DOCSLIB.ORG

The Old, the New, and the Future

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Old, the New, and the Future Cancer Biol Med 2018. doi: 10.20892/j.issn.2095-3941.2018.0030 REVIEW G2/M inhibitors as pharmacotherapeutic opportunities for glioblastoma: the old, the new, and the future Angel Mauricio Castro-Gamero1, Julia Alejandra Pezuk2, María Sol Brassesco3, Luiz Gonzaga Tone4,5 1Human Genetics Laboratory, Institute of Natural Sciences, Federal University of Alfenas (UNIFAL-MG), Alfenas 37130-001, Brazil; 2Biotechnology and Innovation in Health Program and Pharmacy Program, Anhanguera University São Paulo (UNIAN- SP), São Paulo 05145-200, Brazil; 3Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, Brazil; 4Department of Pediatrics; 5Department of Genetics, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, Brazil ABSTRACT Glioblastoma (GBM) is one of the deadliest tumors and has a median survival of 3 months if left untreated. Despite advances in rationally targeted pharmacological approaches, the clinical care of GBM remains palliative in intent. Since the majority of altered signaling cascades involved in cancer establishment and progression eventually affect cell cycle progression, an alternative approach for cancer therapy is to develop innovative compounds that block the activity of crucial molecules needed by tumor cells to complete cell division. In this context, we review promising ongoing and future strategies for GBM therapeutics aimed towards G2/M inhibition such as anti-microtubule agents and targeted therapy against G2/M regulators like cyclin-dependent kinases, Aurora inhibitors, PLK1, BUB, 1, and BUBR1, and survivin. Moreover, we also include investigational agents in the preclinical and early clinical settings. Although several drugs were shown to be gliotoxic, most of them have not yet entered therapeutic trials. The use of either single exposure or a combination with novel compounds may lead to treatment alternatives for GBM patients in the near future. KEYWORDS Chemotherapy; PLK1; AURK; survivin; BUB; BUR1 Introduction cells appear2. Accordingly, a grade IV astrocytoma (also called "glioblastoma", "glioblastoma multiforme", "grade IV Glioblastoma glioblastoma", and "GBM") represents the most common and most aggressive primary malignant brain tumor, with 3 per For many years, tumors of the central nervous system (CNS) 100,000 people diagnosed every year3. GBM is were primarily categorized according to histopathological histopathologically characterized by brisk mitotic activity, criteria determined under microscopic observation, where cellular and nuclear atypia, vascular thrombosis, and similarities and phenotypic differences depended on cellular microvascular hyperproliferation and necrosis, with 80% origin and their presumed levels of differentiation. In being primary or de novo occurring though malignant particular, gliomas are diffusely infiltrating glial cell tumors transformation from lower-grade gliomas (sometimes 4 that are responsible for 80% of malignant tumors initiated in referred to as secondary GBMs) . GBM is one of the most deadly types of tumors5. If left the brain and have been classified by the World Health untreated, this dismal tumor has a median survival of 3 Organization (WHO) depending on the type of the affected months6. In addition to maximal safe surgical resection and glial cell, thus integrating the nomenclature with grading radiotherapy (RT), the standard chemotherapeutic agent for system1. Histological diagnosis is correlated with tumor grade its treatment since 2005 is the alkylant prodrug temozolomide on a scale of I to IV based on how normal or abnormal the (TMZ), which was first approved by the Food and Drug Administration (FDA) for use in recurrent GBM based on Correspondence to: Angel Mauricio Castro-Gamero the phase II trial by Yung and colleagues7. Posteriorly, in the E-mail: [email protected] pivotal phase III study, Stupp and colleagues randomized Received February 19, 2018; accepted June 26, 2018. Available at www.cancerbiomed.org ~600 patients diagnosed with GBM from various treatment Copyright © 2018 by Cancer Biology & Medicine centers. Their investigation consisted of radiation alone or Cancer Biol Med Vol 15, No 4 November 2018 355 radiotherapy with continuous daily TMZ, which wildtype gliomas18,19. demonstrated an improved 14.6-month median survival in This current classification represents a conceptual and the second group, versus 12.1 months in control patients. practical advance over its 2007 predecessor, reinforcing the Two-year survival was also increased by 26.5% compared to need for molecular/genomic diagnosis, new molecular 10.4% for those treated with radiotherapy alone. Nowadays, approaches, as well as further studies to gain a better RT combined with concomitant and adjuvant TMZ after understanding of the role of these mutational profiles in the surgical resection, namely STUPP treatment, is widely used survival of patients and their prognostic values. for newly diagnosed GBM patients8,9. Nonetheless, only Accordingly, many analyses of the genomic landscape of 15%–20% of patients survive 5 years after diagnosis, and no GBM were published by the Cancer Genome Atlas Research other therapies have demonstrated a robust survival benefit Network in 200820-22 and revealed specific genomic, in recurrent disease6,10. epigenomic, transcriptomic, and proteomic alterations in TMZ is an imidazotetrazine derivative of the alkylating core pathways that define novel specific tumor subgroups. agent dacarbazine that delivers a methyl group to the purine Thus, some studies have predicted that genomic diagnoses bases of DNA (O6-guanine, N7-guanine, and N3-adenine). will overrule and dictate the diagnosis in the future23. Although O6-methylguanine (O6-MeG) is the primary However, these subdivisions still play no role in current cytotoxic lesion, it can be reversed by the action of the repair diagnostics and treatment decisions, but do help to overcome enzyme methylguanine methyltransferase (MGMT), thereby some of the molecular heterogeneity in GBM and improve neutralizing the cytotoxic effects of TMZ11. Accordingly, high treatment. expression of MGMT in glioma cells is the predominant The concept of exploiting cell division as a therapeutic mechanism underlying tumor resistance to alkylating target has been in practice since the advent of chemotherapy. agents12. Moreover, patients with methylated-MGMT treated Briefly, antitumor treatments can affect the cell cycle through with TMZ showed a 21.7-month median overall survival three modes of action: blocking DNA synthesis, causing DNA (OS) compared with 12.7 months in those with damage, or perturbing mitotic processes. As with many solid unmethylated promoters13, proving a direct association tumors, GBM is defined as a highly heterogeneous cancer between MGMT expression and tumor response to TMZ with different cell populations coexisting within the tumor therapy14. mass, each one with a distinct proliferative status directly Moreover, results from the European Organization for connected to key molecules regulating cell cycle progression Research and Treatment of Cancer and National Cancer and mitosis. In this regard, the diagnostic and prognostic Institute of Canada trial recognized methylated-MGMT as relevance of cell cycle biomarkers strongly reinforce the need the strongest predictor of outcome and benefit from TMZ to characterize signaling pathways and highlight their treatment8,15. Similarly, the recent meta-analysis by Zhao and potential for novel targeted therapies for GBM. Hence, in the colleagues16 involving 7,886 patients, highlighted the present review, we feature classic compounds used in anti- universal predictive value of MGMT methylation in newly GBM therapy, and review recent advances on new diagnosed GBM patients, elderly GBM patients, and therapeutic approaches that are based on the inhibition of recurrent GBM patients16. cell cycle molecules. Over the last two decades, many researchers have highlighted the importance of GBM molecular subtyping, but Anti-microtubule agents only recently was the WHO Classification for CNS Tumors able to integrate phenotypic and genotypic parameters, and Mitosis disruption is widely used in clinics, and even with the subdivided GBM in three categories based on the status of rapid expansion in the number of classes of compounds with the isocitrate dehydrogenase (IDH) gene17. Consequently, antineoplastic activity, anti-microtubule agents are still GBM are currently classified as IDH-wildtype (approximately among the most strategic and have played a pivotal role in 90% of cases that correspond most frequently to the the curative and palliative treatment of cancer over the last clinically defined primary GBM), GBM IDH-mutant 50 years. (approximately 10% of cases that closely correspond to the In general, anti-microtubule compounds can be divided so-called secondary GBM), and GBM not otherwise specified into tubulin destabilizing and stabilizing agents. In the first (NOS), a diagnosis that is reserved for tumors without full group, we can include vinblastine and vincristine, alkaloids IDH evaluation17. Importantly, some studies already have isolated from the periwinkle plant Cantharanthus rosea, and showed that OS of IDH-mutants are greater than IDH- colchicine, isolated from the meadow saffron Colchicum 356 Castro-Gamero et al. G2/M inhibitors for glioblastoma treatment autumnale, all of which have been shown to inhibit strategies, including conjugates of paclitaxel
Load more

Recommended publications
  • Practice Parameters for the Treatment of Patients with Dominantly Inherited Colorectal Cancer
    Practice Parameters For The Treatment Of Patients With Dominantly Inherited Colorectal Cancer Diseases of the Colon & Rectum 2003;46(8):1001-1012 Prepared by: The Standards Task Force The American Society of Colon and Rectal Surgeons James Church, MD; Clifford Simmang, MD; On Behalf of the Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of the American Society of Colon and Rectal Surgeons. The American Society of Colon and Rectal Surgeons is dedicated to assuring high quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The standards committee is composed of Society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. This Committee was created in order to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus. This is accompanied by developing Clinical Practice Guidelines based on the best available evidence. These guidelines are inclusive, and not prescriptive. Their purpose is to provide information on which decisions can be made, rather than dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, health care workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. Practice Parameters for the Treatment of Patients With Dominantly Inherited Colorectal Cancer Inherited colorectal cancer includes two main syndromes in which predisposition to the disease is based on a germline mutation that may be transmitted from parent to child.
    [Show full text]
  • Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics
    Review Current Advances of Nitric Oxide in Cancer and Anticancer Therapeutics Joel Mintz 1,†, Anastasia Vedenko 2,†, Omar Rosete 3 , Khushi Shah 4, Gabriella Goldstein 5 , Joshua M. Hare 2,6,7 , Ranjith Ramasamy 3,6,* and Himanshu Arora 2,3,6,* 1 Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL 33328, USA; [email protected] 2 John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] (A.V.); [email protected] (J.M.H.) 3 Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] 4 College of Arts and Sciences, University of Miami, Miami, FL 33146, USA; [email protected] 5 College of Health Professions and Sciences, University of Central Florida, Orlando, FL 32816, USA; [email protected] 6 The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA 7 Department of Medicine, Cardiology Division, Miller School of Medicine, University of Miami, Miami, FL 33136, USA * Correspondence: [email protected] (R.R.); [email protected] (H.A.) † These authors contributed equally to this work. Abstract: Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumori- Citation: Mintz, J.; Vedenko, A.; genic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the Rosete, O.; Shah, K.; Goldstein, G.; level of production, the oxidative/reductive (redox) environment in which this radical is generated, Hare, J.M; Ramasamy, R.; Arora, H.
    [Show full text]
  • New Drugs Are Not Enough‑Drug Repositioning in Oncology: an Update
    INTERNATIONAL JOURNAL OF ONCOLOGY 56: 651-684, 2020 New drugs are not enough‑drug repositioning in oncology: An update ROMINA GABRIELA ARMANDO, DIEGO LUIS MENGUAL GÓMEZ and DANIEL EDUARDO GOMEZ Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Bernal B1876, Argentina Received August 15, 2019; Accepted December 16, 2019 DOI: 10.3892/ijo.2020.4966 Abstract. Drug repositioning refers to the concept of discov- 17. Lithium ering novel clinical benefits of drugs that are already known 18. Metformin for use treating other diseases. The advantages of this are that 19. Niclosamide several important drug characteristics are already established 20. Nitroxoline (including efficacy, pharmacokinetics, pharmacodynamics and 21. Nonsteroidal anti‑inflammatory drugs toxicity), making the process of research for a putative drug 22. Phosphodiesterase-5 inhibitors quicker and less costly. Drug repositioning in oncology has 23. Pimozide received extensive focus. The present review summarizes the 24. Propranolol most prominent examples of drug repositioning for the treat- 25. Riluzole ment of cancer, taking into consideration their primary use, 26. Statins proposed anticancer mechanisms and current development 27. Thalidomide status. 28. Valproic acid 29. Verapamil 30. Zidovudine Contents 31. Concluding remarks 1. Introduction 2. Artesunate 1. Introduction 3. Auranofin 4. Benzimidazole derivatives In previous decades, a considerable amount of work has been 5. Chloroquine conducted in search of novel oncological therapies; however, 6. Chlorpromazine cancer remains one of the leading causes of death globally. 7. Clomipramine The creation of novel drugs requires large volumes of capital, 8. Desmopressin alongside extensive experimentation and testing, comprising 9. Digoxin the pioneer identification of identifiable targets and corrobora- 10.
    [Show full text]
  • Antiproliferative and Proapoptotic Activities of Anthocyanin and Anthocyanidin Extracts from Blueberry Fruits on B16-F10 Melanoma Cells
    FOOD & NUTRITION RESEARCH, 2017 VOL. 61, 1325308 https://doi.org/10.1080/16546628.2017.1325308 ORIGINAL ARTICLE Antiproliferative and proapoptotic activities of anthocyanin and anthocyanidin extracts from blueberry fruits on B16-F10 melanoma cells Erlei Wanga, Yanjun Liua, Caina Xub and Jingbo Liua aCollege of Food Science and Engineering, Jilin University, Changchun, Jilin, PR China; bKey Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, PR China ABSTRACT ARTICLE HISTORY Background: Anthocyanins have been proven to affect multiple cancer-associated processes in Received 29 January 2017 different cancer cell lines. However, relatively few studies have investigated the effects of blueberry Accepted 26 April 2017 anthocyanins on metastatic melanoma. Thus, this study focuses on evaluating the chemopreventive KEYWORDS potential of blueberry anthocyanins and their aglycones (anthocyanidins) in B16-F10 melanoma cells. Blueberry; anthocyanins; Methods: Blueberry anthocyanin and anthocyanidin extracts were prepared mainly by combined anthocyanidins; cell chromatography techniques. Their antiproliferative and proapoptotic effects on B16-F10 cells apoptosis; cell cycle were evaluated by MTT assay, calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) staining, and flow cytometry of the cell cycle and apoptosis. Results: The MTT and calcein-AM/PI staining results showed that both anthocyanin (purity of 62.5%) and anthocyanidin (75.1%) extracts could significantly inhibit the viability and proliferation of B16- F10 cells in a dose-dependent manner, while anthocyanidin extracts exhibited significantly higher (p < 0.05) cytotoxicity than anthocyanin extracts. Furthermore, anthocyanin and anthocyanidin extracts blocked cell cycle procession at the G0/G1 phase below 400 and 200 μg/mL, and induced early apoptosis below 400 and 300 μg/mL, respectively.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Annexes to the Annual Report of the European Medicines Agency 2014
    Annexes to the annual report of the European Medicines Agency 2014 Table of contents Annex 1 – Members of the Management Board ............................................................................. 2 Annex 2 – Members of the Committee for Medicinal Products for Human Use ................................... 4 Annex 3 – Members of the Pharmacovigilance Risk Assessment Committee ...................................... 6 Annex 4 – Members of the Committee for Medicinal Products for Veterinary Use ............................... 8 Annex 5 – Members of the Committee on Orphan Medicinal Products ............................................ 10 Annex 6 – Members of the Committee on Herbal Medicinal Products .............................................. 12 Annex 07 – Committee for Advanced Therapies .......................................................................... 14 Annex 8 – Members of the Paediatric Committee ........................................................................ 16 Annex 9 – Working parties and working groups .......................................................................... 18 Annex 10 – CHMP opinions in 2014 on medicinal products for human use ...................................... 22 Annex 11 – CVMP opinions in 2014 on medicinal products for veterinary use .................................. 36 Annex 12 – COMP opinions in 2014 on designation of orphan medicinal products ............................ 41 Annex 13 – HMPC European Union herbal monographs in 2014....................................................
    [Show full text]
  • Sildenafil Increases Chemotherapeutic Efficacy of Doxorubicin in Prostate
    Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction Anindita Dasa,1, David Durranta, Clint Mitchellb, Eric Maytona, Nicholas N. Hokea, Fadi N. Sallouma, Margaret A. Parkb, Ian Qureshia, Ray Leeb, Paul Dentb, and Rakesh C. Kukrejaa,1 aDivision of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Pauley Heart Center and bDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University Medical Center, Richmond, VA 23298 Edited* by Herbert Weissbach, Florida Atlantic University, Boca Raton, FL, and approved August 17, 2010 (received for review May 25, 2010) We have shown that the potent phosphodiesterase-5 (PDE-5) enocarcinoma, bladder squamous carcinoma, and lung cancers inhibitor sildenafil (Viagra) induces a powerful effect on reduction (15–17), suggesting its potential role in controlling tumor cell of infarct size following ischemia/reperfusion injury and improve- growth and death. Sildenafil and vardenafil suppress tumor cell ment of left ventricular dysfunction in the failing heart after growth and induce caspase-dependent apoptosis in B-cell chronic myocardial infarction or doxorubicin (DOX) treatment. In the present lymphatic leukemia (18, 19). Another PDE-5 inhibitor, exisulind study, we further investigated the potential effects of sildenafilon (sulindac sulfone), and its higher affinity analogs also induce ap- improving antitumor efficacy of DOX in prostate cancer. Cotreat- optosis and inhibit cell proliferation in colon tumor cells lines by ment with sildenafil enhanced DOX-induced apoptosis in PC-3 and activating PKG and phosphorylation of β-catenin (20). These DU145 prostate cancer cells, which was mediated by enhanced gen- compounds also inhibit growth and induce apoptosis in several eration of reactive oxygen species, up-regulation of caspase-3 and human prostate cancer cell lines and prostate cancer xenografts in caspase-9 activities, reduced expression of Bcl-xL, and phosphoryla- nude mice (21–23).
    [Show full text]
  • Low-Dose Anti-Inflammatory Combinatorial Therapy Reduced Cancer Stem Cell Formation in Patient-Derived Preclinical Models for Tumour Relapse Prevention
    Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Khoo, Bee Luan, Gianluca Grenci, Joey Sze Yun Lim et al. "Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention." British Journal of Cancer (February 2019) 120:407-423 © 2019, The Author(s). As Published https://dx.doi.org/10.1038/s41416-018-0301-9 Version Final published version Citable link https://hdl.handle.net/1721.1/125700 Terms of Use Creative Commons Attribution 4.0 International license Detailed Terms https://creativecommons.org/licenses/by/4.0/ www.nature.com/bjc ARTICLE Translational Therapeutics Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention Bee Luan Khoo1, Gianluca Grenci2,3, Joey Sze Yun Lim1, Yan Ping Lim4, July Fong5, Wei Hseun Yeap6, Su Bin Lim3,7, Song Lin Chua8, Siew Cheng Wong6, Yoon-Sim Yap9, Soo Chin Lee10,11, Chwee Teck Lim1,2,3,12 and Jongyoon Han1,13 BACKGROUND: Emergence of drug-resistant cancer phenotypes is a challenge for anti-cancer therapy. Cancer stem cells are identified as one of the ways by which chemoresistance develops. METHOD: We investigated the anti-inflammatory combinatorial treatment (DA) of doxorubicin and aspirin using a preclinical microfluidic model on cancer cell lines and patient-derived circulating tumour cell clusters. The model had been previously demonstrated to predict patient overall prognosis.
    [Show full text]
  • I Regulations
    23.2.2007 EN Official Journal of the European Union L 56/1 I (Acts adopted under the EC Treaty/Euratom Treaty whose publication is obligatory) REGULATIONS COUNCIL REGULATION (EC) No 129/2007 of 12 February 2007 providing for duty-free treatment for specified pharmaceutical active ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation and specified products used for the manufacture of finished pharmaceuticals and amending Annex I to Regulation (EEC) No 2658/87 THE COUNCIL OF THE EUROPEAN UNION, (4) In the course of three such reviews it was concluded that a certain number of additional INNs and intermediates used for production and manufacture of finished pharmaceu- ticals should be granted duty-free treatment, that certain of Having regard to the Treaty establishing the European Commu- these intermediates should be transferred to the list of INNs, nity, and in particular Article 133 thereof, and that the list of specified prefixes and suffixes for salts, esters or hydrates of INNs should be expanded. Having regard to the proposal from the Commission, (5) Council Regulation (EEC) No 2658/87 of 23 July 1987 on the tariff and statistical nomenclature and on the Common Customs Tariff (1) established the Combined Nomenclature Whereas: (CN) and set out the conventional duty rates of the Common Customs Tariff. (1) In the course of the Uruguay Round negotiations, the Community and a number of countries agreed that duty- (6) Regulation (EEC) No 2658/87 should therefore be amended free treatment should be granted to pharmaceutical accordingly, products falling within the Harmonised System (HS) Chapter 30 and HS headings 2936, 2937, 2939 and 2941 as well as to designated pharmaceutical active HAS ADOPTED THIS REGULATION: ingredients bearing an ‘international non-proprietary name’ (INN) from the World Health Organisation, specified salts, esters or hydrates of such INNs, and designated inter- Article 1 mediates used for the production and manufacture of finished products.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub
    US 20090226431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub. Date: Sep. 10, 2009 (54) TREATMENT OF CANCER AND OTHER Publication Classification DISEASES (51) Int. Cl. A 6LX 3/575 (2006.01) (76)76) InventorInventor: Nabilabil Habib,Habib. Beirut (LB(LB) C07J 9/00 (2006.01) Correspondence Address: A 6LX 39/395 (2006.01) 101 FEDERAL STREET A6IP 29/00 (2006.01) A6IP35/00 (2006.01) (21) Appl. No.: 12/085,892 A6IP37/00 (2006.01) 1-1. (52) U.S. Cl. ...................... 424/133.1:552/551; 514/182: (22) PCT Filed: Nov.30, 2006 514/171 (86). PCT No.: PCT/US2O06/045665 (57) ABSTRACT .."St. Mar. 6, 2009 The present invention relates to a novel compound (e.g., 24-ethyl-cholestane-3B.5C,6C.-triol), its production, its use, and to methods of treating neoplasms and other tumors as Related U.S. Application Data well as other diseases including hypercholesterolemia, (60) Provisional application No. 60/741,725, filed on Dec. autoimmune diseases, viral diseases (e.g., hepatitis B, hepa 2, 2005. titis C, or HIV), and diabetes. F2: . - 2 . : F2z "..., . Cz: ".. .. 2. , tie - . 2 2. , "Sphagoshgelin , , re Cls Phosphatidiglethanolamine * - 2 .- . t - r y ... CBs .. A . - . Patent Application Publication Sep. 10, 2009 Sheet 1 of 16 US 2009/0226431 A1 E. e'' . Phosphatidylcholine. " . Ez'.. C.2 . Phosphatidylserias. * . - A. z' C. w E. a...2 .". is 2 - - " - B 2. Sphingoshgelin . Cls Phosphatidglethanglamine Figure 1 Patent Application Publication Sep. 10, 2009 Sheet 2 of 16 US 2009/0226431 A1 Chile Phosphater Glycerol Phosphatidylcholine E.
    [Show full text]
  • Customs Tariff - Schedule
    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2019 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, UST, following to be employed in commercial fishing or the commercial MT, MUST, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.
    [Show full text]
  • Recommendations for Scientific Research & Prevention Program (SRPP) Committees
    Recommendations for Scientific Research & Prevention Program (SRPP) Committees Scientific Review Council Ad Hoc Members • Andrea Califano, Ph.D. • X. Shirley Liu, Ph.D. Product Development Research Peer Review Panels • Michael Cheng, MD • Arnab Ghosh, MD, PhD • Mickey C-T. Hu, MS, PhD • Rachel Humphrey, MD • Walter Stadler, MD, FACP • Neil Vasan, MD, PhD OMB No. 0925-0001 and 0925-0002 (Rev. 3/2020 Approved Through 02/28/2023) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: ANDREA CALIFANO eRA COMMONS USER NAME: CALIFANOA POSITION TITLE: Clyde and Helen Wu Professor of Chemical and Systems Biology, Departments of Systems Biology, Biochemistry & Molecular Biophysics, Biomedical Informatics, and Medicine EDUCATION/TRAINING Completion DEGREE INSTITUTION AND LOCATION Date FIELD OF STUDY University of Florence, Italy Equiv B.S. 05/1982 Physics University of Florence, Italy Laurea 04/1985 Physics Istituto Nazionale di Ottica, Florence Res. Assoc. 07/1986 Physics Massachusetts Institute of Technology, MA Post-doc 03/1986 Information Mechanics A. Personal Statement I am the Clyde and Helen Wu Professor of Chemical and Systems Biology and the founding Chair of the Department of Systems Biology at Columbia University. I was trained as a physicist and have applied physics- based approaches, including extensive use of information theory, to reverse engineering and interrogation of gene regulatory networks. I have pioneered use of mammalian networks as models for the quantitative analysis of cancer related phenotypes and for identification of driver genes, driver mutations, and small-molecule modulators of tumor vulnerabilities.
    [Show full text]