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Biochemistry, Genetics, Molecular and Cell Biology) Hit the Newspaper Headlines on a Weekly Basis
The Tenovus-Scotland Symposia and Medal Lectures Today medical advances as a result of discoveries in the Life Sciences (Biochemistry, Genetics, Molecular and Cell Biology) hit the newspaper headlines on a weekly basis. This was not the case at the time of the first Tenovus-Scotland Symposium nearly 35 years ago. Since the discovery of the structure of DNA twenty years earlier, great advances had been made in understanding, at the level of molecules, how genes work in the cell. From study of simple bacteria and viruses, it was known that the information for making all the different proteins in the cell was encoded in the sequence of nucleotides, the individual chemical units of DNA, but study of higher organisms seemed impossibly complex. The chromosomes in each human cell have about 23,000 genes in their DNA that contains a total of about three thousand million nucleotides - how would it be possible to study these genes individually? Three staff from the Biochemistry Department and the Beatson Institute planned a two day meeting at Glasgow University in 1974 to bring together scientists to discuss and learn about the new discoveries that were beginning to provide answers to that fundamental question. Sir Charles Illingworth, who had recently founded Tenovus- Scotland, saw the importance of these studies and their potential future application in medicine and agreed a grant towards the cost of the meeting, which we called the Tenovus-Scotland Symposium although the First Meeting was also jointly sponsored by the Nucleotide Group of the -
NCI RAS Initiative Update
Ras Initiative Update Frank McCormick and Levi Garraway DEPARTMENT OF HEALTH AND HUMAN SERVICES • National Institutes of Health • National Cancer Institute The Frederick National Laboratory is a Federally Funded Research and Development Center operated by Leidos Biomedical Research, Inc., for the National Cancer Institute RAS Initiative Accomplishments: Evaluating Ras dependency 2 SiREN assay for Ras dependency SiREN assay for Ras dependency 70% KD siEGFP 0-10% KD 50% KD 100% KD SiREN assay for Ras dependency RAS Initiative Accomplishments: Biophysical and structural analysis 7 Ras proteins 1 -166 167-185,6 Raf, PI 3’ kinase RalGDS, GAPs Raf, PI 3’ kinase RalGDS, GAPs Raf, PI 3’ kinase RalGDS, GAPs Raf, PI 3’ kinase RalGDS, GAPs Palmitoyl Farnesyl Fully processed KRAS4b A. Gorfe, U-Texas Houston Engineering baculovirus for improved production of processed KRAS • recombineering used to insert FNTA/FNTB genes into the baculovirus genome • eliminated issues with coinfection of multiple viruses • maltose-binding protein (MBP) fusion for greater yield and solubility • Trichoplusia ni (Hi5) insect cells for increased yield Carissa Grose, Dom Esposito, Bill Gillette Processed KRAS4b characterization • Extensive protein characterization – Purified to homogeneity; yield >7mg/L – Intact mass – Predominantly monomeric – Secondary structure equivalent to non-processed KRAS4b KRAS4b- FME – Lower thermal stability Intact mass analysis Analytical ultracentrifugation Secondary structure by CD 2.14 S 25.7 kDa 10 Bill Gillette, Zhaojing Meng, Shelley Perkins, -
Miriam Molina Arcas
CV Miriam Molina Arcas Miriam Molina Arcas Principal Laboratory Research Scientist The Francis Crick Institute 1 Midland Road, NW1 1AT London +442037963313 [email protected] EDUCATION 1999-2005 PhD in Biomedicine, University of Barcelona, Spain Role of equilibrative nucleoside transporters in the sensitivity to antineoplasic drugs. Supervisors: Prof. Marçal Pastor-Anglada and Dr. F. Javier Casado 1994-1999 BSc Biochemistry, University of Barcelona, Spain RESEARCH AND PROFESSIONAL EXPERIENCE June 2016- present Senior Laboratory Research Scientist, Oncogene Biology Laboratory, The Francis Crick Institute. Prof. Julian Downward. Studied combination approaches that improve the efficacy of KRAS inhibitors and reduce resistance mechanisms. March 2015- May 2016 Postdoctoral Fellow, Lung Cancer Team, Institute of Cancer Research. Prof. Julian Downward. Designed and optimized a whole-genome shRNA screen to identify synthetic lethal interactions with MEK and IGF1R inhibitors. Sep 2008- Feb 2015 Postdoctoral Fellow, Signal Transduction Laboratory, Cancer Research UK- London Research Institute. Prof. Julian Downward Using RNA interfering and drug screens, identified new therapeutic strategies to treat tumours harbouring KRAS mutations 2006- Aug 2008 Postdoctoral Fellow, University of Barcelona, Spain Prof. Marçal Pastor-Anglada Studied the role of membrane transporters in nucleoside-derived drug response in cancer and HIV. TEACHING AND MENTORING EXPERIENCE 2018-2021 Honorary Research Associate in the School of Life & Medical Sciences, University College London, part of the Certificate in Core Teaching Practices. 2007-2008 Part-time lecturer of Biochemistry and Molecular Biology (University of Barcelona). 180h of theory and practical lessons. 2003-2005 Teaching assistant of Biochemistry and Molecular Biology (University of Barcelona). 60h of practical lessons. September 2019 Co-supervisor of MSc Experimental Pharmacology and Therapeutics Research of Pablo Romero Clavijo at the University College London. -
Unveiling New Disease, Pathway, and Gene Associations Via Multi-Scale Neural Networks
Unveiling new disease, pathway, and gene associations via multi-scale neural networks Thomas Gaudelet 1, No¨elMalod-Dognin 2, Jon S´anchez-Valle 2, Vera Pancaldi 2,3,4, Alfonso Valencia 2,5,6 and NataˇsaPrˇzulj 2,5,∗ 1 Department of Computer Science, University College London, London, WC1E 6BT 2 Department of Life Sciences, Barcelona Supercomputing Center (BSC), Barcelona, 08034 Spain 3 Centre de Recherches en Canc´erologiede Toulouse (CRCT), UMR1037 Inserm, ERL5294 CNRS, 31037 Toulouse, France 4 University Paul Sabatier III, Toulouse, France 5 ICREA, Pg. Llu´ısCompanys 23, 08010 Barcelona, Spain 6 Coordination Node. Spanish National Bioinformatics Institute, ELIXIR-Spain (INB, ELIXIR-ES), Spain ∗ [email protected]. Abstract Diseases involve complex modifications to the cellular machinery. The gene expression profile of the affected cells contains characteristic patterns linked to a disease. Hence, new biological knowledge about a disease can be extracted from these profiles, improving our ability to diagnose and assess disease risks. This knowledge can be used for drug re-purposing, or by physicians to evaluate a patient's condition and co-morbidity risk. Here, we consider differential gene expressions obtained by microarray technology for patients diagnosed with various diseases. Based on these data and cellular multi-scale organization, we aim at uncovering disease{disease, disease{gene and disease{pathway associations. We propose a neural network with structure based on the multi- scale organization of proteins in a cell into biological pathways. We show that this model is able to correctly predict the diagnosis for the majority of patients. Through the analysis of the trained model, we predict disease{ disease, disease{pathway, and disease{gene associations and validate the predictions by comparisons to known interactions and literature search, proposing putative explanations for the predictions. -
Fellows Opted out of the Mentoring Programme As of 21 July 2020 1 of 3 Professor Chris Abell FRS Fmedsci Professor Philip Jones
Fellows opted out of the Mentoring programme as of 21 July 2020 Professor Chris Abell FRS FMedSci Professor Philip Jones FMedSci Professor David Adams FMedSci Professor Roger Jones FMedSci Professor Judith Allen FRSE FMedSci Professor Kamlesh Khunti FMedSci Professor Thomas Kirkwood CBE Professor Desmond Archer OBE FMedSci FMedSci Professor Louise Arseneault FMedSci Professor Robb Krumlauf FMedSci Professor Charalambos Kyriacou Professor Michael Arthur FMedSci FMedSci Professor Deborah Ashby OBE FMedSci Sir Peter Lachmann FRS FMedSci Professor Dame Frances Ashcroft DBE Professor Leon Lagnado FMedSci FRS FMedSci Professor Anthony Barrett FRS FMedSci Professor Ajit Lalvani FMedSci Professor Gillian Bates FRS FMedSci Professor Deborah Lawlor CBE FMedSci Professor Facundo Batista FMedSci Professor Joy Lawn FMedSci Professor Stephan Beck FMedSci Professor Susan Lea FMedSci Professor Jill Belch OBE FMedSci Professor Sir Robert Lechler PMedSci Professor Sir John Bell GBE FRS Dr Melanie Lee CBE FMedSci HonFREng FMedSci Professor Wendy Bickmore FRS FRSE Professor Andrew Lees FMedSci FMedSci Professor Sir Adrian Bird CBE FRS FRSE Professor Stafford Lightman FRS FMedSci FMedSci Professor Ewan Birney CBE FRS Professor Janet Lord FMedSci FMedSci Professor Dorothy Bishop FRS FBA Professor Thomas MacDonald FMedSci FMedSci Professor Rona MacKie CBE FRSE Professor Jane Blazeby FMedSci Sir Stephen Bloom FRS FMedSci Professor Giovanna Mallucci FMedSci Sir Tom Blundell FRS FMedSci Dr Fiona Marshall FMedSci Professor Dame Theresa Marteau DBE Professor Peter -
Drugging the Undruggable: Advances on RAS Targeting in Cancer
G C A T T A C G G C A T genes Review Drugging the Undruggable: Advances on RAS Targeting in Cancer Miriam Molina-Arcas 1,*, Amit Samani 1,2,* and Julian Downward 1,3 1 Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK; [email protected] 2 Department of Medical Oncology, Imperial College Healthcare NHS Trust, London W2 1NY, UK 3 Lung Cancer Group, Institute of Cancer Research, London SW3 6JB, UK * Correspondence: [email protected] (M.M.-A.); [email protected] (A.S.) Abstract: Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms. -
Happy Birthday to Renato Dulbecco, Cancer Researcher Extraordinaire
pbs.org http://www.pbs.org/newshour/updates/happy-birthday-renato-dulbecco-cancer-researcher-extraordinaire/ Happy birthday to Renato Dulbecco, cancer researcher extraordinaire Photo of Renato Dulbecco (public domain) Every elementary school student knows that Feb. 22 is George Washington’s birthday. Far fewer (if any) know that it is also the birthday of the Nobel Prize-winning scientist Renato Dulbecco. While not the father of his country — he was born in Italy and immigrated to the United States in 1947 — Renato Dulbecco is credited with playing a crucial role in our understanding of oncoviruses, a class of viruses that cause cancer when they infect animal cells. Dulbecco was born in Catanzaro, the capital of the Calabria region of Italy. Early in his childhood, after his father was drafted into the army during World War I, his family moved to northern Italy (first Cuneo, then Turin, and thence to Liguria). A bright boy, young Renato whizzed through high school and graduated in 1930 at the age of 16. From there, he attended the University of Turin, where he studied mathematics, physics, and ultimately medicine. Dulbecco found biology far more fascinating than the actual practice of medicine. As a result, he studied under the famed anatomist, Giuseppe Levi, and graduated at age 22 in 1936 at the top of his class with a degree in morbid anatomy and pathology (in essence, the study of disease). Soon after receiving his diploma, Dr. Dulbecco was inducted into the Italian army as a medical officer. Although he completed his military tour of duty by 1938, he was called back in 1940 when Italy entered World War II. -
Second RAS Initiative Symposium Sponsored by the National Cancer Institute Advanced Technology Research Facility, Frederick, MD December 6-8, 2017
The Second RAS Initiative Symposium Sponsored by the National Cancer Institute Advanced Technology Research Facility, Frederick, MD December 6-8, 2017 December 6 8:00 am – 8:15 am Welcome from the NCI Director Norman Sharpless 8:15 am – 9:00 am Keynote Frank McCormick (RAS Initiative, University of California, San Francisco) 9:00 am – 9:30 am Organoids as Model Systems for Tumorigenesis Calvin Kuo (Stanford University) 9:30 am – 9:50 am Break 9:50 am – 12:10 pm Activated RAS and Oncogenesis - Chair: Jeff Settleman Douglas Lowy (National Cancer Institute) Christopher Counter (Duke University) Matthew Vander Heiden (Massachusetts Institute of Technology) Marie Evangelista (Genentech) Aaron Hobbs (Der Lab, University of North Carolina, Chapel Hill) 12:10 pm – 1:10 pm Lunch on your own 1:10 pm – 3:15 pm Poster Session #1 3:15 pm – 4:15 pm RAS Multimers at the Membrane - Chair: John Hancock Yao-Cheng Li (Wahl Lab, Salk Institute) Margie Sutton (Bast Lab, MD Anderson) Chiara Ambrogio (Jänne Lab, Dana Farber Cancer Institute) 4:15 pm – 5:30 pm RAS Membrane Modeling and Dynamics - Chair: Dwight Nissley Roland Winter (Technische Universität Dortmund) Fred Streitz (Lawrence Livermore National Laboratory) Chris Neale (Garcia Lab, Los Alamos National Laboratory) Walkersville Social Hall 79 West Frederick Street, Walkersville 6:15 – 7:00 pm Hors d’oeuvres, cash bar 7:00 pm Dinner December 7 8:00 am – 10:00 am Tumor Dynamics - Chair: Rosalie Sears Dafna Bar-Sagi (New York University) David Tuveson (Cold Spring Harbor Laboratory) Channing Der (University -
Cambridge's 92 Nobel Prize Winners Part 4 - 1996 to 2015: from Stem Cell Breakthrough to IVF
Cambridge's 92 Nobel Prize winners part 4 - 1996 to 2015: from stem cell breakthrough to IVF By Cambridge News | Posted: February 01, 2016 Some of Cambridge's most recent Nobel winners Over the last four weeks the News has been rounding up all of Cambridge's 92 Nobel Laureates, which this week comes right up to the present day. From the early giants of physics like JJ Thomson and Ernest Rutherford to the modern-day biochemists unlocking the secrets of our genome, we've covered the length and breadth of scientific discovery, as well as hugely influential figures in economics, literature and politics. What has stood out is the importance of collaboration; while outstanding individuals have always shone, Cambridge has consistently achieved where experts have come together to bounce their ideas off each other. Key figures like Max Perutz, Alan Hodgkin and Fred Sanger have not only won their own Nobels, but are regularly cited by future winners as their inspiration, as their students went on to push at the boundaries they established. In the final part of our feature we cover the last 20 years, when Cambridge has won an average of a Nobel Prize a year, and shows no sign of slowing down, with ground-breaking research still taking place in our midst today. The Gender Pay Gap Sale! Shop Online to get 13.9% off From 8 - 11 March, get 13.9% off 1,000s of items, it highlights the pay gap between men & women in the UK. Shop the Gender Pay Gap Sale – now. Promoted by Oxfam 1.1996 James Mirrlees, Trinity College: Prize in Economics, for studying behaviour in the absence of complete information As a schoolboy in Galloway, Scotland, Mirrlees was in line for a Cambridge scholarship, but was forced to change his plans when on the weekend of his interview he was rushed to hospital with peritonitis. -
Balcomk41251.Pdf (558.9Kb)
Copyright by Karen Suzanne Balcom 2005 The Dissertation Committee for Karen Suzanne Balcom Certifies that this is the approved version of the following dissertation: Discovery and Information Use Patterns of Nobel Laureates in Physiology or Medicine Committee: E. Glynn Harmon, Supervisor Julie Hallmark Billie Grace Herring James D. Legler Brooke E. Sheldon Discovery and Information Use Patterns of Nobel Laureates in Physiology or Medicine by Karen Suzanne Balcom, B.A., M.L.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August, 2005 Dedication I dedicate this dissertation to my first teachers: my father, George Sheldon Balcom, who passed away before this task was begun, and to my mother, Marian Dyer Balcom, who passed away before it was completed. I also dedicate it to my dissertation committee members: Drs. Billie Grace Herring, Brooke Sheldon, Julie Hallmark and to my supervisor, Dr. Glynn Harmon. They were all teachers, mentors, and friends who lifted me up when I was down. Acknowledgements I would first like to thank my committee: Julie Hallmark, Billie Grace Herring, Jim Legler, M.D., Brooke E. Sheldon, and Glynn Harmon for their encouragement, patience and support during the nine years that this investigation was a work in progress. I could not have had a better committee. They are my enduring friends and I hope I prove worthy of the faith they have always showed in me. I am grateful to Dr. -
Cleavage Stage and Cell Division Kinetics
Cleavage stage and cell division kinetics Thorir Hardarson, PhD. Possible conflict of interest NO Kinetics? Greek: κίνησις "kinesis", movement or to move i.e. Cleavage rate (of embryos) Cleavage rate then …? Cleavage rate = Cell division rate Cell division is the process by which a parent cell divides into two or more daughter cells, i.e. mitosis. A human being's body experiences about 10,000 trillion cell divisions in a lifetime Before division can occur, the chromosomes must be replicated, and the duplicated genome separated cleanly between cells. The Nobel Prize in Physiology or Medicine 2001 Leland H. Hartwell, Tim Hunt, Sir Paul Nurse For their discoveries of "key regulators of the cell cycle" ”Start -G”Genes” “Checkpoints” “CDK” (Cyclin dependent kinase) “Cyclins, (proteins that regulate CDK) Mitosis Cell cycle control Hundred of genes and macromolecules involved Checkpoints of DNA damage and order of cell cycle events Hundred of genes and macromolecules involved Checkpoints of DNA damage and order of cell cycle events Cell cycle checkpoints So… For all living eukaryotic organisms it is essential that the differen t ph ases o f th e cell cyc le are prec ise ly coordinated. The phases must follow in correct order, and one phase must be completed before the next phase can begin. Errors in this coordination may lead to chromosomal alterations. Chromosomes or parts of chromosomes may be lost, rearranged or distributed unequally between the two daughter cells, often seen in cancer cells. Checkpoints in oocytes High chromosomal aberration rates in the human oocyte/embryo Has evolution favored low fecundity in humans? Fertil. -
ILAE Historical Wall02.Indd 10 6/12/09 12:04:44 PM
2000–2009 2001 2002 2003 2005 2006 2007 2008 Tim Hunt Robert Horvitz Sir Peter Mansfi eld Barry Marshall Craig Mello Oliver Smithies Luc Montagnier 2000 2000 2001 2002 2004 2005 2007 2008 Arvid Carlsson Eric Kandel Sir Paul Nurse John Sulston Richard Axel Robin Warren Mario Capecchi Harald zur Hauser Nobel Prizes 2000000 2001001 2002002 2003003 200404 2006006 2007007 2008008 Paul Greengard Leland Hartwell Sydney Brenner Paul Lauterbur Linda Buck Andrew Fire Sir Martin Evans Françoise Barré-Sinoussi in Medicine and Physiology 2000 1st Congress of the Latin American Region – in Santiago 2005 ILAE archives moved to Zurich to become publicly available 2000 Zonismide licensed for epilepsy in the US and indexed 2001 Epilepsia changes publishers – to Blackwell 2005 26th International Epilepsy Congress – 2001 Epilepsia introduces on–line submission and reviewing in Paris with 5060 delegates 2001 24th International Epilepsy Congress – in Buenos Aires 2005 Bangladesh, China, Costa Rica, Cyprus, Kazakhstan, Nicaragua, Pakistan, 2001 Launch of phase 2 of the Global Campaign Against Epilepsy Singapore and the United Arab Emirates join the ILAE in Geneva 2005 Epilepsy Atlas published under the auspices of the Global 2001 Albania, Armenia, Arzerbaijan, Estonia, Honduras, Jamaica, Campaign Against Epilepsy Kyrgyzstan, Iraq, Lebanon, Malta, Malaysia, Nepal , Paraguay, Philippines, Qatar, Senegal, Syria, South Korea and Zimbabwe 2006 1st regional vice–president is elected – from the Asian and join the ILAE, making a total of 81 chapters Oceanian Region