the future. Co-Investigators: David Claxton, M.D. Hong Zheng, M.D. Ph.D. Seema Naik, M.D. Muhammad Khawaja, M.D. Jason Liao, Ph.D. Co-Investigator/MD Coordinator Kevin Rakszawski, MD Fellow, Hematology & Oncology Email:[email protected] Version Date: Version 1.8.5, 07-26-2018 Clinicaltrials.gov Registration #: 03709576 Page 1 of 75 (V.1.8.5, 07/26/2018) STUDY00008815 Approval: 4/1/2019 Contents LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS......................................................................................................6 1.0 Objectives .......................................................................................................................................................10 1.1. Primary Objective.................................................................................................................................................10 1.2. Secondary Objectives ...........................................................................................................................................10
    [Show full text]