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  • Precision Medicine for Human Cancers with Notch Signaling Dysregulation (Review)
    INTERNATIONAL JOURNAL OF MOleCular meDICine 45: 279-297, 2020 Precision medicine for human cancers with Notch signaling dysregulation (Review) MASUKO KATOH1 and MASARU KATOH2 1M & M PrecMed, Tokyo 113-0033; 2Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan Received September 16, 2019; Accepted November 20, 2019 DOI: 10.3892/ijmm.2019.4418 Abstract. NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are conjugate (ADC) Rova-T, and DLL3-targeting chimeric antigen transmembrane receptors that transduce juxtacrine signals of receptor‑modified T cells (CAR‑Ts), AMG 119, are promising the delta-like canonical Notch ligand (DLL)1, DLL3, DLL4, anti-cancer therapeutics, as are other ADCs or CAR-Ts targeting jagged canonical Notch ligand (JAG)1 and JAG2. Canonical tumor necrosis factor receptor superfamily member 17, Notch signaling activates the transcription of BMI1 proto-onco- CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibro- gene polycomb ring finger, cyclin D1, CD44, cyclin dependent blast growth factor receptor (FGFR)2, FGFR3, receptor-type kinase inhibitor 1A, hes family bHLH transcription factor 1, tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor hes related family bHLH transcription factor with YRPW receptor, NECTIN4, inactive tyrosine-protein kinase 7, inac- motif 1, MYC, NOTCH3, RE1 silencing transcription factor and tive tyrosine-protein kinase transmembrane receptor ROR1 transcription factor 7 in a cellular context-dependent manner, and tumor-associated calcium signal transducer 2. ADCs and while non-canonical Notch signaling activates NF-κB and Rac CAR-Ts could alter the therapeutic framework for refractory family small GTPase 1. Notch signaling is aberrantly activated cancers, especially diffuse-type gastric cancer, ovarian cancer in breast cancer, non-small-cell lung cancer and hematological and pancreatic cancer with peritoneal dissemination.
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  • 9 the Present and Future of Tocolysis
    Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 21, No. 5, pp. 857–868, 2007 doi:10.1016/j.bpobgyn.2007.03.011 available online at http://www.sciencedirect.com 9 The present and future of tocolysis Warwick Giles* MBBS, FRANZCOG, PhD, CMFM Conjoint Professor Reproductive Medicine and Director Maternal Fetal Medicine Andrew Bisits MBMS, FRANZCOG, Dip Clin Epidemiol Conjoint Senior Lecture and Director of Obstetrics Faculty of Health, University of Newcastle, Australia This chapter discusses the tocolytic agents currently in use for the treatment of preterm labour and considers them in light of the evidence base. These agents are the b2 sympathomimetic ag- onists, magnesium sulphate (MgSO4), indomethacin, nifedipine and atosiban. The available evidence for these agents shows that the b2 agents are effective but have sig- nificant maternal side effects and no effect on perinatal outcome. MgSO4 and glyceryl trinitrate are clearly ineffective. Nifedipine is effective with a low maternal side effect profile and is asso- ciated with improved perinatal outcomes. Meta-analyses of the several randomized controlled trials of atosiban show that it is no more effective than other tocolytic therapies. Possible direc- tions for the future will be discussed. Key words: tocolysis; preterm delivery. It has long been the desire of clinicians to have therapies that can interrupt premature labour and allow the delivery of more mature infants with lower morbidity and mor- tality, time to use antenatal corticosteroids and transfer to tertiary care centres for delivery. The promising therapies of each recent generation have often been tried and found wanting. Observations from the 1990s have described preterm labour (PTL) as a syndrome rather than a distinct entity (as the causes are varied) reflecting the possible causes of a breakdown in the normal functional uterine quiescence with a short-circuiting or overwhelming of the normal parturition cascade.
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  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
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  • Metabotropic Glutamate Receptors
    mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Agonists, Antagonists, Inhibitors, Modulators & Activators (-)-Camphoric acid (1R,2S)-VU0155041 Cat. No.: HY-122808 Cat. No.: HY-14417A (-)-Camphoric acid is the less active enantiomer (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is of Camphoric acid. Camphoric acid stimulates a partial mGluR4 agonist with an EC50 of 2.35 osteoblast differentiation and induces μM. glutamate receptor expression. Camphoric acid also significantly induced the activation of NF-κB and AP-1. Purity: ≥98.0% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 100 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg (2R,4R)-APDC (R)-ADX-47273 Cat. No.: HY-102091 Cat. No.: HY-13058B (2R,4R)-APDC is a selective group II metabotropic (R)-ADX-47273 is a potent mGluR5 positive glutamate receptors (mGluRs) agonist.
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  • Muscarinic Acetylcholine Receptor
    mAChR Muscarinic acetylcholine receptor mAChRs (muscarinic acetylcholine receptors) are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certainneurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibersin the parasympathetic nervous system. mAChRs are named as such because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpineand scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists. Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. www.MedChemExpress.com 1 mAChR Inhibitors & Modulators (+)-Cevimeline hydrochloride hemihydrate (-)-Cevimeline hydrochloride hemihydrate Cat. No.: HY-76772A Cat. No.: HY-76772B Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic receptor agonist, is a candidate therapeutic drug for receptor agonist, is a candidate therapeutic drug for xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR The general pharmacol. properties of this drug on the The general pharmacol. properties of this drug on the gastrointestinal, urinary, and reproductive systems and other… gastrointestinal, urinary, and reproductive systems and other… Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg 1 mg, 5 mg AC260584 Aclidinium Bromide Cat. No.: HY-100336 (LAS 34273; LAS-W 330) Cat.
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  • Where Do Novel Drugs of 2016 Fit In?
    FORMULARY JEOPARDY: WHERE DO NOVEL DRUGS OF 2016 FIT IN? Maabo Kludze, PharmD, MBA, CDE, BCPS, Associate Director Elizabeth A. Shlom, PharmD, BCPS, SVP & Director Clinical Pharmacy Program Acurity, Inc. Privileged and Confidential August 15, 2017 Privileged and Confidential Program Objectives By the end of the presentation, the pharmacist or pharmacy technician participant will be able to: ◆ Identify orphan drugs and first-in-class medications approved by the FDA in 2016. ◆ Describe the role of new agents approved for use in oncology patients. ◆ Identify and discuss the role of novel monoclonal antibodies. ◆ Discuss at least two new medications that address public health concerns. Neither Dr. Kludze nor Dr. Shlom have any conflicts of interest in regards to this presentation. Privileged and Confidential 2016 NDA Approvals (NMEs/BLAs) ◆ Nuplazid (primavanserin) P ◆ Adlyxin (lixisenatide) ◆ Ocaliva (obeticholic acid) P, O ◆ Anthim (obitoxaximab) O ◆ Rubraca (rucaparib camsylate) P, O ◆ Axumin (fluciclovive F18) P ◆ Spinraza (nusinersen sodium) P, O ◆ Briviact (brivaracetam) ◆ Taltz (ixekizumab) ◆ Cinqair (reslizumab) ◆ Tecentriq (atezolizumab) P ◆ Defitelio (defibrotide sodium) P, O ◆ Venclexta (venetoclax) P, O ◆ Epclusa (sofosburvir and velpatasvir) P ◆ Xiidra (lifitigrast) P ◆ Eucrisa (crisaborole) ◆ Zepatier (elbasvir and grazoprevir) P ◆ Exondys 51 (eteplirsen) P, O ◆ Zinbyrta (daclizumab) ◆ Lartruvo (olaratumab) P, O ◆ Zinplava (bezlotoxumab) P ◆ NETSTPOT (gallium Ga 68 dotatate) P, O O = Orphan; P = Priority Review; Red = BLA Privileged and Confidential History of FDA Approvals Privileged and Confidential Orphan Drugs ◆FDA Office of Orphan Products Development • Orphan Drug Act (1983) – drugs and biologics . “intended for safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S.
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  • Cancer Drug Pharmacology Table
    CANCER DRUG PHARMACOLOGY TABLE Cytotoxic Chemotherapy Drugs are classified according to the BC Cancer Drug Manual Monographs, unless otherwise specified (see asterisks). Subclassifications are in brackets where applicable. Alkylating Agents have reactive groups (usually alkyl) that attach to Antimetabolites are structural analogues of naturally occurring molecules DNA or RNA, leading to interruption in synthesis of DNA, RNA, or required for DNA and RNA synthesis. When substituted for the natural body proteins. substances, they disrupt DNA and RNA synthesis. bendamustine (nitrogen mustard) azacitidine (pyrimidine analogue) busulfan (alkyl sulfonate) capecitabine (pyrimidine analogue) carboplatin (platinum) cladribine (adenosine analogue) carmustine (nitrosurea) cytarabine (pyrimidine analogue) chlorambucil (nitrogen mustard) fludarabine (purine analogue) cisplatin (platinum) fluorouracil (pyrimidine analogue) cyclophosphamide (nitrogen mustard) gemcitabine (pyrimidine analogue) dacarbazine (triazine) mercaptopurine (purine analogue) estramustine (nitrogen mustard with 17-beta-estradiol) methotrexate (folate analogue) hydroxyurea pralatrexate (folate analogue) ifosfamide (nitrogen mustard) pemetrexed (folate analogue) lomustine (nitrosurea) pentostatin (purine analogue) mechlorethamine (nitrogen mustard) raltitrexed (folate analogue) melphalan (nitrogen mustard) thioguanine (purine analogue) oxaliplatin (platinum) trifluridine-tipiracil (pyrimidine analogue/thymidine phosphorylase procarbazine (triazine) inhibitor)
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  • Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study
    Ophthalmol Ther https://doi.org/10.1007/s40123-020-00280-8 ORIGINAL RESEARCH Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study Asim V. Farooq . Simona Degli Esposti . Rakesh Popat . Praneetha Thulasi . Sagar Lonial . Ajay K. Nooka . Andrzej Jakubowiak . Douglas Sborov . Brian E. Zaugg . Ashraf Z. Badros . Bennie H. Jeng . Natalie S. Callander . Joanna Opalinska . January Baron . Trisha Piontek . Julie Byrne . Ira Gupta . Kathryn Colby Received: April 21, 2020 Ó The Author(s) 2020, corrected publication 2020 ABSTRACT monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study Introduction: Patients with relapsed or refrac- (NCT03525678), single-agent belamaf (2.5 mg/kg) tory multiple myeloma (RRMM) represent an demonstrated clinically meaningful anti-mye- unmet clinical need. Belantamab mafodotin loma activity (overall response rate 32%) in (belamaf; GSK2857916) is a first-in-class anti- patients with heavily pretreated disease. Micro- body–drug conjugate (ADC; or immunoconju- cyst-like epithelial changes (MECs) were com- gate) that delivers a cytotoxic payload, mon, consistent with reports from other MMAF- containing ADCs. Methods: Corneal examination findings from Digital Features To view digital features for this article patients in DREAMM-2 were reviewed, and the go to https://doi.org/10.6084/m9.figshare.12326546. clinical descriptions and accompanying images The original version of this article was revised based upon recent changes to the FDA label and guidance on D. Sborov the use of belamaf. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA A. V. Farooq (&) Á A.
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  • Horizon Scanning Status Report June 2019
    Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors.
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  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
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  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
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  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
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