DOCSLIB.ORG

WO 2016/201377 Al 15 December 2016 (15.12.2016) P O P C T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2016/201377 Al 15 December 2016 (15.12.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/201377 Al 15 December 2016 (15.12.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 39/00 (2006.01) C12N 9/52 (2006.01) kind of national protection available): AE, AG, AL, AM, C07K 14/31 (2006.01) G01N 33/569 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 16/037095 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 10 June 2016 (10.06.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/173,783 10 June 2015 (10.06.2015) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: MODERNA THERAPEUTICS, INC. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 200 Technology Square, Cambridge, Massachu TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, setts 02139 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (71) Applicants : YI-CHUN HUANG, Eric [US/US]; 90 GW, KM, ML, MR, NE, SN, TD, TG). Wareham Street, Unit 302, Boston, Massachusetts 02 118 (US). HOGE, Stephen [US/US]; 66 Summit Ave, Brook- Published: line, Massachusetts 02446 (US). — with international search report (Art. 21(3)) (74) Agents: LAHERTY, Carol D. et al; Cooley LLP, 1299 — with sequence listing part of description (Rule 5.2(a)) Pennsylvania Avenue, NW, Suite 700, Washington, Dis trict of Columbia 20004 (US). (54) Title: TARGETED ADAPTIVE VACCINES o- , :; v - (57) Abstract: The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynuc - leotide molecules encoding targeted adaptive vaccines (TAVs), such as PCSK9 TAVs, TNF alpha TAVs, IL-17A TAVs, or GDF8 TAVs. O TARGETED ADAPTIVE VACCINES CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 62/173,783, filed on June 10, 2015; which is incorporated by reference herein in its entirety. STATEMENT REGARDING SEQUENCE LISTIN [0002] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is MRNA_012_01WO_ST25.txt. The text file is 1,333 KB, was created on June 10, 2016, and is being submitted electronically via EFS-Web. FIELD OF THE INVENTION [0003] The present invention relates to compositions, methods, processes, kits and devices for the design, preparation, manufacture, formulation and use of polynucleotides encoding targeted adaptive vaccines (TAVs). BACKGROUND OF THE INVENTION [0004] Vaccination is an effective way to provide prophylactic protection against infectious diseases, such as influenza, AIDS, hepatotisis virus infection, cholera, malaria and tuberculosis, and many other diseases. Vaccines may also be used to treat diseases, such as cancers. For example, the first cancer treatment vaccine, sipuleucel- T (Provenge®, manufactured by Dendreon) is used for certain men with metastatic prostate cancer. It is designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells. (Kantoff PW, et al, 2010, New England Journal of Medicine, 365, 411-422, which is incorporated herein by reference in its entirety). [0005] A typical vaccine contains an antigenic target molecule, e.g., an agent that resembles a weakened or dead form of the disease-causing agent, which could be a microorganism, such as bacteria, virus, fungi, parasite and prion, or the toxins or one or more surface proteins (often called antigens) of such a microorganism. The antigenic target molecule may alternatively be an endogenous polypeptide, e.g., an antigenic polypeptide or fragment thereof expressed or cancer cells or associated with a disease. The antigen or agent in the vaccine can stimulate the body's immune system to recognize the agent as a foreign invader, generate antibodies against it, destroy it and develop a memory of it. The vaccine-induced memory enables the immune system to act quickly to protect the body from any of these agents that it later encounters. [0006] Vaccine production used in the art has several stages, including the generation of antigens, antigen purification and inactivation, and vaccine formulation. First, the antigen is generated through culturing viruses in cell lines, growing bacteria in bioreactors, or producing recombinant proteins derived from viruses and bacteria in cell cultures, yeast or bacteria. Recombinant proteins are then purified and the viruses and bacteria are inactivated before they are formulated with adjuvants in vaccines. It has been a challenge to drastically reduce the time and expense associated with current technologies in vaccine development. [0007] It is of great interest to develop new approaches for developing new vaccines, not only for infectious agents and cancer but for other therapeutic indications. SUMMARY OF THE INVENTION [0008] Described herein are compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of polynucleotides encoding targeted adaptive vaccines (TAVs). [0009] In one embodiment, the present invention comprises an mRNA comprising: (a) a first region comprising a sequence encoding one or more polypeptide (e.g., an immunogenic polypeptide); and, optionally, (b) a second region comprising a sequence encoding one or more immunomodulatory polypeptide, wherein the mRNA comprises a modified nucleobase. In particular embodiments, the mRNA comprises the second region. In particular embodiments, the mRNA further comprises a third region between the first region and the second region, wherein the third region comprises a sequence encoding a spacer or a cleavage site. In certain embodiments, the spacer or cleavage site is a 2A peptide or a cathepsin S cleavage site. In particular embodiments, first region comprises two or more sequences encoding polypeptides, which may comprise the same or different amino acid sequences. In particular embodiments, the first region further comprises a sequence encoding a linker or a cleavage site between the sequences encoding the two or more polypeptides. In certain embodiments, the linker or cleavage site is a 2A peptide or a cathepsin cleavage site. In particular embodiments, the one or more polypeptide comprises a human or murine polypeptide or fragment or variant thereof. In particular embodiments, the one or more polypeptides is proprotein convertase subtilisin/kexin type 9 (PCSK9), interleukin-17A (IL-17A), tumor necrosis factor alpha (TNF alpha) or growth differentiation factor 8 (GDF8). [00010] In particular embodiments, the second region of the mRNA comprises two or more sequences encoding immunomodulatory polypeptides, which may be the same or different. In some embodiments, the second region further comprises a sequence encoding a linker or a cleavage site between the sequences encoding the two or more immunomodulatory polypeptides. [00011] In particular embodiments, the linker or cleavage site is a 2A peptide or a cathepsin cleavage site. In certain embodiments, the immunomodulatory polypeptide is selected from the group consisting of: GM-CSF, IL2, IL12, IL15, IL21, IL23, soluble LAG3, agonist CD28, anti-PD1, anti-PDL1/2, anti-OX40/OX40L, anti- GITR/GITRL, and anti-TIM3. In particular embodiments, the one or more immunomodulatory polypeptide is an immune enhancing polypeptide. In particular embodiments, the immune enhancing polypeptide is selected from the group consisting of: mannose binding protein, flagellin derived immunogens, T cell epitopes from Tetanus toxin, T cell epitope of M2 protein of H1N1 Puerto Rico/8, epitope from influenza HA antigen, universal T helper epitope, and a chimeric MHC class II peptide with epitopes from tetanus toxoid and diphtheria toxoid. In particular embodiments, the immune enhancing polypeptide is T cell epitope of M2 protein of H1N1 Puerto Rico/8 or mannose binding protein. In certain embodiments, the mRNA encodes a fusion polypeptide comprising a scaffold polypeptide, the first region, and the second region, wherein the first region and the second region are inserted into the scaffold polypeptide. In certain embodiments, the mRNA further comprises a fourth region comprising a sequence encoding a dendritic cell targeting polypeptide. In particular embodiments, the dendritic cell targeting polypeptide is selected from the group consisting of a polypeptide encoding an antibody, a polypeptide encoding an antibody fragment, and a peptide that targets one or more dendritic cell surface markers. In certain embodiments, the dendritic cell surface marker is selected
Load more

Recommended publications
  • Assessing Immunomodulatory Effects of Penicillium Mycotoxins Using Bovine Macrophages Cell Line
    Assessing Immunomodulatory Effects of Penicillium Mycotoxins using Bovine Macrophages Cell Line by Se-Young Oh A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Doctor of Philosophy in Animal and Poultry Science (Toxicology) Guelph, Ontario, Canada © Se-Young Oh, December, 2014 ABSTRACT Assessing Immunomodulatory Effects of Penicillium Mycotoxins using Bovine Macrophages Cell Line Se-Young Oh Advisor: Dr. Niel A. Karrow University of Guelph , 2014 Co-Advisor: Dr. Herman J. Boermans The present study assessed the immunomodulatory effects on macrophages of the following Penicillium mycotoxins (PMs), including citrinin (CIT), ochratoxin A (OTA), patulin (PAT), mycophilic acid (MPA) and penicillic acid (PA), by using a bovine macrophage cell line (BoMacs). Initially, concentration-response curves for each of these PMs were established based on cell proliferation and viability. The potency of these PMs based on their IC50s (concentration that inhibits 50% cell proliferation) from highest to lowest was: 0.56 µM (PAT) > 12.88 µM (OTA) > 29.85 µM (PA) > 91.20 µM (CIT) > not determined (MPA). LC50s (concentrations that kill 50% of cells) for PAT and PA were determined to be 4.46 μM and 175.79 μM, respectively. In addition to this, binary mixtures of some PMs at their respective IC25 and lower were shown to have significant interactions on cell proliferation. CIT+OTA had significant synergism, while PAT+MPA, CIT+MPA, CIT+PA and MPA+PA exhibited significant antagonism. PAT+PA showed significant antagonism at their respective IC25s, but were antagonistic at lower concentrations. The PMs at their sub-lethal levels of IC25s also differentially altered the gene expression of the following cytokines, including IL-1α, IL-6, IL-10, IL-12, IL-23 and TGF-.
    [Show full text]
  • Surface Display of an Anti-DEC-205 Single Chain Fv Fragment in Lactobacillus Plantarum Increases Internalization and Plasmid
    Christophe et al. Microb Cell Fact (2015) 14:95 DOI 10.1186/s12934-015-0290-9 RESEARCH Open Access Surface display of an anti‑DEC‑205 single chain Fv fragment in Lactobacillus plantarum increases internalization and plasmid transfer to dendritic cells in vitro and in vivo Michon Christophe1,2, Katarzyna Kuczkowska3, Philippe Langella1,2, Vincent G H Eijsink3, Geir Mathiesen3 and Jean‑Marc Chatel1,2* Abstract Background: Lactic acid bacteria (LAB) are promising vehicles for delivery of a variety of medicinal compounds, including antigens and cytokines. It has also been established that LAB are able to deliver cDNA to host cells. To increase the efficiency of LAB-driven DNA delivery we have constructed Lactobacillus plantarum strains targeting DEC- 205, which is a receptor located at the surface of dendritic cells (DCs). The purpose was to increase uptake of bacterial cells, which could lead to improved cDNA delivery to immune cells. Results: Anti-DEC-205 antibody (aDec) was displayed at the surface of L. plantarum using three different anchoring strategies: (1) covalent anchoring of aDec to the cell membrane (Lipobox domain, Lip); (2) covalent anchoring to the cell wall (LPXTG domain, CWA); (3) non-covalent anchoring to the cell wall (LysM domain, LysM). aDec was success‑ fully expressed in all three strains, but surface location of the antibody could only be demonstrated for the two strains with cell wall anchors (CWA and LysM). Co-incubation of the engineered strains and DCs showed increased uptake when anchoring aDec using the CWA or LysM anchors. In a competition assay, free anti-DEC abolished the increased uptake, showing that the internalization is due to specific interactions between the DEC-205 receptor and aDec.
    [Show full text]
  • Immuno-Endocrine Interactions in Intestinal Inflammation
    IMMUNO-ENDOCRINE INTERACTIONS IN INTESTINAL INFLAMMATION PhD Thesis- Shajib, MS; McMaster University-Medical Sciences Immuno-endocrine interactions in intestinal inflammation By Md. Sharif Shajib, BSc. (Hons) A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy McMaster University © Copyright by Md. Sharif Shajib, 2017. PhD Thesis- Shajib, MS; McMaster University-Medical Sciences Descriptive notes Doctor of Philosophy (2017) McMaster University, Hamilton, Ontario (Medical Sciences) TITLE Immuno-endocrine interactions in intestinal inflammation AUTHOR Md. Sharif Shajib, BSc. (Hons) SUPERVISOR Dr. Waliul I. Khan NUMBER OF PAGES: XX, 292. II PhD Thesis- Shajib, MS; McMaster University-Medical Sciences Lay abstract The gut produces most of the serotonin found in our body, where it regulates many normal functions. A group of special cells, named enterochromaffin cells, produces nearly all of the serotonin in the gut. In diseases of the gut, especially ones that involve inflammation resulting in symptoms like abdominal pain, diarrhea and bleeding, the number of these cells and serotonin concentration are different from that in the normal gut. I found that these changes are controlled by a particular protein produced by immune cells, called interleukin-13, and alteration in serotonin levels, in turn, contributes to the inflammatory process. Our laboratory experiments with cells and animals establish this connection between interleukin-13 and serotonin in gut inflammation. We further confirm this association between interleukin-13 and serotonin in human inflammatory bowel disease. Moreover, we identify a potential genetic cause of these changes in serotonin concentrations which may ultimately result in inflammatory bowel disease.
    [Show full text]
  • University of Alberta DENDRITIC CELL-TARGETED NANOPARTICLES for the DELIVERY of DNA and PROTEIN VACCINES by Dharmendra Raghuwans
    University of Alberta DENDRITIC CELL-TARGETED NANOPARTICLES FOR THE DELIVERY OF DNA AND PROTEIN VACCINES By Dharmendra Raghuwanshi A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences Faculty of Pharmacy and Pharmaceutical Sciences © Dharmendra Raghuwanshi Fall 2012 Edmonton, Alberta Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission. Dedication I dedicate this thesis to my beloved Mother with all my love and respect. Your memories and affection will always be alive in my heart. ABSTRACT Dendritic cells (DCs) play a central role in shaping antigen-specific immune response. Antibody-mediated antigen targeting to DC-specific surface receptors is a promising approach to enhance vaccine efficacy. The objective of this thesis was to develop DC-targeted nanoparticulate formulations for the delivery of DNA and protein antigen using a novel strategy. The approach involved use of a two- component DC targeted delivery system for enhanced immune response.
    [Show full text]
  • Science Journals
    SCIENCE IMMUNOLOGY | RESEARCH RESOURCE T CELL MEMORY Copyright © 2020 The Authors, some rights reserved; Early precursors and molecular determinants of tissue- exclusive licensee + American Association resident memory CD8 T lymphocytes revealed by for the Advancement of Science. No claim single-cell RNA sequencing to original U.S. Nadia S. Kurd1*†, Zhaoren He2,3*, Tiani L. Louis1, J. Justin Milner3, Kyla D. Omilusik3, Government Works Wenhao Jin2, Matthew S. Tsai1, Christella E. Widjaja1, Jad N. Kanbar1, Jocelyn G. Olvera1, Tiffani Tysl1, Lauren K. Quezada1, Brigid S. Boland1, Wendy J. Huang2, Cornelis Murre3, Ananda W. Goldrath3, Gene W. Yeo2,4‡, John T. Chang1,5‡§ + During an immune response to microbial infection, CD8 T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including Downloaded from a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid + tissues. Here, we used single-cell RNA sequencing to examine the gene expression patterns of individual CD8 T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional + heterogeneity within the siIEL CD8 T cell population at several stages of differentiation, representing functionally distinct TRM cell subsets and a subset of TRM cell precursors within the tissue early in infection. Together, these http://immunology.sciencemag.org/ + findings may inform strategies to optimize CD8 T cell responses to protect against microbial infection and cancer. INTRODUCTION composed of distinct subsets that play unique roles in mediating CD8+ T cells responding to microbial challenge differentiate into protective immunity.
    [Show full text]
  • NIH Public Access Author Manuscript Eur J Immunol
    NIH Public Access Author Manuscript Eur J Immunol. Author manuscript; available in PMC 2010 May 5. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Eur J Immunol. 2008 January ; 38(1): 20±29. doi:10.1002/eji.200737799. Broad T cell immunity to the LcrV virulence protein is induced by targeted delivery to DEC-205/CD205 positive mouse dendritic cells Yoonkyung Do1, Chae Gyu Park1, Young-Sun Kang1,3, Sung Ho Park1, Rebecca M. Lynch1, Haekyung Lee1, Bradford S. Powell2, and Ralph M. Steinman1,* 1 Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065 2 U. S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 3 Department of Biomedical Science and Technology, Institute of Biomedical Science and Technology, Konkuk University, 1 Hwayang-dong, Kwangjin-gu, Seoul 143-701, Republic of Korea SUMMARY There is a need for a more efficient vaccine against the bacterium Y. pestis, the agent of pneumonic plague. The F1-LcrV subunit vaccine in alhydrogel is known to induce humoral immunity. In this study, we utilized dendritic cells to investigate cellular immunity. We genetically engineered the LcrV virulence protein into the αDEC-205/CD205 monoclonal antibody and thereby targeted the conjugated protein directly to mouse DEC-205+ DCs in situ. We observed antigen-specific CD4+ T cell immunity measured by intracellular staining for interferon- γ in three different mouse strains (C57BL/6, BALB/c, and C3H/HeJ), while we could not observe such T cell responses with F1-V vaccine in alhydrogel.
    [Show full text]
  • Molecular Mechanisms of Neuroprotection by an Alternative Drug Scutellaria Lateriflora by Madhukar Lohani a Dissertation Submitt
    Molecular Mechanisms of Neuroprotection by an Alternative Drug Scutellaria lateriflora by Madhukar Lohani A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama August 02, 2014 Key words: American skullcap, Anxiety, Memory, Neuroprotection, Scutellaria lateriflora Copyright 2014 by Madhukar Lohani Approved by Barbara W Kemppainen, Chair, Professor of Anatomy, Physiology and Pharmacology Dean D Schwartz, Associate Professor of Anatomy, Physiology and Pharmacology Kellye Joiner, Associate Professor of Pathobiology Muralikrishnan Dhanasekaran, Associate Professor of Pharmacal sciences Frederik W Van Ginkel, Associate Professor of Pathobiology i Abstract Anxiety is one of the most prevalent neuropsychological disorders around the world. In the United States of America (USA), it is a serious health problem affecting a large number of people and is considered as one of the common disorder seen in the primary health care. Based on the current understanding of the pathologic mechanisms of anxiety, there are limited pharmacological and non-pharmacological therapies. Benzodiazepine (the current first line of therapy) has severe adverse effects such as anterograde amnesia, tolerance, psychomotor impairment, memory disruption, impaired psychomotor function, paradoxical anxiety or aggression, risks of accidents and even mortality. A double blind, placebo- controlled clinical trial indicated that commercial preparations of Scutellaria lateriflora have therapeutic benefits in anxiety with no evidence of toxicity. The purpose of this study was to examine the biological activities of S. lateriflora that may contribute to its neuroprotective mechanisms. The research study was conducted in four phases. The first two experimental approaches determined anti-oxidative potential and protective activities of S.
    [Show full text]
  • Vaccine Strategies Utilizing C-Type Lectin Receptors on Dendritic Cells in Vivo
    Review article CLINICAL Vaccine strategies utilizing EXPERIMENTAL VACCINE C-type lectin receptors on RESEARCH dendritic cells in vivo Clin Exp Vaccine Res 2014;3:149-154 http://dx.doi.org/10.7774/cevr.2014.3.2.149 pISSN 2287-3651 • eISSN 2287-366X Chae Gyu Park Dendritic cells (DCs) are professional antigen-presenting cells capable of initiating and regu- Laboratory of Immunology, Severance Biomedical lating innate and adaptive immunity. The development of effective ways to produce a large Science Institute, Brain 21 PLUS project for Medical Science, Yonsei University College of number of DCs in laboratories made the use of DCs available in various vaccine approaches. Medicine, Seoul, Korea Compared to conventional vaccines, focused on protective antibody responses, DC vaccines Received: February 8, 2014 emphasize protective T cell immunity but might elicit strong antibody responses as well. In ad- Revised: March 26, 2014 dition, the recent discoveries of functionally distinct DC subsets in various organs and tissues Accepted: March 30, 2014 are likely to increase the potential of exploiting DCs in vaccines and immunotherapy. Vac- Corresponding author: Chae Gyu Park, PhD Laboratory of Immunology, Severance Biomedi- cines composed of DCs generated ex vivo, pulsed with antigens, and matured prior to being re- cal Science Institute, Brain 21 PLUS project for infused to the body have been widely tried clinically but resulted in limited success due to vari- Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul ous obstacles. In this review, new approaches that protein vaccines are selectively targeted 120-752, Korea to the endocytic C-type lectin receptors on surface of DCs in vivo are discussed.
    [Show full text]
  • Evaluator Manual Transmittal Sheet
    STATE OF CALIFORNIA - HEALTH AND HUMAN SERVICES AGENCY DEPARTMENT OF SOCIAL SERVICES EVALUATOR MANUAL TRANSMITTAL SHEET Transmittal No. Distribution: 06APX-14 X All Child Care Evaluator Manual Holders Date Issued All Residential Care Evaluator Manual Holders November 2006 All Evaluator Manual Holders Subject: Statewide Matrix of Early Childhood Programs APPENDIX G California Community College Systems Reason For Change: To provide a complete revision of the “California Community College System Statewide Matrix of Early Childhood Programs”. The Matrix is a guideline that defines the relationship between a community college’s Early Childhood Education/Child Development (ECE/CD) program and the Title 22 requirement for 12 semester units (or equivalent quarter units). Filing Instructionss: REMOVE: EM Appendix G (EM Issue 03APX-01) in its entirety INSERT: Attached Matrix dated November 2006 under EM Appendix G Approved: Linda Inglett for 11/16/06 ______________________ GLORIA MERK, Program Administrator Date Statewide Child Care Program Community Care Licensing Division Contact Person: Linda Inglett Phone Number: (916) 229-4500 LIC 9025 (7/99 CALIFORNIA COMMUNITY COLLEGE SYSTEM STATEWIDE MATRIX of EARLY CHILDHOOD PROGRAMS for CALIFORNIA STATE DEPARTMENT OF SOCIAL SERVICES CA COMMUNITY COLLEGES SYSTEM OFFICE CHILD DEVELOPMENT ADVISORY COMMITTEE and CALIFORNIA COMMUNITY COLLEGES EARLY CHILDHOOD EDUCATORS FALL 2006 California Community Colleges System Office Student Services and Special Programs 1102 Q Street Sacramento, CA 95814 (916) 323-5276 Introduction The Statewide Community College Matrix of Early Childhood Programs was originally developed from a state-level request by the California Department of Social Services to assist licensing evaluators in identifying which community college courses complied with Title 22 requirements for child development teachers and directors.
    [Show full text]
  • A Personalised Dietary Approach—A Way Forward to Manage Nutrient Deficiency, Effects of the Western Diet, and Food Intolerance
    nutrients Review A Personalised Dietary Approach—A Way Forward to Manage Nutrient Deficiency, Effects of the Western Diet, and Food Intolerances in Inflammatory Bowel Disease Bobbi B Laing 1,2 , Anecita Gigi Lim 1 and Lynnette R Ferguson 1,* 1 Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand 2 Nutrition Society of New Zealand, Palmerston North 4444, New Zealand * Correspondence: [email protected] Received: 7 May 2019; Accepted: 2 July 2019; Published: 5 July 2019 Abstract: This review discusses the personalised dietary approach with respect to inflammatory bowel disease (IBD). It identifies gene–nutrient interactions associated with the nutritional deficiencies that people with IBD commonly experience, and the role of the Western diet in influencing these. It also discusses food intolerances and how particular genotypes can affect these. It is well established that with respect to food there is no “one size fits all” diet for those with IBD. Gene–nutrient interactions may help explain this variability in response to food that is associated with IBD. Nutrigenomic research, which examines the effects of food and its constituents on gene expression, shows that—like a number of pharmaceutical products—food can have beneficial effects or have adverse (side) effects depending on a person’s genotype. Pharmacogenetic research is identifying gene variants with adverse reactions to drugs, and this is modifying clinical practice and allowing individualised treatment. Nutrigenomic research could enable individualised treatment in persons with IBD and enable more accurate tailoring of food intake, to avoid exacerbating malnutrition and to counter some of the adverse effects of the Western diet.
    [Show full text]
  • Bio-Inspired and Smart Nanoparticles for Triple Negative Breast Cancer Microenvironment
    pharmaceutics Review Bio-Inspired and Smart Nanoparticles for Triple Negative Breast Cancer Microenvironment Mahsa Keihan Shokooh 1,†, Fakhrossadat Emami 2,†, Jee-Heon Jeong 3,* and Simmyung Yook 2,* 1 Department of Pharmaceutics, College of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran; [email protected] 2 College of Pharmacy, Keimyung University, Daegu 42601, Korea; [email protected] 3 College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Korea * Correspondence: [email protected] (J.-H.J.); [email protected] (S.Y.); Tel.: +82-53-810-2822 (J.-H.J.); +82-53-580-6656 (S.Y.) † These authors contributed equally to this work. Abstract: Triple negative breast cancer (TNBC) with poor prognosis and aggressive nature accounts for 10–20% of all invasive breast cancer (BC) cases and is detected in as much as 15% of individuals diagnosed with BC. Currently, due to the absence of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) receptor, there is no hormone-based therapy for TNBC. In addition, there are still no FDA-approved targeted therapies for patients with TNBC. TNBC treatment is challenging owing to poor prognosis, tumor heterogeneity, chemotherapeutic side effects, the chance of metastasis, and multiple drug-resistance. Therefore, various bio-inspired tumor-homing nano systems responding to intra- and extra- cellular stimuli are an urgent need to treat TNBC patients who do not respond to current chemotherapy. In this review, intensive efforts have been made for exploring cell-membrane coated nanoparticles and immune cell-targeted nanoparticles (immunotherapy) to modulate the tumor microenvironment and deliver accurate Citation: Keihan Shokooh, M.; amounts of therapeutic agents to TNBC without stimulating the immune system.
    [Show full text]
  • Immune Response and Immunomodulation in Chronic Hepatitis B Virus Infection
    IMMUNERESPONSEANDIMMUNOMODULATIONIN CHRONICHEPATITISBVIRUSINFECTION D.SPRENGERS Immune response and immunomodulation in chronic hepatitis B virus infection Immuunresponsenimmunomodulatieinchronische HepatitisBvirusinfectie PROEFSCHRIFT terverkrijgingvandegraadvandoctor aandeErasmusUniversiteitRotterdam opgezagvandeRectorMagnificus Prof.dr.S.W.J.Lamberts envolgensbesluitvanhetCollegevoorPromoties. Deopenbareverdedigingzalplaatsvindenop woensdag1november2006om13.45uur door Dave Sprengers geborenteGoirle Promotiecommissie Promotor: Prof.dr.H.L.A.Janssen Copromotor: Dr.R.G.vanderMolen Overigeleden: Prof.dr.J.H.P.Wilson Prof.dr.A.D.M.E.Osterhaus Prof.dr.S.W.Schalm ThisstudywassupportedbyagrantfromTheNetherlandsOrganisationfor HealthResearchandDevelopment(ZonMw ,Agikostipendium dossiernum mer92003244). Publicationofthisthesiswasfi nanciallysupportedby:ZonMw ,ZambonNederlandBV , NovartisPharmaBV, Aanmijnouders TU REMANEBIS AMICUS MAXIMUS PERPETUO Contents Page Chapter1: introduction 1 Chapter2: Functionalimpairmentofmyeloidandplasmacytoid 17 dendriticcellsofchronichepatitisBpatients Chapter3: Flowcytometryoffi neneedleaspirationbiopsies:anew 33 methodtomonitorintrahepaticimmunologicalenvironmentin chronicviralhepatitis Chapter4: Differentcompositionofintrahepaticlymphocytesinthe 45 immunetoleranceandimmuneclearancephaseofchronic hepatitisB Chapter5: Analysisofintrahepatic HBVspecifi ccytotoxicTcellsduring 59 andafteracuteHBVinfectioninhumans Chapter6: In vivo immunizationfollowingvirussuppression:anovel 73 approachforinducingimmunecontrolinchronichepatitisB
    [Show full text]