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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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  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
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  • The Extracellular Matrix: an Accomplice in Gastric Cancer Development and Progression
    cells Review The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression Ana Margarida Moreira 1,2,3, Joana Pereira 1,2,4, Soraia Melo 1,2,4 , Maria Sofia Fernandes 1,2, Patrícia Carneiro 1,2 , Raquel Seruca 1,2,4 and Joana Figueiredo 1,2,* 1 Epithelial Interactions in Cancer Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; [email protected] (A.M.M.); [email protected] (J.P.); [email protected] (S.M.); [email protected] (M.S.F.); [email protected] (P.C.); [email protected] (R.S.) 2 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal 3 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal 4 Medical Faculty, University of Porto, 4200-319 Porto, Portugal * Correspondence: jfi[email protected]; Tel.: +351-220408800; Fax: +351-225570799 Received: 15 January 2020; Accepted: 6 February 2020; Published: 8 February 2020 Abstract: The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies.
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  • Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
    antibodies Review Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients Andrew T. Lucas 1,2,3,*, Ryan Robinson 3, Allison N. Schorzman 2, Joseph A. Piscitelli 1, Juan F. Razo 1 and William C. Zamboni 1,2,3 1 University of North Carolina (UNC), Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; [email protected] (J.A.P.); [email protected] (J.F.R.); [email protected] (W.C.Z.) 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-966-5242; Fax: +1-919-966-5863 Received: 30 November 2018; Accepted: 22 December 2018; Published: 1 January 2019 Abstract: The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution.
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  • The Evolution of Antibodies Into Versatile Tumor-Targeting Agents
    Vol. 11, 129–138, January 1, 2005 Clinical Cancer Research 129 The Evolution of Antibodies into Versatile Tumor-Targeting Agents Michael Z. Lin,1 Michael A. Teitell,2 cancer is an old idea, often credited to Paul Ehrlich and William 1 Coley over 100 years ago, a time that predates our understanding and Gary J. Schiller of the cellular and molecular components of the immune system. 1 2 Departments of Medicine and Pathology and Laboratory Medicine, It was the elucidation of mechanisms of immunity and the David Geffen School of Medicine at University of California at introduction of a theory of cancer immunosurveillance by Lewis Los Angeles, Los Angeles, California Thomas and MacFarlane Burnet in the 1960s, however, that gave rise to the modern concept of using the adaptive immune system ABSTRACT to recognize and eliminate tumor cells whereas sparing normal In recent years, monoclonal antibodies have become tissue. After decades of waxing and waning interest, the idea of important weapons in the arsenal of anticancer drugs, and in immunotherapy has recently achieved widespread acceptance select cases are now the drugs of choice due to their favor- (1), in large part owing to the successful introduction within the able toxicity profiles. Originally developed to confer passive last decade of antibody-based cancer therapies into the clinic. immunity against tumor-specific antigens, clinical uses of Having accumulated several years of experience with anticancer monoclonal antibodies are expanding to include growth fac- antibodies, researchers are now in a position evaluate these first tor sequestration, signal transduction modulation, and tumor- examples of immunotherapeutic drugs, looking back to relate specific drug delivery.
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  • Ontario Drug Benefit Formulary Edition 43
    Ministry of Health and Long-Term Care Ontario Drug Benefit Formulary/Comparative Drug Index Edition 43 Drug Programs Policy and Strategy Branch Ontario Public Drug Programs Ministry of Health and Long-Term Care Effective February 28, 2018 Visit Formulary Downloads: Edition 43 Table of Contents Part I Introduction ....................................................................................................... I.1 Part II Preamble .......................................................................................................... II.1 Part III-A Benefits List ........................................................................................... III-A.1 Part III-B Off-Formulary Interchangeable Drugs (OFI) ........................................ III-B.1 Part IV Section Currently Not In Use ......................................................................... IV Part V Index of Pharmacologic-Therapeutic Classification .................................... V.1 Part VI-A Facilitated Access - HIV/AIDS .............................................................. VI-A.1 Part VI-B Facilitated Access - Palliative Care ..................................................... VI-B.1 Part VI-C Temporary Facilitated Access - Rheumatology ................................. VI-C.1 Part VII Trillium Drug Program ................................................................................ VII.1 Part VIII Exceptional Access Program (EAP) ........................................................ VIII.1 Part IX-A Nutrition Products ................................................................................
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  • Etude Des Résistances Adaptatives Aux Inhibiteurs De Tyrosine Kinase De L’EGFR Dans Les Cancers Bronchiques
    Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 3 Licence CC BY-NC-ND 3.0 Liste des enseignants Le 1er septembre 2019 PROFESSEURS : BATTU Serge CHIMIE ANALYTIQUE CARDOT Philippe CHIMIE ANALYTIQUE ET BROMATOLOGIE DESMOULIERE Alexis PHYSIOLOGIE DUROUX Jean-Luc BIOPHYSIQUE,
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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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  • The Role of Biological Therapy in Metastatic Colorectal Cancer After First-Line Treatment: a Meta-Analysis of Randomised Trials
    REVIEW British Journal of Cancer (2014) 111, 1122–1131 | doi: 10.1038/bjc.2014.404 Keywords: colorectal; biological; meta-analysis The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials E Segelov1, D Chan*,2, J Shapiro3, T J Price4, C S Karapetis5, N C Tebbutt6 and N Pavlakis2 1St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2052, Australia; 2Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; 3Monash University and Cabrini Hospital, Melbourne, VIC 3800, Australia; 4The Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA 5011, Australia; 5Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, SA, 5042, Australia and 6Austin Health, VIC 3084, Australia Purpose: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. Methods: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. Results: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82–0.91, Po0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67–0.74, Po0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03–2.78, Po0.00001).
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  • IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer
    cancers Article IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer Mai Badarni 1,2, Manu Prasad 1,2 , Artemiy Golden 3, Baisali Bhattacharya 1,2, Liron Levin 4,5, Ksenia M. Yegodayev 1,2, Orr Dimitstein 2,6, Ben-Zion Joshua 2,7, Limor Cohen 1,2, Ekaterina Khrameeva 3, Dexin Kong 8 , Angel Porgador 1,2, Alex Braiman 1,2, Jennifer R. Grandis 9, Barak Rotblat 5,10,* and Moshe Elkabets 1,2,* 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] (M.B.); [email protected] (M.P.); [email protected] (B.B.); [email protected] (K.M.Y.); [email protected] (L.C.); [email protected] (A.P.); [email protected] (A.B.) 2 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] (O.D.); [email protected] (B.-Z.J.) 3 Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia; [email protected] (A.G.); [email protected] (E.K.) 4 Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] 5 The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel 6 Department of Otolaryngology—Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva 84105, Israel 7 Citation: Badarni, M.; Prasad, M.; Department of Otorhinolaryngology and Head & Neck Surgery, Barzilay Medical Center, Ashkelon 7830604, Israel Golden, A.; Bhattacharya, B.; Levin, 8 School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China; [email protected] L.; Yegodayev, K.M.; Dimitstein, O.; 9 Department of Otolaryngology—Head and Neck Surgery, University of California San Francisco, Joshua, B.-Z.; Cohen, L.; Khrameeva, San Francisco, CA 94143, USA; [email protected] E.; et al.
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  • Deciphering Molecular Mechanisms and Prioritizing Therapeutic Targets in Cardio-Oncology
    Figure 1. This is a pilot view to explore the potential of EpiGraphDB to inform us about proteins that are linked to the pathophysiology of cancer and cardiovascular disease (CVD). For each cancer type (pink diamonds), we searched for cancer related proteins (light blue circles) that interact with other proteins identified as protein quantitative trait loci (pQTLs) for CVD (red diamonds for pathologies, orange triangles for risk factors). These pQTLs can be acting in cis (solid lines) or trans-acting (dotted lines). Proteins can interact either directly, a protein-protein interaction (dotted blue edges), or through the participation in the same pathway (red parallel lines). Shared pathways are represented with blue hexagons. We also queried which of these proteins are targeted by existing drugs. We found that the cancer drug cetuximab (yellow circle) inhibits EGFR. Other potential drugs are depicted in light brown hexagonal meta-nodes that are detailed below. Deciphering molecular mechanisms and prioritizing therapeutic targets in cardio-oncology Pau Erola1,2, Benjamin Elsworth1,2, Yi Liu2, Valeriia Haberland2 and Tom R Gaunt1,2,3 1 CRUK Integrative Cancer Epidemiology Programme; 2 MRC Integrative Epidemiology Unit, University of Bristol; 3 The Alan Turing Institute Cancer and cardiovascular disease (CVD) make by far the immense What is EpiGraphDB? contribution to the totality of human disease burden, and although mortality EpiGraphDB is an analytical platform and graph database that aims to is declining the number of those living with the disease shows little address the necessity of innovative and scalable approaches to harness evidence of change (Bhatnagar et al., Heart, 2016).
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  • Protocol Supplementary
    Optimal Pharmacological Management and Prevention of Glucocorticoid-Induced Osteoporosis (GIOP) Protocol for a Systematic Review and Network Meta-Analysis Supplementary Materials: Sample Search Strategy Supplementary 1: MEDLINE Search Strategy Database: OVID Medline Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present Line 1 exp Osteoporosis/ 2 osteoporos?s.ti,ab,kf. 3 Bone Diseases, Metabolic/ 4 osteop?eni*.ti,ab,kf. 5 Bone Diseases/ 6 exp Bone Resorption/ 7 malabsorption.ti,ab,kf. 8 Bone Density/ 9 BMD.ti,ab,kf. 10 exp Fractures, Bone/ 11 fracture*.ti,ab,kf. 12 (bone* adj2 (loss* or disease* or resorption* or densit* or content* or fragil* or mass* or demineral* or decalcif* or calcif* or strength*)).ti,ab,kf. 13 osteomalacia.ti,ab,kf. 14 or/1-13 15 exp Glucocorticoids/ 16 exp Steroids/ 17 (glucocorticoid* or steroid* or prednisone or prednisolone or hydrocortisone or cortisone or triamcinolone or dexamethasone or betamethasone or methylprednisolone).ti,ab,kf. 18 or/15-17 19 14 and 18 20 ((glucocorticoid-induced or glucosteroid-induced or corticosteroid-induced or glucocorticosteroid-induced) adj1 osteoporos?s).ti,ab,kf. 21 19 or 20 22 exp Diphosphonates/ 23 (bisphosphon* or diphosphon*).ti,ab,kf. 24 exp organophosphates/ or organophosphonates/ 25 (organophosphate* or organophosphonate*).ti,ab,kf. 26 (alendronate or alendronic acid or Fosamax or Binosto or Denfos or Fosagen or Lendrate).ti,ab,kf. 27 (Densidron or Adrovance or Alenotop or Alned or Dronat or Durost or Fixopan or Forosa or Fosval or Huesobone or Ostemax or Oseolen or Arendal or Beenos or Berlex or Fosalen or Fosmin or Fostolin or Fosavance).ti,ab,kf.
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