
Phenotypic and Biomarker-Based Drug Discovery
Tuesday, October 27, 2015
Phenotypic screening programs were the mainstay of target-based drug discovery and development until the 1980s. While over half of the compounds approved by the FDA between 1999 and 2008 were derived from phenotypic screening programs, recent challenges have shown the limitations of target- or pathway-based drug discovery, and this method of drug discovery struggles to gain acceptance. Many investigators are now revisiting the strategy of finding effective compounds using unbiased disease models, then using these effectors to identify a relevant drug target.
This symposium aims to deepen the level of scientific understanding behind phenotypic drug discovery and to foster the exchange of ideas between industry and academic research scientists. In this symposium, we will explore current strategies enabling phenotypic drug discovery to become more mainstream. We will discuss the ability of stem cell-based and -omics technologies to create highly relevant disease model systems in vitro. We will also discuss successful approaches to effectively identify specific targets to the effectors discovered using this strategy. Specific case studies will highlight notable successes in this approach.
*Reception to follow.
This event will also be broadcast as a webinar.
Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.
Registration and Webinar Pricing
Member | $30 |
Student / Postdoc Member | $15 |
Nonmember (Academia) | $65 |
Nonmember (Corporate) | $85 |
Nonmember (Non-profit) | $65 |
Nonmember (Student / Postdoc / Resident / Fellow) | $45 |
The Biochemical Pharmacology Discussion Group is proudly supported by
American Chemical Society
Agenda
* Presentation times are subject to change.
Tuesday, October 27, 2015 | |
8:00 AM | Registration and Continental Breakfast |
8:45 AM | Introductory Remarks |
9:00 AM | Phenotypic Drug Discovery: Take Two |
9:10 AM | Identifying Subtype-selective Vulnerabilities in Non-small Cell Lung Cancer Using Phenotypic Screening |
9:40 AM | Using the Library of Integrated Network-based Cellular Signatures (LINCS) to Characterize the Mechanism of Action of Small-molecule Therapeutics |
10:10 AM | Networking Coffee Break |
10:40 AM | Phenotypic Drug Discovery at AstraZeneca |
11:10 AM | Target Hypothesis Generation and Validation for PTS Hits Using Target Space Annotations |
Young Investigator and Data Blitz PresentationsModerator: Jonathan A. Lee, PhD, Eli Lilly | |
11:40 AM | Systematic, Master-Regulator-Based Assessment of Compound Activity in Human Malignancies |
12:00 PM | Identification of GPR31 as a Novel Mediator of Kras Membrane-Association and Kras-Driven Oncogenesis |
12:05 PM | Direct Targets Identification of a Bioactive Compound Using Chemical Biology |
12:10 PM | Phenotypic Screening Assays for the Discovery of SREBP Activation Inhibitors |
12:15 PM | Networking Lunch and Poster Session |
1:30 PM | High-Content, Full Genome siRNA Screen for Regulators of Oncogenic H-Ras Driven Macropinocytosis |
2:00 PM | High-power Phenotyping and Target Deconvolution by Pharmacoscopy and Thermal Shiftome |
2:30 PM | High Content Screening of Patient Derived Cells: Balancing Biological Relevance with Throughput |
3:00 PM | Networking Coffee Break |
3:20 PM | Phenotypic Drug Discovery in Spinal Muscular Atrophy Disease: Parallel Efforts in Preclinical Development and Target Identification |
3:40 PM | Spinal Muscular Atrophy: Screening for Molecular Phenotypes to Identify a Disease-Modifying Therapy |
4:00 PM | Pathway Reporter Genes Define Molecular Phenotypes of Human Cells—Application to Compound Screening and Prioritization |
4:20 PM | Q&A |
4:50 PM | Poster Prize Awards and Closing Remarks |
5:00 PM | Networking Reception |
Speakers
Organizers
Michael Foley, PhD
Tri-Institutional Therapeutics Discovery Institute
Dr. Foley is an accomplished chemist and entrepreneur with more than 25 years of industry and academic experience. He has been scientific co-founder of four companies and one academic institute and has placed twelve single agent or combination drugs into clinical development. He was most recently the Director of the Chemical Biology Platform at the Broad Institute of Harvard and MIT, which successfully established over 150 high throughput screening development collaborations under his leadership. Dr. Foley previously worked at Bristol-Myers Squibb and GlaxoSmithKline, and obtained his PhD in chemistry at Harvard.
Ralph Garippa, PhD
Memorial Sloan Kettering Cancer Center
Ralph J. Garippa is the Director of the RNAi and Gene Editing Core Facility at MSKCC and interim Head of the HTS/HCS Core. His RNAi group develops protocols in the design and execution of loss-of-function screens, provides consultation in the areas of RNAi library design, vector construction, CRISPR Cas9 knockout protocols, and data management. The HTS Core curates a collection of ~350,000 small molecules and performs screens using 384/1536 well formats via plate readers and high content microscopy. Dr. Garippa is the former Head of Cell-Based High Throughput Screening (HTS) and Microscopic Imaging-based High Content Screening (HCS) at Hoffmann-La Roche’s Nutley NJ facility from 1998-2008. Additionally, he was central member of a task force which explored the rollout of the Research-Based Stem Cells at Roche, with academic and industrial partners including Harvard University, Massachusetts General Hospital, and The Hebrew University in Israel. He also participated in the Therapeutic Stem Cell Task Force, investigating corporate opportunities with allogeneic and autologous mesenchymal stem cells (MSCs). From 1982 to 1998, he served in various positions at Roche, including pre-clinical Project Manager in Metabolic Diseases (1994-1998) and Laboratory Leader in Bronchopulmonary Pharmacology (1986-1992). He was also involved with the NIH’s Small Molecule Repository (SMR) probe screening effort, as an ad hoc scientific advisor, since the project’s inception. Dr. Garippa holds a PhD in Pharmacology from Columbia University in New York City (where he studied with Drs. Fred Maxfield and Tim McGraw) and a BA degree in Biology from Fairleigh Dickinson University in New Jersey (where he studied developmental biology in the axolotl, Ambystoma mexicanum with Dr Gervasia Schreckenberg).
David Mark, PhD
F. Hoffmann-La Roche, Ltd.
David joined Hoffmann-La Roche at Nutley, New Jersey in 1999 as Head of Assay Development and High Throughput Screening. He was the Deputy Site Head of Discovery Technologies at the Nutley site until its closure in 2013. During his tenure in Nutley, he introduced high content cell imaging technology to Roche and established a group to apply this technology in high throughput phenotypic screening of small molecule libraries. David had ten additional years of assay development and screening experience at Merck & Co. where he was responsible for a major portion of the Natural Products Discovery Program, including the Assay Development group in Rahway, New Jersey and the Natural Product Screening group in Madrid, Spain. David also had ten years of drug discovery experience at Cetus Corporation, where he participated in the discovery and development of two protein therapeutics: Betaseron and Proleukin. David received his PhD in Biochemistry from Harvard University in 1977, and was a postdoctoral fellow at Stanford University Medical Center, Department of Biochemistry in the laboratory of Dr. Paul Berg (1977-79). David has published over 30 papers and holds 19 patents and is the recipient of several awards.
Lorenz Mayr, PhD
Astra Zeneca
Lorenz is working since September 2012 as Vice President, Reagents & Assay Development with global responsibility for generation of biological reagents and assay development activities at AstraZeneca. This includes generation of proteins and cell lines for hit finding, hit-to-lead and lead optimisation activities including structure & biophysics activities across all therapeutic areas, the generation of tool antibodies, transgenic animals, stem cells and primary cells as tools for target validation studies and lead optimisation programmes. His department in the UK and Sweden is responsible for assay development activities for biochemical, cell-based and phenotypic assays for all therapeutic areas at AstraZeneca. Before that, he has been working as Executive Director at Novartis Pharma in Basel/Switzerland, at Bayer Pharma Research in Wuppertal/Germany, at Bayer Central Research in Leverkusen/ Germany and at the M.I.T./Whitehead Institute in Cambridge/Massachusetts (U.S.A.). He has published more than 50 papers in peer-reviewed journals and serves on several editorial and scientific advisory boards, including two terms at the Board of Directors for the Society of Biomolecular Sciences (2004-2011) and working as the Conference Chair of the MipTec Drug Discovery Conference, Europe’s largest drug discovery event, held in Basel/Switzerland.
John Moffat, PhD
Genentech
Marco Prunotto, PhD
F. Hoffmann-La Roche Ltd.
Sonya Dougal, PhD
The New York Academy of Sciences
Speakers
Andras J. Bauer, PhD, PharmD
Boehringer Ingelheim USA
Andras Bauer received his PharmD in 2003 from Semmelweis University and in 2004 started working in the laboratory of Dr. Brent Stockwell at Columbia University where he focused on rational drug design directed against protein-protein interactions and characterizing the mechanism of action of the genotype-selective lethal compound erastin. Upon being awarded his PhD in Biology in 2011 he became a presidential post-doctoral fellow at the Novartis Institute for Biomedical Research in Cambridge Massachusetts, where he worked on developing a platform for label-free target identification of bioactive small molecules. He is currently a Senior Scientist, Immunology and Respiratory at Boehringer Ingelheim involved in drug concept discovery and leveraging chemical biology approaches for early drug concept validation and target identification of phenotypic screening hits.
Myles Fennell, PhD
Memorial Sloan-Kettering Cancer Center
Myles Fennell has been a Senior Research Scientist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY since 2013. He is currently responsible for developing and running RNAi, CRISPR and small molecule screens in both arrayed and pooled formats using a variety of technologies including high-content screening, FACS and next-generation sequencing. After receiving his PhD from the University of Edinburgh he went on to hold positions at Wyeth Neuroscience, Bristol Myers-Squibb and Gigacyte. His experience in high-content screening has been pivotal in developing novel image based screens for researchers at MSKCC and other institutions. Areas of impact include the development of HCS synaptogenesis and neurodegeneration assays, tumor organoid 3D models, as well as cellular physiology and signaling.
Michael R. Jackson, PhD
Sanford Burnham Prebys Medical Discovery Institute
Dr. Jackson is responsible for the operations of the Prebys Center, a multidisciplinary Drug Discovery enterprise focused on identifying and developing transformational new drugs to address unmet medical needs. The overall mission of the Center is to generate a pipeline of first-in-class drugs based on breakthrough research conducted by investigators at the Sanford Burnham Prebys Medical Discovery Institute (SBP) as well as external collaborators. Prior to joining SBP in 2009, Dr. Jackson spent 15 years at Johnson & Johnson developing a track record of managing large research and development organizations. Under his leadership many novel drugs were advanced to the clinic, and several drug delivery products successfully gained regulatory approval. He received his PhD from the Department of Biochemistry at the University of Dundee in Scotland and completed his post-doctoral training at The Scripps Research Institute.
Jonathan A. Lee, PhD
Eli Lilly
Dr. Lee is scientific leader in the pharmaceutical industry with a history of identifying/enabling innovative technologies/strategies and integrating them into the drug discovery process. Scientific background includes targeted and phenotypic drug discovery, high content cellular imaging, functional genomics, primary and stem cell-based assay development and screening, project management, and early discovery portfolio review. Dr. Lee was scientific initiator of the PD2 Initiative, a collaborative Lilly venture where compounds from academic and biotech institutes are tested in Lilly’s phenotypic assay platform in a manner where external collaborators receive test results free of charge and retain intellectual property. Jonathan is a recognized thought leader in phenotypic drug discovery and has networked with the global research community through creation of a LinkedIn discussion group, organizing/editing (with Ellen Berg) special issues, and through multiple invited lectures on phenotypic drug discovery.
Martin Main, PhD
AstraZeneca
Martin Main leads the Reagents & Assay Development UK department at AstraZeneca, which operates out of Alderley Park and Cambridge. An ion channel electrophysiologist by training, Martin has worked in the pharmaceutical industry for 20 years, at Merck, GlaxoSmithKline and AstraZeneca. The remit of Martin’s department is to generate the reagents & tools that drive innovative drug discovery projects: proteins, cells, antibodies, biochemical & cellular assays and experimental data-sets are developed in close collaboration with project teams, with a focus on Oncology and Neuroscience targets.
Friedrich Metzger, PhD
F. Hoffmann-La Roche Ltd.
Friedrich Metzger is Head of Discovery in Rare Diseases at Roche, where he is responsible for developing and leading a portfolio of discovery projects that aim to treat rare genetic disorders with high unmet medical need. He has studied Biology at the Universities of Freiburg and Tübingen, Germany, where he received a PhD degree in pharmacology in 1996. After Post-Docs in Würzburg and Freiburg, Germany, where he did research in the field of rare neuromuscular disorders Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) as well as in neuronal plasticity, he became Associate Professor at the University in Groningen, Netherlands, continuing his research on ALS. In 2002, he joined Roche, where he initiated and coordinated several drug development programs for treatment of Alzheimer’s Disease, Parkinson’s Disease, ALS, Duchenne Muscular Dystrophy (DMD) and myotonic dystrophy I (DM1). Currently, he is coordinating all preclinical aspects in the SMA program in collaboration with PTC Therapeutics and the SMA Foundation, which is in patient trials. He has his specific scientific expertise and a strong track record in rare genetic neuromuscular and neurodevelopmental disorders. In 2011, Friedrich has been appointed adjunct professor in Neurobiology at the University of Freiburg, Germany, where he teaches in neurobiology, synaptic plasticity and neurological diseases.
Bruce A. Posner, PhD
University of Texas, Southwestern Medical Center
Dr. Posner received his PhD in biochemistry with Professor Stephen Benkovic at Penn State University in 1994 and then carried out an NIH-sponsored post-doctoral fellowship with Professor Alfred G. Gilman at the University of Texas’ Southwestern Medical Center (UTSMC). Subsequently, he joined Pfizer, Inc as a Principal Scientist in the High Throughput Screening Center of Emphasis. During his 9 year tenure there, he led over 60 HTS campaigns and identified more than 20 hit-to-lead starts for early drug discovery programs. Two of these chemical series were submitted to first-in-human clinical trials. His efforts resulted in his recognition with Pfizer’s Discovery Recognition Award 2004 and subsequent promotion to Senior Principal Scientist. In 2009, he joined the biochemistry faculty at UTSMC as an associate professor and the director of the High Throughput Screening (HTS) Core. In this capacity, he leads the core facility efforts to aid in the discovery and the early stage, pre-clinical development of new small molecule therapeutics. He has co-authored over 18 publications (papers and patents) since joining UT Southwestern in 2009. His efforts at UT Southwestern have contributed to the licensing of 4 candidate small molecules to 3 pharmaceutical companies.
Yao Shen, PhD
Columbia University
Yao Shen received her PhD in Chemistry and MSc in Computer Science in 2011 from University of Notre Dame. Her PhD thesis focused on applying structural-based drug discovery techniques to predict hits for essential genes in pathogens identified using metabolic network analysis. After that, she joined the laboratory of Dr. Andrea Califano at Columbia University as a postdoc scientist, where she worked on projects involving inferring compound mode-of-action, predicting synergistic compound combinations, and reversing drug resistance using systems biology approaches.
Aravind Subramanian, PhD
Broad Institute
Aravind Subramanian is Director of Computational R&D at the Broad Institute of MIT and Harvard. He is also co-PI of the NIH-funded Center for Transcriptomics at the Broad which is part of the Library of Integrated Network-based Cellular Signatures (LINCS) program and the Big Data to Knowledge (BD2K) initiative.
As a graduate student at the Whitehead Institute for Genome Research, Dr. Subramanian helped develop Gene Set Enrichment Analysis (GSEA) - a widely cited algorithm for the interpretation of high-dimensionality genomic datasets. Dr. Subramanian extended this approach to the analysis of genome-scale pooled genetic screens for the identification of essential genes in cancer cells (RIGER).
In postdoctoral work, Dr. Subramanian collaborated with Broad Institute scientists to invent a novel approach to gene expression profiling that combines highly automated laboratory workflow with a computational framework that selects a representative subset of the transcriptome for measurement. This platform, called L1000, is now in routine use at the Broad for the Connectivity Map project and is increasingly used by the pharmaceutical industry as part of their drug discovery process.
In his current work, Dr. Subramanian leads a group of molecular biologists, software engineers and computational analysts whose efforts are directed towards developing new technologies for perturbational profiling and in using these data with pattern recognition approaches to discover relationships between genes, drugs and diseases. The group has three goals a) to construct a comprehensive reference dataset of perturbational signatures b) to develop algorithms and software to make these data and results accessible to the biomedical community and c) to engage in collaborative efforts - within academic and with industry - that leverage these resources to make biological and therapeutic discoveries.
Giulio Superti-Furga, PhD
Austrian Academy of Sciences
Giulio Superti-Furga, PhD, is Scientific Director of the Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna (CeMM), Austria and Professor of Medical Systems Biology at the Medical University of Vienna. He is an Italian citizen. He performed studies in molecular biology at the University Zurich, while doing research also at Genentech, and the IMP/Vienna. Post-doctoral fellow and Team Leader at EMBL. He co-founded and was Scientific Director of Cellzome until 2005. He later founded Haplogen. Since 2005 he directs CeMM in the middle of the general hospital campus in Vienna, where, together with some 130 scientists/medical doctors, he is trying to bring the genomic and systems-views close to the clinical world to improve medical practice. Among his major achievements to date are the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers, the discovery of fundamental organization principles of the proteome and lipidome of higher organisms, the characterization of the molecular machinery involved in innate immunity and the development of integrated approach to understand the mechanism of action of drugs at the molecular level. His work on the organization of the eukaryotic proteome is among most highly cited in the field.
Susanne Swalley, PhD
Novartis Institutes for BioMedical Research
Susanne Swalley, PhD, is an Investigator in the Developmental and Molecular Pathways department at the Novartis Institutes for Biomedical Research. Trained as a chemist, her current research focuses on biochemical and biophysical approaches to target identification. Prior to Novartis, she was a scientist at Vertex Pharmaceuticals where she contributed to a wide variety of project teams on the evaluation and screening of new targets. Susanne graduated from Amherst College with bachelor’s degrees in chemistry and music, and obtained a PhD in chemistry from the California Institute of Technology with Dr. Peter Dervan. She completed her postdoctoral training at Harvard University in the laboratories of Dr. Don Wiley and Dr. Stephen Harrison with fellowships from the Damon Runyon-Walter Winchell Cancer Research Fund and the Charles A. King Trust.
Jitao David Zhang, PhD
F. Hoffmann-La Roche Ltd.
Jitao David Zhang studied biology in Peking University, received an MSc in bioinformatics in University of Heidelberg and a PhD in computational biology and biostatistics in German Cancer Research Center, Germany. Dr. Zhang’s research focuses on modelling and integrative analysis of signaling and transcriptional networks for disease understanding and drug development.
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The Biochemical Pharmacology Discussion Group is proudly supported by
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Abstracts
Phenotypic Drug Discovery: Take Two
Jonathan A. Lee, PhD, Eli Lilly
Identifying Subtype-selective Vulnerabilities in Non-small Cell Lung Cancer Using Phenotypic Screening
Bruce A. Posner, PhD, University of Texas Southwestern Medical Center, Dallas, Texas, United States
Coauthors: Panayotis C. Theodoropoulos, BS, Stephen S. Gonzales, PhD, Sarah E. Winterton, BS, Carlos Rodriguez-Navas, PhD, Michael G. Roth, PhD, John D. Minna, MD, Michael A. White, PhD, Hamid Mirzaei, PhD, Noelle S. Williams, PhD, Joseph M. Ready, PhD, Deepak Nijhawan, PhD
University of Texas Southwestern Medical Center, Dallas, Texas, United States
Using the Library of Integrated Network-based Cellular Signatures (LINCS) to Characterize the Mechanism of Action of Small-Molecule Therapeutics
Aravind Subramanian, PhD, Broad Institute
This talk will describe the LINCS resource (data and analytical tools) and demonstrate how they are being used to characterize query signatures. Importantly, as the number of signatures has grown dramatically, it has become vital to use readouts from complementary assays including phenotypic measurements to prioritize hypothesis for laboratory testing. Analytical approaches to data integration will be described as well as a cloud-based informatics platform that allows analysis within web-browser based user interfaces and programmatic access via APIs. Finally, example applications of these resources for identification of putative gene targets by integrating readouts from small-molecules, shRNAs and CRISPRs will be described.
Systematic, Master-Regulator-Based Assessment of Compound Activity in Human Malignancies
Yao Shen, PhD1
Coauthors: Mariano J. Alvarez, PhD1, Andrea Califano, PhD1,2,3,4,5,6
1 Department of Systems Biology, Columbia University, New York, New York
2 JP Sulzberger Columbia Genome Center, Columbia University, New york, New York
3 Department of Biomedical Informatics, Columbia University, New york, New York
4 Department of Biochemistry & Molecular Biophysics, Columbia University, New york, New York
5 Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
6 Motor Neuron Center and Columbia Initiative in Stem Cells, Columbia University, New York, New York
Phenotypic Drug Discovery at AstraZeneca
Martin Main, PhD, AstraZeneca
Target Hypothesis Generation and Validation for PTS Hits using Target Space Annotations
Andras J. Bauer PhD1
Coauthors: Qiang Zhang PhD2, Jonathan Hill MSc3, Jehrod Brenneman PhD2, Charles E. Whitehurst PhD1
1 Immunology and Respiratory Therapeutic Area, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America
2 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America
3 Department of Computational Biology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States of America
High-Content, Full Genome siRNA Screen for Regulators of Oncogenic H-Ras Driven Macropinocytosis
Myles Fennell1
Coauthors: Cosimo Commisso2, Craig Ramirez3, Ralph Garippa1, Dafna Bar-Sagi3
1 RNAi & Gene Editing Core Facility, Memorial Sloan-Kettering Cancer Center, 417 East 68th Street, New York, NY 10065
2 NCI-Designated Cancer Center-Cell Death and Survival Networks Program Sanford-Burnham medical research institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037
3 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA
High-power Phenotyping and Target Deconvolution by Pharmacoscopy and Thermal Shiftome
Giulio Superti-Furga, PhD1,2
Coauthors: Snijder B, PhD1, Vladimer G, PhD1, Jeryczynski G3, Jäger, U, MD3, Gisslinger H, MD3, Rebsamen M, PhD1, César-Razquin A, MSc1, Lardeau C, MSc1,4, Colinge, J, PhD1, Bennett KL, PhD1, Kubicek S, PhD1,4, Huber KVM, PhD1
1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
2 Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
3 Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
4 Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, Vienna, Austria
High Content Screening of Patient Derived Cells: Balancing Biological Relevance with Throughput
Michael R. Jackson, PhD, Sanford Burnham Prebys Medical Discovery Institute
Phenotypic Drug Discovery in Spinal Muscular Atrophy Disease: Parallel Efforts in Preclinical Development and Target Identification
Susanne Swalley, PhD, Novartis Institutes for BioMedical Research
SMA: Screening for Molecular Phenotypes to Identify a Disease-Modifying Therapy
Friedrich Metzger, PhD, F. Hoffmann-La Roche Ltd.
Pathway Reporter Genes Define Molecular Phenotypes of Human Cells - Application to Compound Screening and Prioritization
Jitao David Zhang, PhD, F. Hoffmann-La Roche Ltd.
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