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Posts Tagged ‘Aviva Lev-Ari’

Compilation of References in Leaders in Pharmaceutical Intelligence about proteomics, metabolomics, signaling pathways, and cell regulation


Compilation of References in Leaders in Pharmaceutical Intelligence about 
proteomics, metabolomics, signaling pathways, and cell regulation

 

Proteomics

  1. The Human Proteome Map Completed  

         Reporter and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/08/28/the-human-proteome-map-completed/

  1. Proteomics – The Pathway to Understanding and Decision-making in Medicine

        Author and Curator, Larry H Bernstein, MD, FCAP 

        http://pharmaceuticalintelligence.com/2014/06/24/proteomics-the-pathway-to-
        understanding-and-decision-making-in-medicine/

    3. Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

       Author and Curator, Larry H Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-         of-therapeutic-targets/

  1. Expanding the Genetic Alphabet and Linking the Genome to the Metabolome 

        Author and Curator, Larry H Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-                metabolome/

    5. Genomics, Proteomics and standards

        Larry H Bernstein, MD, FCAP, Author and Curator

        http://pharmaceuticalintelligence.com/2014/07/06/genomics-proteomics-and-standards/

    6. Proteins and cellular adaptation to stress

        Larry H Bernstein, MD, FCAP, Author and Curator

        http://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

     

Metabolomics

  1. Extracellular evaluation of intracellular flux in yeast cells

         Larry H. Bernstein, MD, FCAP, Reviewer and Curator

         http://pharmaceuticalintelligence.com/2014/08/25/extracellular-evaluation-of-intracellular-flux-in-yeast-cells/

  1. Metabolomic analysis of two leukemia cell lines. I.

         Larry H. Bernstein, MD, FCAP, Reviewer and Curator

         http://pharmaceuticalintelligence.com/2014/08/23/metabolomic-analysis-of-two-leukemia-cell-lines-_i/

  1. Metabolomic analysis of two leukemia cell lines. II.

         Larry H. Bernstein, MD, FCAP, Reviewer and Curator

         http://pharmaceuticalintelligence.com/2014/08/24/metabolomic-analysis-of-two-leukemia-cell-lines-ii/

  1. Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

         Reviewer and Curator, Larry H. Bernstein, MD, FCAP 

         http://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-          in-nutritional-metabolism-and-biotherapeutics/

  1. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

         Larry H. Bernstein, MD, FCAP, Reviewer and curator

         http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

 

Metabolic Pathways

  1. Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

         Reviewer and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/08/21/pentose-shunt-electron-transfer-galactose-more-lipids-in-brief/

  1. Mitochondria: More than just the “powerhouse of the cell”    

        Ritu Saxena, PhD 

         http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

  1. Mitochondrial fission and fusion: potential therapeutic targets?   

        Ritu saxena   

       http://pharmaceuticalintelligence.com/2012/10/31/mitochondrial-fission-and-fusion-potential-therapeutic-target/

   4.  Mitochondrial mutation analysis might be “1-step” away    

        Ritu Saxena 

       http://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

  1. Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

        Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-                     leaders-in-pharmaceutical-intelligence/

  1. Metabolic drivers in aggressive brain tumors

        Prabodh Kandal, PhD

        http://pharmaceuticalintelligence.com/2012/11/11/metabolic-drivers-in-aggressive-brain-tumors/

  1. Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

         Writer and Curator, Aviva Lev-Ari, PhD, RD

         http://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-                        information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

  1. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

         Larry H Bernstein, MD, FCAP, author and curator

         http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-            glycolysis-metabolic-adaptation/

  1. Therapeutic Targets for Diabetes and Related Metabolic Disorders

         Reporter, Aviva Lev-Ari, PhD, RD

         http://pharmaceuticalintelligence.com/2012/08/20/therapeutic-targets-for-diabetes-and-related-metabolic-disorders/ 

  10.  Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

         Larry H. Bernstein, MD, FCAP, Reviewer and curator

         http://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/ 

   11. The multi-step transfer of phosphate bond and hydrogen exchange energy

          Larry H. Bernstein, MD, FCAP, Curator:

         http://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-                          exchange-energy/ 

   12. Studies of Respiration Lead to Acetyl CoA

         

         http://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/ 

   13. Lipid Metabolism    

         Author and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/08/15/lipid-metabolism/   

   14. Carbohydrate Metabolism

          Author and Curator: Larry H. Bernstein, MD, FCAP

          http://pharmaceuticalintelligence.com/2014/08/13/carbohydrate-metabolism/   

   15. Update on mitochondrial function, respiration, and associated disorders

         Larry H. Bernstein, MD, FCAP, Author and Curator           

         http://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                   disorders/

    16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

         Author and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/04/13/prologue-to-cancer-ebook-4-where-are-we-in-this-journey/ 

    17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

        Author and Curator: Larry H. Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-          how-we-got-here/

   18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

       Author and Curator: Larry H. Bernstein, MD, FCAP

      http://pharmaceuticalintelligence.com/2013/11/01/inhibition-of-the-cardiomyocyte-specific-kinase-tnni3k/ 

   19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

         Author and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2013/05/15/the-binding-of-oligonucleotides-in-dna-and-3-d-lattice-structures/

  20. Mitochondrial Metabolism and Cardiac Function

        Author and Curator: Larry H. Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

   21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

        Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-leads_to_hyperhomocysteinemia/

  22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

        Author and Curator: Stephen J. Williams, PhD

        http://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-         tumor-growth-in-vivo/

  23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

        Author and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-                         conundrum/

  24. Mitochondrial Damage and Repair under Oxidative Stress

       Author and Curator: Larry H. Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

  25. Nitric Oxide and Immune Responses: Part 2

        Author and Curator: Aviral Vatsa, PhD, MBBS

        http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

  26. Overview of Posttranslational Modification (PTM)

        Writer and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/07/29/overview-of-posttranslational-modification-ptm/

  27. Malnutrition in India, high newborn death rate and stunting of children age under five years

        Writer and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-                   children-age-under-five-years/

  28. Update on mitochondrial function, respiration, and associated disorders

        Writer and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                  disorders/

  29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

        Larry H. Bernstein, MD, FCAP, Curator

        http://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-         in-renal-disease/

  30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

       Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

       http://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-                                  translational_medicine-part_2/

  31. Epilogue: Envisioning New Insights in Cancer Translational Biology 
       Series C: e-Books on Cancer & Oncology

      Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant

      http://pharmaceuticalintelligence.com/2014/03/29/epilogue-envisioning-new-insights/

  32. Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone                         and Neurotransmitter

       Writer and Curator: Larry H Bernstein, MD, FCAP and 
       Curator and Content Editor: Aviva Lev-Ari, PhD, RN

       http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-                    hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

  33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-                           related Contractile Dysfunction) and Catecholamine Responses

       Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC  
      Author and Curator: Larry H Bernstein, MD, FCAP
      and Article Curator: Aviva Lev-Ari, PhD, RN

     http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-      and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-                    contractile/

  34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

       Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN

       http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

  35. Identification of Biomarkers that are Related to the Actin Cytoskeleton  

        Larry H Bernstein, MD, FCAP, Author and Curator

        http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-                           cytoskeleton/

  36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

       Author: Larry H Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-              End-Stage/

  37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

       Demet Sag, PhD, Author and Curator

      http://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-               immunology/

  38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

        Demet Sag, PhD, Author and Curator

        http://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-             ido-indolamine-2-3-dioxygenase/

  39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

        Curator: Demet Sag, PhD, CRA, GCP

        http://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-           of-immune-responses-for-good-and-bad/

  40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

        Reporter: Aviva Lev-Ari, PhD, RN

        http://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-                     discovered-scripps-research-institute/

  41. Naked Mole Rats Cancer-Free

        Writer and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2013/06/20/naked-mole-rats-cancer-free/

  42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

        Reporter and Curator: Dr. Sudipta Saha, Ph.D.

        http://pharmaceuticalintelligence.com/2013/05/06/alzheimers-disease-and-one-carbon-metabolism/

  43. Problems of vegetarianism

        Reporter and Curator: Dr. Sudipta Saha, Ph.D.

        http://pharmaceuticalintelligence.com/2013/04/22/problems-of-vegetarianism/

44.  Amyloidosis with Cardiomyopathy

      Writer and Curator: Larry H. Bernstein, MD, FCAP

      http://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

  45. Liver endoplasmic reticulum stress and hepatosteatosis

        Larry H Bernstein, MD, FACP 

        http://pharmaceuticalintelligence.com/2013/03/10/liver-endoplasmic-reticulum-stress-and-hepatosteatosis/

  46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

  47. Nitric Oxide Function in Coagulation – Part II

        Curator and Author: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

  48. Nitric Oxide, Platelets, Endothelium and Hemostasis

        Curator and Author: Larry H Bernstein, MD, FACP 

        http://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

  49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

        Curator and Author: Larry H Bernstein, MD, FACP 

        http://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

  50. Nitric Oxide and Immune Responses: Part 1

       Curator and Author:  Aviral Vatsa PhD, MBBS

       http://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

  51. Nitric Oxide and Immune Responses: Part 2

        Curator and Author:  Aviral Vatsa PhD, MBBS

        http://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

  52. Mitochondrial Damage and Repair under Oxidative Stress

        Curator and Author: Larry H Bernstein, MD, FACP

         http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

  53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-                 century-view/

  54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

       Curator and Author: Larry H Bernstein, MD, FACP

       http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                  proteolysis-and-cell-apoptosis/

  55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis-reconsidered/

  56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

  57. New Insights on Nitric Oxide donors – Part IV

       Curator and Author: Larry H Bernstein, MD, FACP

       http://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

  58. Crucial role of Nitric Oxide in Cancer

        Curator and Author: Ritu Saxena, Ph.D.

        http://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

  59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

  60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

        Curator and Author: Ziv Raviv, PhD, RN 04/06/2013

        http://pharmaceuticalintelligence.com/2013/04/06/targeting-mitochondrial-bound-hexokinase-for-cancer-therapy/

  61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

        Curator and Author: Larry H Bernstein, MD, FACP

        http://pharmaceuticalintelligence.com/2012/11/26/biochemistry-of-the-coagulation-cascade-and-platelet-aggregation/

 

Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

         Writer and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/08/06/what-is-the-meaning-of-so-many-rnas/

  1. RNA and the transcription the genetic code

         Larry H. Bernstein, MD, FCAP, Writer and Curator

         http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

  1. A Primer on DNA and DNA Replication

        Writer and Curator: Larry H. Bernstein, MD, FCAP

        http://pharmaceuticalintelligence.com/2014/07/29/a_primer_on_dna_and_dna_replication/

    4. Synthesizing Synthetic Biology: PLOS Collections

        Reporter: Aviva Lev-Ari

        http://pharmaceuticalintelligence.com/2012/08/17/synthesizing-synthetic-biology-plos-collections/

   5. Pathology Emergence in the 21st Century

       Author and Curator: Larry Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2014/08/03/pathology-emergence-in-the-21st-century/

  6. RNA and the transcription the genetic code

         Writer and Curator, Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/08/02/rna-and-the-transcription-of-the-genetic-code/

  7. A Great University engaged in Drug Discovery: University of Pittsburgh

      Larry H. Bernstein, MD, FCAP, Reporter and Curator

      http://pharmaceuticalintelligence.com/2014/07/15/a-great-university-engaged-in-drug-discovery/

 8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone  marrow give                              rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

     Aviva Lev-Ari, PhD, RN, Author and Curator

    http://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the-                   immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen-             bearing-red-blood-cells/

 9. Genes, proteomes, and their interaction

     Larry H. Bernstein, MD, FCAP, Writer and Curator

     http://pharmaceuticalintelligence.com/2014/07/28/genes-proteomes-and-their-interaction/

10. Regulation of somatic stem cell Function

      Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

      http://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/

11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

      Larry H. Bernstein, MD, FCAP, Reporter

      http://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-           adult-organisms/

12. Bzzz! Are fruitflies like us?

      Larry H Bernstein, MD, FCAP, Author and Curator   

      http://pharmaceuticalintelligence.com/2014/07/07/bzzz-are-fruitflies-like-us/

13. Long Non-coding RNAs Can Encode Proteins After All

      Larry H Bernstein, MD, FCAP, Reporter

      http://pharmaceuticalintelligence.com/2014/06/29/long-non-coding-rnas-can-encode-proteins-after-all/

14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an 
      allele-specific full-length transcriptome

     Aviva Lev-Ari, PhD, RN, Author and Curator

     http://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid-            transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H                                     Bernstein, MD, FCAP

        Author: Larry H Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-                        cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

      Author an curator: Larry H Bernstein, MD, FCAP

      http://pharmaceuticalintelligence.com/2013/05/18/observations-on-finding-the-genetic-links/

17. Silencing Cancers with Synthetic siRNAs

      Larry H. Bernstein, MD, FCAP, Reviewer and Curator

      http://pharmaceuticalintelligence.com/2013/12/09/silencing-cancers-with-synthetic-sirnas/

18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

      Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/12/cardiometabolic-syndrome-and-the-genetics-of-hypertension-the-neuroendocrine-transcriptome-control-points/

19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

      Larry H. Bernstein, MD, FCAP, Reviewer and Curator

      http://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-           mellitus-and-treatment-targets/

20. Loss of normal growth regulation

      Larry H Bernstein, MD, FCAP, Curator

      http://pharmaceuticalintelligence.com/2014/07/06/loss-of-normal-growth-regulation/

21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

      Reporter: Aviva Lev-Ari, PhD, RN

      http://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-           new-therapeutic-targets-to-atherosclerosis/

22.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics 

       Genomics Curator, Larry H Bernstein, MD, FCAP 

       http://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-                      computational-genomics/

 23. Big Data in Genomic Medicine 

      Author and Curator, Larry H Bernstein, MD, FCAP

      http://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

 24. From Genomics of Microorganisms to Translational Medicine

       Author and Curator: Demet Sag, PhD

       http://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-                      microorganisms-to-translational-medicine/

 25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

       Author and Curator, Larry H Bernstein, MD, FCAP

      http://pharmaceuticalintelligence.com/2014/01/06/summary-of-genomics-and-medicine-role-in-cardiovascular-diseases/

 26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious                      Depression

       Author and Curator, Larry H Bernstein, MD, FCAP

       http://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-        spectrum-schizophrenia-and-serious-depression/

 27.  BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

        Sudipta Saha, PhD 

        http://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-         in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer 

      Ritu Saxena, PhD  
         
      http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

      Stephen J Williams, PhD   

      http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment 

     Aviva Lev-Ari, PhD, RN

     http://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-          detection-treatment/ 

31. The Molecular pathology of Breast Cancer Progression

      Tilde Barliya, PhD

      http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression 

32. Gastric Cancer: Whole-genome reconstruction and mutational signatures  

      Aviva Lev-Ari, PhD, RN  

      http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/ 

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine –                                                       Part 1 (pharmaceuticalintelligence.com)  

      Aviva  Lev-Ari, PhD, RN

      http://pharmaceuticalntelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/                                           

34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer                                         Personalized Treatment: Part 2 

      A Lev-Ari, PhD, RN

      http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-       drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3 

     Aviva Lev-Ari, PhD, RN  

     http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-        research-part-3/ 

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of                           Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

      Aviva Lev-Ari, PhD, RN  
 
     http://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management-      Prospects_of_Prevention_and_Cure/   

37.  GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico 
       effect of the inhibitor in its “virtual clinical trial”

      Aviva Lev-Ari, PhD, RN

      http://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-             systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/ 

38. Personalized medicine-based cure for cancer might not be far away

      Ritu Saxena, PhD      

      http://pharmaceuticalintelligence.com/2012/11/20/personalized-medicine-based-cure-for-cancer-might-not-be-far-away/

39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence 

      Aviva Lev-Ari, PhD, RN

      http://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-         indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

      Aviva Lev-Ari, PhD, RN  

     http://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-                genomic-sequencing-to-cancer-diagnostics/       

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

      Aviva Lev-Ari, PhD, RN

      http://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-         of-dna-wcrick-41953/ 

42. What can we expect of tumor therapeutic response?

       Author and curator: Larry H Bernstein, MD, FACP

       http://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

43. Directions for genomics in personalized medicine 

      Author and Curator: Larry H. Bernstein, MD, FCAP 

      http://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. 

     Stephen J Williams, PhD  

     http://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-            mediated-tumorigenesis/ 

45. mRNA interference with cancer expression 

      Author and Curator, Larry H. Bernstein, MD, FCAP

     http://pharmaceuticalintelligence.com/2012/10/26/mrna-interference-with-cancer-expression/

46. Expanding the Genetic Alphabet and linking the genome to the metabolome  

      Aviva Lev-Ari, PhD, RD

      http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-               metabolome/   

47. Breast Cancer, drug resistance, and biopharmaceutical targets 

      Author and Curator: Larry H Bernstein, MD, FCAP

     http://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/

48.  Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression                            Analysis   

      Aviva Lev-Ari, PhD, RD

      http://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-           histopathology-and-gene-expression-analysis 

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

      Aviva  Lev-Ari, PhD, RD

      http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/ 

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology  

      Aviva Lev-Ari, PhD, RD

      http://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-                   agricultural-biotechnology/ 

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.  

      Aviva Lev-Ari, PhD, RD

     http://pharmaceuticalintelligence.com/2013_Genomics 

52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

      Aviva Lev-Ari, PhD, RD 

http://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

 

Signaling Pathways

  1. Proteins and cellular adaptation to stress

         Larry H Bernstein, MD, FCAP, Curator

         http://pharmaceuticalintelligence.com/2014/07/08/proteins-and-cellular-adaptation-to-stress/

  1. A Synthesis of the Beauty and Complexity of How We View Cancer: 
    Cancer Volume One – Summary

         Author and Curator: Larry H. Bernstein, MD, FCAP

         http://pharmaceuticalintelligence.com/2014/03/26/a-synthesis-of-the-beauty-and-complexity-of-how-we-view-cancer/

  1. Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in 
    serous endometrial tumors                                         

        Sudipta Saha, PhD 

        http://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin-           ligase-complex-genes-in-serous-endometrial-tumors/ 

4.  Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

    Stephen J Williams, PhD

   http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-              transition-in-prostate-cancer-cells/   

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis 

    Author and Curator: Larry H Bernstein, MD, FCAP  

    http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis/   

6. Signaling and Signaling Pathways

     Larry H. Bernstein, MD, FCAP, Reporter and Curator

      http://pharmaceuticalintelligence.com/2014/08/12/signaling-and-signaling-pathways/ 

7.  Leptin signaling in mediating the cardiac hypertrophy associated with obesity

     Larry H. Bernstein, MD, FCAP, Reporter and Curator

    http://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-            with-obesity/

  1. Sensors and Signaling in Oxidative Stress

         Larry H. Bernstein, MD, FCAP, Reporter and Curator

         http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel 
    Treatments

         Larry H. Bernstein, MD, FCAP, Reporter and Curator

         http://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-                      endothelial-reactions-in-atherosclerosis-and-novel-treatments

10.   Platelets in Translational Research – Part 1

        Larry H. Bernstein, MD, FCAP, Reporter and Curator

        http://pharmaceuticalintelligence.com/2013/10/07/platelets-in-translational-research-1/

11.  Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and 
      Cardiovascular Calcium Signaling Mechanism

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A: 
    Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

    http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-             smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and 
      Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia
     Similarities and Differences, and Pharmaceutical Targets

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to 
     e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and 
    Curator: Aviva Lev-Ari, PhD, RN

    http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-       kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-           differen/ 

13.  Nitric Oxide Signalling Pathways  

      Aviral Vatsa, PhD, MBBS

     http://pharmaceuticalintelligence.com/2012/08/22/nitric-oxide-signalling-pathways/   

14. Immune activation, immunity, antibacterial activity

      Larry H. Bernstein, MD, FCAP, Curator

      http://pharmaceuticalintelligence.com/2014/07/06/immune-activation-immunity-antibacterial-activity/  

15.  Regulation of somatic stem cell Function

       Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator

      http://pharmaceuticalintelligence.com/2014/07/29/regulation-of-somatic-stem-cell-function/  

16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

      Larry H. Bernstein, MD, FCAP, Reporter

      http://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-adult-organisms/

 

Read Full Post »


Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson

Life-cycle of Science 2

 

 

 

 

 

 

 

 

 

 

 

Curators and Writer: Stephen J. Williams, Ph.D. with input from Curators Larry H. Bernstein, MD, FCAP, Dr. Justin D. Pearlman, MD, PhD, FACC and Dr. Aviva Lev-Ari, PhD, RN

(this discussion is in a three part series including:

Using Scientific Content Curation as a Method for Validation and Biocuration

Using Scientific Content Curation as a Method for Open Innovation)

 

Every month I get my Wired Magazine (yes in hard print, I still like to turn pages manually plus I don’t mind if I get grease or wing sauce on my magazine rather than on my e-reader) but I always love reading articles written by Clive Thompson. He has a certain flair for understanding the techno world we live in and the human/technology interaction, writing about interesting ways in which we almost inadvertently integrate new technologies into our day-to-day living, generating new entrepreneurship, new value.   He also writes extensively about tech and entrepreneurship.

October 2013 Wired article by Clive Thompson, entitled “How Successful Networks Nurture Good Ideas: Thinking Out Loud”, describes how the voluminous writings, postings, tweets, and sharing on social media is fostering connections between people and ideas which, previously, had not existed. The article was generated from Clive Thompson’s book Smarter Than you Think: How Technology is Changing Our Minds for the Better.Tom Peters also commented about the article in his blog (see here).

Clive gives a wonderful example of Ory Okolloh, a young Kenyan-born law student who, after becoming frustrated with the lack of coverage of problems back home, started a blog about Kenyan politics. Her blog not only got interest from movie producers who were documenting female bloggers but also gained the interest of fellow Kenyans who, during the upheaval after the 2007 Kenyan elections, helped Ory to develop a Google map for reporting of violence (http://www.ushahidi.com/, which eventually became a global organization using open-source technology to affect crises-management. There are a multitude of examples how networks and the conversations within these circles are fostering new ideas. As Clive states in the article:

 

Our ideas are PRODUCTS OF OUR ENVIRONMENT.

They are influenced by the conversations around us.

However the article got me thinking of how Science 2.0 and the internet is changing how scientists contribute, share, and make connections to produce new and transformative ideas.

But HOW MUCH Knowledge is OUT THERE?

 

Clive’s article listed some amazing facts about the mountains of posts, tweets, words etc. out on the internet EVERY DAY, all of which exemplifies the problem:

  • 154.6 billion EMAILS per DAY
  • 400 million TWEETS per DAY
  • 1 million BLOG POSTS (including this one) per DAY
  • 2 million COMMENTS on WordPress per DAY
  • 16 million WORDS on Facebook per DAY
  • TOTAL 52 TRILLION WORDS per DAY

As he estimates this would be 520 million books per DAY (book with average 100,000 words).

A LOT of INFO. But as he suggests it is not the volume but how we create and share this information which is critical as the science fiction writer Theodore Sturgeon noted “Ninety percent of everything is crap” AKA Sturgeon’s Law.

 

Internet live stats show how congested the internet is each day (http://www.internetlivestats.com/). Needless to say Clive’s numbers are a bit off. As of the writing of this article:

 

  • 2.9 billion internet users
  • 981 million websites (only 25,000 hacked today)
  • 128 billion emails
  • 385 million Tweets
  • > 2.7 million BLOG posts today (including this one)

 

The Good, The Bad, and the Ugly of the Scientific Internet (The Wild West?)

 

So how many science blogs are out there? Well back in 2008 “grrlscientistasked this question and turned up a total of 19,881 blogs however most were “pseudoscience” blogs, not written by Ph.D or MD level scientists. A deeper search on Technorati using the search term “scientist PhD” turned up about 2,000 written by trained scientists.

So granted, there is a lot of

goodbadugly

 

              ….. when it comes to scientific information on the internet!

 

 

 

 

 

I had recently re-posted, on this site, a great example of how bad science and medicine can get propagated throughout the internet:

http://pharmaceuticalintelligence.com/2014/06/17/the-gonzalez-protocol-worse-than-useless-for-pancreatic-cancer/

 

and in a Nature Report:Stem cells: Taking a stand against pseudoscience

http://www.nature.com/news/stem-cells-taking-a-stand-against-pseudoscience-1.15408

Drs.Elena Cattaneo and Gilberto Corbellini document their long, hard fight against false and invalidated medical claims made by some “clinicians” about the utility and medical benefits of certain stem-cell therapies, sacrificing their time to debunk medical pseudoscience.

 

Using Curation and Science 2.0 to build Trusted, Expert Networks of Scientists and Clinicians

 

Establishing networks of trusted colleagues has been a cornerstone of the scientific discourse for centuries. For example, in the mid-1640s, the Royal Society began as:

 

“a meeting of natural philosophers to discuss promoting knowledge of the

natural world through observation and experiment”, i.e. science.

The Society met weekly to witness experiments and discuss what we

would now call scientific topics. The first Curator of Experiments

was Robert Hooke.”

 

- from The History of the Royal Society

 

Royal Society CoatofArms

 

 

 

 

 

 

The Royal Society of London for Improving Natural Knowledge.

(photo credit: Royal Society)

(Although one wonders why they met “in-cognito”)

Indeed as discussed in “Science 2.0/Brainstorming” by the originators of OpenWetWare, an open-source science-notebook software designed to foster open-innovation, the new search and aggregation tools are making it easier to find, contribute, and share information to interested individuals. This paradigm is the basis for the shift from Science 1.0 to Science 2.0. Science 2.0 is attempting to remedy current drawbacks which are hindering rapid and open scientific collaboration and discourse including:

  • Slow time frame of current publishing methods: reviews can take years to fashion leading to outdated material
  • Level of information dissemination is currently one dimensional: peer-review, highly polished work, conferences
  • Current publishing does not encourage open feedback and review
  • Published articles edited for print do not take advantage of new web-based features including tagging, search-engine features, interactive multimedia, no hyperlinks
  • Published data and methodology incomplete
  • Published data not available in formats which can be readably accessible across platforms: gene lists are now mandated to be supplied as files however other data does not have to be supplied in file format

(put in here a brief blurb of summary of problems and why curation could help)

 

Curation in the Sciences: View from Scientific Content Curators Larry H. Bernstein, MD, FCAP, Dr. Justin D. Pearlman, MD, PhD, FACC and Dr. Aviva Lev-Ari, PhD, RN

Curation is an active filtering of the web’s  and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes. Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view.  Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blind men of the Sufi tale.  One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive.

- Larry H. Bernstein, MD, FCAP

Curation is Uniquely Distinguished by the Historical Exploratory Ties that Bind -Larry H. Bernstein, MD, FCAP

The explosion of information by numerous media, hardcopy and electronic, written and video, has created difficulties tracking topics and tying together relevant but separated discoveries, ideas, and potential applications. Some methods to help assimilate diverse sources of knowledge include a content expert preparing a textbook summary, a panel of experts leading a discussion or think tank, and conventions moderating presentations by researchers. Each of those methods has value and an audience, but they also have limitations, particularly with respect to timeliness and pushing the edge. In the electronic data age, there is a need for further innovation, to make synthesis, stimulating associations, synergy and contrasts available to audiences in a more timely and less formal manner. Hence the birth of curation. Key components of curation include expert identification of data, ideas and innovations of interest, expert interpretation of the original research results, integration with context, digesting, highlighting, correlating and presenting in novel light.

- Justin D Pearlman, MD, PhD, FACC from The Voice of Content Consultant on The  Methodology of Curation in Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation The Art of Scientific & Medical Curation

 

In Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison, Drs. Larry Bernstein and Aviva Lev-Ari likens the medical and scientific curation process to curation of musical works into a thematic program:

 

Work of Original Music Curation and Performance:

 

Music Review and Critique as a Curation

Work of Original Expression what is the methodology of Curation in the context of Medical Research Findings Exposition of Synthesis and Interpretation of the significance of the results to Clinical Care

… leading to new, curated, and collaborative works by networks of experts to generate (in this case) ebooks on most significant trends and interpretations of scientific knowledge as relates to medical practice.

 

In Summary: How Scientific Content Curation Can Help

 

Given the aforementioned problems of:

        I.            the complex and rapid deluge of scientific information

      II.            the need for a collaborative, open environment to produce transformative innovation

    III.            need for alternative ways to disseminate scientific findings

CURATION MAY OFFER SOLUTIONS

        I.            Curation exists beyond the review: curation decreases time for assessment of current trends adding multiple insights, analyses WITH an underlying METHODOLOGY (discussed below) while NOT acting as mere reiteration, regurgitation

 

      II.            Curation providing insights from WHOLE scientific community on multiple WEB 2.0 platforms

 

    III.            Curation makes use of new computational and Web-based tools to provide interoperability of data, reporting of findings (shown in Examples below)

 

Therefore a discussion is given on methodologies, definitions of best practices, and tools developed to assist the content curation community in this endeavor.

Methodology in Scientific Content Curation as Envisioned by Aviva lev-Ari, PhD, RN

 

At Leaders in Pharmaceutical Business Intelligence, site owner and chief editor Aviva lev-Ari, PhD, RN has been developing a strategy “for the facilitation of Global access to Biomedical knowledge rather than the access to sheer search results on Scientific subject matters in the Life Sciences and Medicine”. According to Aviva, “for the methodology to attain this complex goal it is to be dealing with popularization of ORIGINAL Scientific Research via Content Curation of Scientific Research Results by Experts, Authors, Writers using the critical thinking process of expert interpretation of the original research results.” The following post:

Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation

 

http://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/

demonstrate two examples how content co-curation attempts to achieve this aim and develop networks of scientist and clinician curators to aid in the active discussion of scientific and medical findings, and use scientific content curation as a means for critique offering a “new architecture for knowledge”. Indeed, popular search engines such as Google, Yahoo, or even scientific search engines such as NCBI’s PubMed and the OVID search engine rely on keywords and Boolean algorithms …

which has created a need for more context-driven scientific search and discourse.

In Science and Curation: the New Practice of Web 2.0, Célya Gruson-Daniel (@HackYourPhd) states:

To address this need, human intermediaries, empowered by the participatory wave of web 2.0, naturally started narrowing down the information and providing an angle of analysis and some context. They are bloggers, regular Internet users or community managers – a new type of profession dedicated to the web 2.0. A new use of the web has emerged, through which the information, once produced, is collectively spread and filtered by Internet users who create hierarchies of information.

.. where Célya considers curation an essential practice to manage open science and this new style of research.

As mentioned above in her article, Dr. Lev-Ari represents two examples of how content curation expanded thought, discussion, and eventually new ideas.

  1. Curator edifies content through analytic process = NEW form of writing and organizations leading to new interconnections of ideas = NEW INSIGHTS

i)        Evidence: curation methodology leading to new insights for biomarkers

 

  1. Same as #1 but multiple players (experts) each bringing unique insights, perspectives, skills yielding new research = NEW LINE of CRITICAL THINKING

ii)      Evidence: co-curation methodology among cardiovascular experts leading to cardiovascular series ebooks

Life-cycle of Science 2

The Life Cycle of Science 2.0. Due to Web 2.0, new paradigms of scientific collaboration are rapidly emerging.  Originally, scientific discovery were performed by individual laboratories or “scientific silos” where the main method of communication was peer-reviewed publication, meeting presentation, and ultimately news outlets and multimedia. In this digital era, data was organized for literature search and biocurated databases. In an era of social media, Web 2.0, a group of scientifically and medically trained “curators” organize the piles of data of digitally generated data and fit data into an organizational structure which can be shared, communicated, and analyzed in a holistic approach, launching new ideas due to changes in organization structure of data and data analytics.

 

The result, in this case, is a collaborative written work above the scope of the review. Currently review articles are written by experts in the field and summarize the state of a research are. However, using collaborative, trusted networks of experts, the result is a real-time synopsis and analysis of the field with the goal in mind to

INCREASE THE SCIENTIFIC CURRENCY.

For detailed description of methodology please see Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation The Art of Scientific & Medical Curation

 

In her paper, Curating e-Science Data, Maureen Pennock, from The British Library, emphasized the importance of using a diligent, validated, and reproducible, and cost-effective methodology for curation by e-science communities over the ‘Grid:

“The digital data deluge will have profound repercussions for the infrastructure of research and beyond. Data from a wide variety of new and existing sources will need to be annotated with metadata, then archived and curated so that both the data and the programmes used to transform the data can be reproduced for use in the future. The data represent a new foundation for new research, science, knowledge and discovery”

— JISC Senior Management Briefing Paper, The Data Deluge (2004)

 

As she states proper data and content curation is important for:

  • Post-analysis
  • Data and research result reuse for new research
  • Validation
  • Preservation of data in newer formats to prolong life-cycle of research results

However she laments the lack of

  • Funding for such efforts
  • Training
  • Organizational support
  • Monitoring
  • Established procedures

 

Tatiana Aders wrote a nice article based on an interview with Microsoft’s Robert Scoble, where he emphasized the need for curation in a world where “Twitter is the replacement of the Associated Press Wire Machine” and new technologic platforms are knocking out old platforms at a rapid pace. In addition he notes that curation is also a social art form where primary concerns are to understand an audience and a niche.

Indeed, part of the reason the need for curation is unmet, as writes Mark Carrigan, is the lack of appreciation by academics of the utility of tools such as Pinterest, Storify, and Pearl Trees to effectively communicate and build collaborative networks.

And teacher Nancy White, in her article Understanding Content Curation on her blog Innovations in Education, shows examples of how curation in an educational tool for students and teachers by demonstrating students need to CONTEXTUALIZE what the collect to add enhanced value, using higher mental processes such as:

  • Knowledge
  • Comprehension
  • Application
  • Analysis
  • Synthesis
  • Evaluation

curating-tableA GREAT table about the differences between Collecting and Curating by Nancy White at http://d20innovation.d20blogs.org/2012/07/07/understanding-content-curation/

 

 

 

 

 

 

 

 

 

 

 

University of Massachusetts Medical School has aggregated some useful curation tools at http://esciencelibrary.umassmed.edu/data_curation

Although many tools are related to biocuration and building databases but the common idea is curating data with indexing, analyses, and contextual value to provide for an audience to generate NETWORKS OF NEW IDEAS.

See here for a curation of how networks fosters knowledge, by Erika Harrison on ScoopIt

(http://www.scoop.it/t/mobilizing-knowledge-through-complex-networks)

 

“Nowadays, any organization should employ network scientists/analysts who are able to map and analyze complex systems that are of importance to the organization (e.g. the organization itself, its activities, a country’s economic activities, transportation networks, research networks).”

- Andrea Carafa insight from World Economic Forum New Champions 2012 “Power of Networks

 

Creating Content Curation Communities: Breaking Down the Silos!

 

An article by Dr. Dana Rotman “Facilitating Scientific Collaborations Through Content Curation Communities” highlights how scientific information resources, traditionally created and maintained by paid professionals, are being crowdsourced to professionals and nonprofessionals in which she termed “content curation communities”, consisting of professionals and nonprofessional volunteers who create, curate, and maintain the various scientific database tools we use such as Encyclopedia of Life, ChemSpider (for Slideshare see here), biowikipedia etc. Although very useful and openly available, these projects create their own challenges such as

  • information integration (various types of data and formats)
  • social integration (marginalized by scientific communities, no funding, no recognition)

The authors set forth some ways to overcome these challenges of the content curation community including:

  1. standardization in practices
  2. visualization to document contributions
  3. emphasizing role of information professionals in content curation communities
  4. maintaining quality control to increase respectability
  5. recognizing participation to professional communities
  6. proposing funding/national meeting – Data Intensive Collaboration in Science and Engineering Workshop

A few great presentations and papers from the 2012 DICOSE meeting are found below

Judith M. Brown, Robert Biddle, Stevenson Gossage, Jeff Wilson & Steven Greenspan. Collaboratively Analyzing Large Data Sets using Multitouch Surfaces. (PDF) NotesForBrown

 

Bill Howe, Cecilia Aragon, David Beck, Jeffrey P. Gardner, Ed Lazowska, Tanya McEwen. Supporting Data-Intensive Collaboration via Campus eScience Centers. (PDF) NotesForHowe

 

Kerk F. Kee & Larry D. Browning. Challenges of Scientist-Developers and Adopters of Existing Cyberinfrastructure Tools for Data-Intensive Collaboration, Computational Simulation, and Interdisciplinary Projects in Early e-Science in the U.S.. (PDF) NotesForKee

 

Ben Li. The mirages of big data. (PDF) NotesForLiReflectionsByBen

 

Betsy Rolland & Charlotte P. Lee. Post-Doctoral Researchers’ Use of Preexisting Data in Cancer Epidemiology Research. (PDF) NoteForRolland

 

Dana Rotman, Jennifer Preece, Derek Hansen & Kezia Procita. Facilitating scientific collaboration through content curation communities. (PDF) NotesForRotman

 

Nicholas M. Weber & Karen S. Baker. System Slack in Cyberinfrastructure Development: Mind the Gaps. (PDF) NotesForWeber

Indeed, the movement of Science 2.0 from Science 1.0 had originated because these “silos” had frustrated many scientists, resulting in changes in the area of publishing (Open Access) but also communication of protocols (online protocol sites and notebooks like OpenWetWare and BioProtocols Online) and data and material registries (CGAP and tumor banks). Some examples are given below.

Open Science Case Studies in Curation

1. Open Science Project from Digital Curation Center

This project looked at what motivates researchers to work in an open manner with regard to their data, results and protocols, and whether advantages are delivered by working in this way.

The case studies consider the benefits and barriers to using ‘open science’ methods, and were carried out between November 2009 and April 2010 and published in the report Open to All? Case studies of openness in research. The Appendices to the main report (pdf) include a literature review, a framework for characterizing openness, a list of examples, and the interview schedule and topics. Some of the case study participants kindly agreed to us publishing the transcripts. This zip archive contains transcripts of interviews with researchers in astronomy, bioinformatics, chemistry, and language technology.

 

see: Pennock, M. (2006). “Curating e-Science Data”. DCC Briefing Papers: Introduction to Curation. Edinburgh: Digital Curation Centre. Handle: 1842/3330. Available online: http://www.dcc.ac.uk/resources/briefing-papers/introduction-curation- See more at: http://www.dcc.ac.uk/resources/briefing-papers/introduction-curation/curating-e-science-data#sthash.RdkPNi9F.dpuf

 

2.      cBIO -cBio’s biological data curation group developed and operates using a methodology called CIMS, the Curation Information Management System. CIMS is a comprehensive curation and quality control process that efficiently extracts information from publications.

 

3. NIH Topic Maps – This website provides a database and web-based interface for searching and discovering the types of research awarded by the NIH. The database uses automated, computer generated categories from a statistical analysis known as topic modeling.

 

4. SciKnowMine (USC)- We propose to create a framework to support biocuration called SciKnowMine (after ‘Scientific Knowledge Mine’), cyberinfrastructure that supports biocuration through the automated mining of text, images, and other amenable media at the scale of the entire literature.

 

  1. OpenWetWare- OpenWetWare is an effort to promote the sharing of information, know-how, and wisdom among researchers and groups who are working in biology & biological engineering. Learn more about us.   If you would like edit access, would be interested in helping out, or want your lab website hosted on OpenWetWare, pleasejoin us. OpenWetWare is managed by the BioBricks Foundation. They also have a wiki about Science 2.0.

6. LabTrove: a lightweight, web based, laboratory “blog” as a route towards a marked up record of work in a bioscience research laboratory. Authors in PLOS One article, from University of Southampton, report the development of an open, scientific lab notebook using a blogging strategy to share information.

7. OpenScience Project- The OpenScience project is dedicated to writing and releasing free and Open Source scientific software. We are a group of scientists, mathematicians and engineers who want to encourage a collaborative environment in which science can be pursued by anyone who is inspired to discover something new about the natural world.

8. Open Science Grid is a multi-disciplinary partnership to federate local, regional, community and national cyberinfrastructures to meet the needs of research and academic communities at all scales.

 

9. Some ongoing biomedical knowledge (curation) projects at ISI

IICurate
This project is concerned with developing a curation and documentation system for information integration in collaboration with the II Group at ISI as part of the BIRN.

BioScholar
It’s primary purpose is to provide software for experimental biomedical scientists that would permit a single scientific worker (at the level of a graduate student or postdoctoral worker) to design, construct and manage a shared knowledge repository for a research group derived on a local store of PDF files. This project is funded by NIGMS from 2008-2012 ( RO1-GM083871).

10. Tools useful for scientific content curation

 

Research Analytic and Curation Tools from University of Queensland

 

Thomson Reuters information curation services for pharma industry

 

Microblogs as a way to communicate information about HPV infection among clinicians and patients; use of Chinese microblog SinaWeibo as a communication tool

 

VIVO for scientific communities- In order to connect this information about research activities across institutions and make it available to others, taking into account smaller players in the research landscape and addressing their need for specific information (for example, by proving non-conventional research objects), the open source software VIVO that provides research information as linked open data (LOD) is used in many countries.  So-called VIVO harvesters collect research information that is freely available on the web, and convert the data collected in conformity with LOD standards. The VIVO ontology builds on prevalent LOD namespaces and, depending on the needs of the specialist community concerned, can be expanded.

 

 

11. Examples of scientific curation in different areas of Science/Pharma/Biotech/Education

 

From Science 2.0 to Pharma 3.0 Q&A with Hervé Basset

http://digimind.com/blog/experts/pharma-3-0/

Hervé Basset, specialist librarian in the pharmaceutical industry and owner of the blog “Science Intelligence“, to talk about the inspiration behind his recent book  entitled “From Science 2.0 to Pharma 3.0″, published by Chandos Publishing and available on Amazon and how health care companies need a social media strategy to communicate and convince the health-care consumer, not just the practicioner.

 

Thomson Reuters and NuMedii Launch Ground-Breaking Initiative to Identify Drugs for Repurposing. Companies leverage content, Big Data analytics and expertise to improve success of drug discovery

 

Content Curation as a Context for Teaching and Learning in Science

 

#OZeLIVE Feb2014

http://www.youtube.com/watch?v=Ty-ugUA4az0

Creative Commons license

 

DigCCur: A graduate level program initiated by University of North Carolina to instruct the future digital curators in science and other subjects

 

Syracuse University offering a program in eScience and digital curation

 

Curation Tips from TED talks and tech experts

Steven Rosenbaum from Curation Nation

http://www.youtube.com/watch?v=HpncJd1v1k4

 

Pawan Deshpande form Curata on how content curation communities evolve and what makes a good content curation:

http://www.youtube.com/watch?v=QENhIU9YZyA

 

 

Future postings on the relevance and application of scientific curation will include:

Using Scientific Content Curation as a Method for Validation and Biocuration

 

Using Scientific Content Curation as a Method for Open Innovation

 

Other posts on this site related to Content Curation and Methodology include:

The growing importance of content curation

Data Curation is for Big Data what Data Integration is for Small Data

6 Steps to More Effective Content Curation

Stem Cells and Cardiac Repair: Content Curation & Scientific Reporting

Cancer Research: Curations and Reporting

Cardiovascular Diseases and Pharmacological Therapy: Curations

Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation The Art of Scientific & Medical Curation

Exploring the Impact of Content Curation on Business Goals in 2013

Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison

conceived: NEW Definition for Co-Curation in Medical Research

The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Reconstructed Science Communication for Open Access Online Scientific Curation

 

 

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PCCI’s 7th Annual Roundtable “Crowdfunding for Life Sciences: A Bridge Over Troubled Waters?”

Reporter: Stephen J. Williams, Ph.D.

 

http://www.rxpcci.com/meetings.htm

Monday, May 12 2014 Embassy Suites Hotel, Chesterbrook PA 6:00 -9:30 PM

Pharmaceutical Consulting Consortium International Inc. presents their 7th annual Roundtable on Crowdfunding for the Life Sciences and how this funding mechanism applies to early stage life science companies and changes the funding landscape. The conference will examine the types of crowdfunding out there and attempts to answer many questions including:

  • Which one is right for which new companies at which stage of the funding process?
  • And how will choosing the right or wrong one influence follow-on funders and funding rounds?
  • Will the advent of crowdfunding speed up the investment process?
  • Will it really bridge the yawning “valley of death”?

The panel is made up of notables and practitioners who will be called upon to deal with the pros and cons of crowdfunding in real life and let them discuss how all this is likely to apply to life science entrepreneurs and investors.

The panel includes:

  1. Mark Roderick, Attorney Flaster/Greenberg PC (Moderator)
  2. Valerie Gaydos, President, Capital Growth (represents angel/venture community)
  3. Samuel Wertheimer, Chief Investment Officer, Poliwogg Darrick Mix
  4. Duane Morris, LLP (journalist who covers crowdfunding

Register by clicking on www.rxpcci.com and following directions The event will be webcast.

Leaders in Pharmaceutical Business Intelligence had recently launched a new, real-time based methodology for meeting coverage using social media as a platform to foster discussion and commentary.

This methodology is described in the following post REAL TIME Cancer Conference Coverage: A Novel Methodology for Authentic Reporting on Presentations and Discussions launched via Twitter.com @ The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum in Drug Development, 19th March 2014 • New York Academy of Sciences • USA

This new method was successfully used and curated at the 2nd Annual Sachs Cancer Bio Partnering &Investment Forum at the New York Academy of Sciences and will be featured at the forthcoming Sachs Global Conferences in 2014 and 2015.

Related articles on this site include:

conceived: NEW Definition for Co-Curation in Medical Research

Cancer Biology and Genomics for Disease Diagnosis, Volume One Pre-ePub Announcement

Volatile Organic Compounds (VOCs) as Biomarkers in Cancer Detection: • Alnion Ranked #1 in “Top 10 Israeli medical advances to watch in 2014”.

Investing and inventing: Is the Tango of Mars and Venus Still on

SACHS Associates, London – Planning Forthcoming Conferences: 2014 – 2015

 

 

 

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Heroes in Medical Research: Developing Models for Cancer Research

Author, Curator: Stephen J. Williams, Ph.D.

 

The current rapid progress in cancer research would have never come about if not for the dedication of past researchers who had developed many of the scientific tools we use today. In this issue of Heroes in Medical Research I would like to give tribute to the researchers who had developed the some of the in-vivo and in-vitro models which are critical for cancer research.

 

The Animal Modelers in Cancer Research

Helen Dean King, Ph.D. (1869-1955)

Helen Dean King

Helen Dean King, Ph.D. from www.ExplorePAhistory.com; photo Courtesy of the Wistar Institute Archive Collection, Philadelphia, PA

 

 

The work of Dr. Helen Dean King on rat inbreeding led to development of strains of laboratory animals. Dr. King taught at Bryn Mawr College, then worked at University of Pennsylvania and the Wistar Institute under famed geneticist Thomas Hunt Morgan, researching if inbreeding would produce harmful genetic traits.   At University of Pennsylvania she examined environmental and genetic factors on gender determination.

 

 

 

 

Important papers include [1-6]as well as the following contributions:

“Studies in Inbreeding”, “Life Processes in Gray Norway Rats During Fourteen Years in Captivity”, doctoral thesis on embryologic development in toads (1899)

 

Milestones include:

 

1909    started albino rat breeding and bred 20 female and male from same litter (King colony) to 25

successive generations (inbreeding did not cause harmful traits)

 

1919     started to domesticate the wild Norwegian rats that ran thru Philadelphia (six pairs Norway rats

thru 28 generations)

A good reference for definitions of rat inbreeding versus line generation including a history of Dr. King’s work can be found at the site: Munificent Mischief Rattery and a brief history here.[7] In addition, Dr. King had investigated using rat strains as a possible recipient for tumor cells. The work was an important advent to the use of immunodeficient models for cancer research.

 

As shown below Philadelphia became a hotbed for research into embryology, development, genetics, and animal model development.

 

Beatrice Mintz, Ph.D.

(Beatrice Minz, Ph.D.; photo credit Fox Chase Cancer Center, www.pubweb.fccc.edu) Mintz

Dr. Mintz, an embryologist and cancer researcher from Fox Chase Cancer Center in Philadelphia, PA, contributed some of the most seminal discoveries leading to our current understanding of genetics, embryo development, cellular differentiation, and oncogenesis, especially melanoma, while pioneering techniques which allowed the development of genetically modified mice.

If you get the privilege of hearing her talk, take advantage of it. Dr. Mintz is one of those brilliant scientists who have the ability to look at a clinical problem from the viewpoint of a basic biological question and, at the same time, has the ability to approach the well-thought out questions with equally well thought out experimental design. For example, Dr. Mintz asked if a cell’s developmental fate was affected by location in the embryo. This led to her work by showing teratocarcinoma tumor cells in the developing embryo could revert to a more normal phenotype, essentially proving two important concepts in development and tumor biology:

  1. The existence of pluripotent stem cells
  2. That tumor cells are affected by their environment (which led to future concepts of the importance of tumor microenvironment on tumor growth

Other seminal discoveries included:

  • Development of the first mouse chimeras using novel cell fusion techniques
  • With Rudolf Jaenisch in 1974, showed integration of viral DNA from SV40, could be integrated into the DNA of developing mice and persist into adulthood somatic cells, the first transgenesis in mice which led ultimately to:
  • Development of the first genetically modified mouse model of human melanoma in 1993

Her current work, seen on the faculty webpage here, is developing mice with predisposition to melanoma to uncover risk factors associated with the early development of melanoma.

In keeping with the Philadelphia tradition another major mouse model which became seminal to cancer drug discovery was co-developed in the same city, same institute and described in the next section.

It is interesting to note that the first cloning of an animal, a frog, had taken place at the Institute for Cancer Research, later becoming Fox Chase Cancer Center, which was performed by Drs. Robert Briggs and Thomas J. King and reported in the 152 PNAS paper Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs.[8]

 

 The Immunodeficient Animal as a Model System for Cancer Research – Dr. Mel Bosma, Ph.D.

 

Bosma

Melvin J. Bosma, Ph.D.; photo credit Fox Chase Cancer Center

In the summer of 1980 at Fox Chase Cancer Center, Dr. Melvin J. Bosma and his co-researcher wife Gayle discovered mice with deficiencies in common circulating antibodies and since, these mice were littermates, realized they had found a genetic defect which rendered the mice immunodeficient (upon further investigation these mice were unable to produce mature B and T cells). These mice were the first scid (severe combined immunodeficiency) colony. The scid phenotype was later found to be a result of a spontaneous mutation in the enzyme Prkdc {protein kinase, DNA activated, catalytic polypeptide} involved in DNA repair, and ultimately led to a defect in V(D)J recombination of immunoglobulins.

The emergence of this scid mouse was not only crucial for AIDS research but was another turning point in cancer research , as researchers now had a robust in-vivo recipient for human tumor cells. The orthotopic xenograft of human tumor cells now allowed for studies on genetic and microenvironmental factors affecting tumorigenicity, as well as providing a model for chemotherapeutic drug development (see Suggitt for review and references)[9]. A discussion of the pros and cons of the xenograft system for cancer drug discovery would be too voluminous for this post and would warrant a full review by itself. But before the advent of such scid mouse systems researchers relied on spontaneous and syngeneic mouse tumor models such as the B16 mouse melanoma and Lewis lung tumor model.

Other scid systems have been developed such as in the dog, horse, and pig. Please see the following post on this site The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research. The athymic (nude) mouse (nu/nu) also is a popular immunodeficient mouse model used for cancer research

Two other in-vivo tumor models: Patient Derived Xenografts (PDX) and Genetically Engineered Mouse models (GEM) deserve their own separate discussion however the success of these new models can be attributed to the hard work of the aforementioned investigators. Therefore I will post separately and curate PDX and GEM models of cancer and highlight some new models which are having great impact on cancer drug development.

 

References

1.         Loeb L, King HD: Transplantation and Individuality Differential in Strains of Inbred Rats. The American journal of pathology 1927, 3(2):143-167.

2.         Lewis MR, Aptekman PM, King HD: Retarding action of adrenal gland on growth of sarcoma grafts in rats. J Immunol 1949, 61(4):315-319.

3.         Aptekman PM, Lewis MR, King HD: Tumor-immunity induced in rats by subcutaneous injection of tumor extract. J Immunol 1949, 63(4):435-440.

4.         Lewis MR, Aptekman PM, King HD: Inactivation of malignant tissue in tumor-immune rats. J Immunol 1949, 61(4):321-326.

5.         Lewis MR, King HD, et al.: Further studies on oncolysis and tumor immunity in rats. J Immunol 1948, 60(4):517-528.

6.         Aptekman PM, Lewis MR, King HD: A method of producing in inbred albino rats a high percentage of immunity from tumors native in their strain. J Immunol 1946, 52:77-86.

7.         Ogilvie MB: Inbreeding, eugenics, and Helen Dean King (1869-1955). Journal of the history of biology 2007, 40(3):467-507.

8.         Briggs R, King TJ: Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proceedings of the National Academy of Sciences of the United States of America 1952, 38(5):455-463.

9.         Suggitt M, Bibby MC: 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clinical cancer research : an official journal of the American Association for Cancer Research 2005, 11(3):971-981.

 

Other posts on this site about Cancer, Animal Models of Disease, and other articles in this series include:

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

A Synthesis of the Beauty and Complexity of How We View Cancer

Guidelines for the welfare and use of animals in cancer research

Importance of Funding Replication Studies: NIH on Credibility of Basic Biomedical Studies

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations:

What`s new in pancreatic cancer research and treatment?

Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

 

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Leaders in Pharmaceutical Business Intelligence announce their latest addition to the BioMed e-Series ebooks: Cancer Biology and Genomics for Disease Diagnosis, Volume One.

This ebook is a compendium of recent breakthroughs, articles, and commentary on cancer research, cancer detection and diagnosis and treatment, written and curated by a team of PhD, MD, MD/PhD, PharmD clinicians, scientists, and writers having expertise in oncology.

Leaders in Pharmaceutical Business Intelligence will demonstrate this e-book at  The Sachs Cancer Bio Partnering and Investment Forum, held March 19, 2014 at the New York Academy of Sciences in New York, USA.

A post on this site entitled The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development, 19th March 2014 • New York Academy of Sciences • USA explains the program, agenda, a description of this investment conference.

A flyer of the demonstration by Leaders in Pharmaceutical Intelligence is included below (please click on picture):

SACHS FLYER 2014 CANCER EBOOKjpeg-page1

SACHS FLYER 2014 CANCER EBOOKjpeg-page2

 

The flyer can be downloaded as a .pdf here: SACHS FLYER 2014 CANCER EBOOK

April 2014 will see LAUNCH of next VOLUME in Series C: e-Books on Cancer & Oncology Radiation Oncology & Immunotherapy in Cancer

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Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology

Reporter: Aviva Lev-Ari, PhD, RN

Immunotherapy startup lands $120M Series A for cancer-killing drugs

December 4, 2013 | By 

Once-rival researchers from the Fred Hutchinson Cancer Research Center and Memorial Sloan-Kettering Cancer Center have decided to join forces and dive into drug development, hauling in a massive $120 million Series A round to advance “smart” T cells that spur an immunologic attack on cancers.

Their startup, Juno Therapeutics, unites some of the brightest minds in immunotherapy development around the idea of using chimeric antigen receptors to reprogram a patient’s T cells and transform them into cancer-fighting agents. Juno’s leadership believes the platform will lead to promising drug candidates for hematologic and solid tumor cancers, and they’ve recruited the Seattle Children’s Research Institute to pitch in on pediatric development.

The $120 million raise, provided by investors like ARCH Venture Partners and the Alaska Permanent Fund, will help get some of Juno’s candidates through Phase I, and the company is already trumpeting its early results as “unprecedented.” Juno’s drug completely eradicated cancer cells in 10 of 12 leukemia patients after a single infusion, the company said–results cofounder and former National Cancer Institute Director Richard Klausner called the most exciting data he’s seen in 30 years of immunotherapy research. 

The new company has yet to disclose side effects, survival rates or full-scale data from those studies, but the early promise was enough to lure some high-dollar backing, and Juno has recruited a CEO with experience bringing a T cell-altering immunotherapy to market, installing former Dendreon chief Hans Bishop to lead the way. And the company is hardly short on ambition, setting course on a broad clinical program with plans to run concurrent trials on numerous cancers, Bishop said.

“Juno brings together renowned scientists and exceptional investment partners to launch and quickly scale an enterprise that will deliver cutting-edge cancer immunotherapy,” Bishop said in a statement. “It is a completely unique opportunity that holds the potential to truly save lives while transforming how we treat cancer.”

- read the announcement
– check out FiercePharmaManufacturing‘s take

Related Articles:
Merck spotlights promising data on ‘breakthrough’ cancer immunotherapy MK-3475
Roche, immatics forge immunotherapy cancer R&D deal worth up to $1B
Immune Design recruits new team, lands $32.5M for cancer immunotherapies

Read more: Immunotherapy startup lands $120M Series A for cancer-killing drugs – FierceBiotech http://www.fiercebiotech.com/story/immunotherapy-startup-lands-120m-series-cancer-killing-drugs/2013-12-04#ixzz2qPjUNOxe

SOURCE

Amazon ($AMZN) founder and new media mogul Jeff Bezos is investing a bit of his personal fortune in Seattle-based Juno Therapeutics, a biotech startup that’s been making some big waves in the immunotherapy world.

Just weeks after Juno launched with great fanfare, the biotech announced that Bezos’ personal investment group, Bezos Expeditions, helped add $25 million to Juno’s already bountiful $120 million A round with the assistance of Venrock. Juno also added some marquee players to its board today, including Marc Tessier-Lavigne, the former CSO at Genentech and current president of The Rockefeller University in New York City.

Juno is the brainchild of some of the world’s top scientists at the Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering and the Seattle Children’s Research Institute. The company in-licensed technology from St. Jude’s regarding chimeric antigen receptors, which its founders believe can be used to reprogram immune T cells that can then be directed against cancer cells. That CAR-T tech is similar to the approach being used by Novartis ($NVS) and the University of Pennsylvania’s Carl June, and the principals are already deep into litigation over the intellectual property that’s being employed.

In early research, the founders say that Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology.

Bezos has been investing some of his Amazon fortune in a variety of ventures, including Business Insider, the Washington Post and Sapphire Energy. But this is the first straight biotech investment that Fierce has come across so far.

“This is an exciting time for Juno,” said Hans Bishop, CEO, in a statement. “The investments from Bezos Expeditions and Venrock will help accelerate our growth as we work to transform how we treat cancer.”

SOURCE
From: FierceBiotech <editors@fiercebiotech.com>
Date: Tue, 14 Jan 2014 18:24:32 +0000 (GMT)
To: <avivalev-ari@alum.berkeley.edu>

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Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Reviewer and Co-Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

The role of ion channels in Na(+)-K(+)-ATPase: regulation of ion
transport across the plasma membrane has been studied by our Team in 2012 and 2013. This is article TWELVE in a 13 article series listed at the end of this article.

Chiefly, our sources of inspiration were the following:

1.            2013 Nobel work on vesicles and calcium flux at the neuromuscular junction

Machinery Regulating Vesicle Traffic, A Major Transport System in our Cells 

The 2013 Nobel Prize in Physiology or Medicine is awarded to Dr. James E. Rothman, Dr. Randy W. Schekman and Dr. Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells. This represents a paradigm shift in our understanding of how the eukaryotic cell, with its complex internal compartmentalization, organizes the routing of molecules packaged in vesicles to various intracellular destinations, as well as to the outside of the cell. Specificity in the delivery of molecular cargo is essential for cell function and survival. 

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/advanced-medicineprize2013.pdf

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

2. Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

3.            Professor David Lichtstein, Hebrew University of Jerusalem, Dean, School of Medicine

Lichtstein’s main research focus is the regulation of ion transport across the plasma membrane of eukaryotic cells. His work led to the discovery that specific steroids that have crucial roles, as the regulation of cell viability, heart contractility, blood pressure and brain function. His research has implications for the fundamental understanding of body functions, as well as for several pathological states such as heart failure, hypertension and neurological and psychiatric diseases.

Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

Reporter: Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/18/physiologist-professor-lichtstein-chair-in-heart-studies-at-the-hebrew-university-elected-dean-of-the-faculty-of-medicine-at-the-hebrew-university-of-jerusalem/

4.            Professor Roger J. Hajjar, MD at Mount Sinai School of Medicine

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

5.            Seminal Curations by Dr. Aviva Lev-Ari on Genetics and Genomics of Cardiovascular Diseases with a focus on Conduction and Cardiac Contractility

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Other related research by the Team of Leaders in Pharmaceutical Business Intelligence published on the Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

See References to articles at the end of this article on

  • ION CHANNEL and Cardiovascular Diseases

http://pharmaceuticalintelligence.com/?s=Ion+Channel

  • Calcium Role in Cardiovascular Diseases – The Role of Calcium Calmodulin Kinase  (CKCaII) and Ca(2) flux
  • Mitochondria and Oxidative Stress Role in Cardiovascular Diseases

Thus, the following article follows a series of articles on ion-channels and cardiac contractility mentioned, above. The following article is closely related to the work of Prof. Lichtstein.

These investigators studied the possible correlation between

  • Myocardial Ischemia (Coronary Artery Disease (CAD)) aka Ischemic Heart Disease (IHD) and
  • single-nucleotide polymorphisms  (SNPs) genes encoding several regulators involved in Coronary Blood Flow Regulation (CBFR), including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

They completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as

  • the whole coding region of KCN5A gene (Kv1.5 channel).
The work suggests certain genetic polymorphisms may represent a non-modifiable protective factor that could be used
  • to identify individuals at relatively low-risk for cardiovascular disease
  • an independent protective role of the
    • rs5215_GG against developing CAD and
    • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction

Their findings are a lead into further investigations on ion channels and IHD affecting the microvasculature.

Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

F Fedele1•M Mancone1•WM Chilian2•P Severino2•E Canali•S Logan•ML DeMarchis3•M Volterrani4•R Palmirotta3•F Guadagni3

1Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences,Sapienza University of Rome, UmbertoI Policlinic, Rome, Italy  e-mail:francesco.fedele@uniroma1.it
2Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, Rootstown,OH
3Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana,Rome,It
4Cardiovascular Research Unit, Department of Medical Sciences, Centre for Clinical and Basic Research, Raffaele Pisana, Rome, Italy (CBFR)

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4
This article is published with open access at Springerlink.com

Abstract

Conventionally,ischemic heart disease (IHD) study is equated with large vessel coronary disease (CAD). However, recent evidence has suggested

  • a role of compromised microvascular regulation in the etiology of IHD.

Because regulation of coronary blood flow likely involves

  • activity of specific ion-channels, and
  • key factors involved in endothelium-dependent dilation,

genetic anomalies of ion-channels or specific endothelial-regulators may underlie coronary microvascular disease.

We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for

  • ion-channels expressed in the coronary vasculature and the possible
  • correlation with IHD resulting from microvascular dysfunction.

242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, 

  • analyzing genetic polymorphisms relative to

(1) NOS3 encoding for endothelial nitric oxide synthase (eNOS);
(2) ATP2A2 encoding for the Ca/H-ATP-ase pump (SERCA);
(3) SCN5A encoding for the voltage-dependent Na channel (Nav1.5);
(4) KCNJ8 and in KCNJ11 encoding for the Kir6.1and Kir6.2 subunits
of genetic K-ATP channels, respectively;and
(5) KCN5A encoding for the voltage-gated K channel (Kv1.5).

No significant associations between clinical IHD manifestations and

  • polymorphisms for SERCA, Kir6.1, and Kv1.5. were observed (p[0.05),

whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with

  • IHD and microvascular dysfunction.

 Interestingly, genetic polymorphisms of ion-channels  seem to have an important clinical impact

  • influencing the susceptibility for microvascular dysfunction and (IHD,
  • independent of the presence of classic cardiovascular risk factors: atherosclerosis   

http//dx.dio.org/10.1007/s00395-013-0387-4

Keywords: Ion-channels, Genetic polymorphisms, Coronary microcirculation, Endothelium, Atherosclerosis Ischemic heart disease

 Introduction

Historically, in the interrogation of altered vascular function in patientswith ischemic heart disease (IHD), scientists have focused their attention on the correlation between

  • endothelial dysfunction and
  • atherosclerosis [11, 53, 6567].

The endothelium-independent dysfunction in coronary microcirculation and its possible correlations with  

  • atherosclerotic disease and
  • myocardial ischemia has not been extensively investigated.

In normal conditions, coronary blood flow regulation (CBFR) is mediated by several different systems, including

  • endothelial,
  • nervous,
  • neurohumoral,
  • myogenic, and
  • metabolic mechanisms [2, 10, 14, 15, 63, 64, 69].

Physiologic CBFR depends also on several ion channels, such as

  • ATP-sensitive potassium (KATP) channels,
  • voltage-gated potassium (Kv) channels,
  • voltage-gated sodium (Nav) channels, and others.

Ion channels regulate the concentration of calcium in both

  • coronary smooth muscle and endothelial cells, which
  • modulates the degree of contractile tone in vascular muscle and
  • the amount of nitric oxide that is produced by the endothelium

Ion channels play a primary role in the rapid response of both

  • the endothelium and vascular smooth muscle cells of coronary arterioles
  • to the perpetually fluctuating demands of the myocardium for blood flow
    [5, 6, 13, 18, 33, 45, 46, 51, 52, 61, 73, 75].

Despite this knowledge, there still exists an important gap about 

  • the clinical relevance and 
  • causes of microvascular dysfunction in IHD

By altering the overall

  • regulation of blood flow in the coronary system,
  • microvascular dysfunction could alter the normal distribution of shear forces in large coronary arteries

Proximal coronary artery stenosis could

  • contribute to microvascular dysfunction [29, 60]. But
  • ion channels play a critical role in microvascular endothelial
  • and smooth muscle function.

Therefore, we hypothesized  that alterations of coronary ion  channels could be the primary cause in a chain of events leading to

  • microvascular dysfunction and 
  • myocardial ischemia

independent of the presence of atherosclerosis.

Therefore, the objective of our study was to evaluate the possible correlation between

  • IHD and single-nucleotide polymorphisms  (SNPs) for genes encoding several regulators involved in CBFR, including
  • ion channels acting in vascular smooth muscle and/or
  • endothelial cells of coronary arteries.

Discussion

Implications of the present work. This study describes the possible correlation of polymorphisms in genes encoding for CBFR effectors (i.e., ion channels, nitric oxide synthase, and SERCA) with the susceptibility for microcirculation dysfunction and IHD.

Our main findings are as follows: (Group 3 – Normal Patients – anatomically and functionally normal coronary arteries).

  • In Group 3, the genotype distribution of SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
  • In Group 1 (CAD), the polymorphism rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
  • The genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 is inconsistent with the HW equilibrium in groups 1, 2, and 3 (p = 0.0001, p = 0.0012 and p = 0.0001, respectively).

Haplotype analyses revealed that there is no linkage disequilibrium between polymorphisms of the analyzed genes. There was no significant difference in the prevalence of T2DM (p = 0.185) or dyslipidemia (p = 0.271) between groups, as shown in Table2. In regards to genetic characteristics, no significant differences between the three.

1. A marked HW disequilibrium in the genotypic distribution of rs1799983 polymorphism for eNOS/NOS3 was observed in all three populations. Moreover, this SNP seems to be an independent risk factor for microvascular dysfunction, as evidenced by multivariate analysis;
2. The SNPs rs5215_GG, rs5218_CT, and rs5219_AA for Kir6.2/KCJ11 could reduce susceptibility to IHD, since they were present more frequently in patients with anatomically and functionally normal coronary arteries;
3. In particular, with regard to rs5215 for Kir6.2/KCJ11, we observed a moderate deviation from the HW equilibrium in the genotypic
distribution in the control group. In addition, this genotype appears to be an independent protective factor in the development of IHD, as evidenced by multivariate analysis;
4. Furthermore, the trend observed for the SNP  rs5219_AA of Kir6.2/KCNJ11 may suggest an independent protective factor  in the development of coronary microvascular dysfunction
5. The rs1805124_GG genotype of Nav1.5/SCN5A seems to play a role against CAD;
6. No association seems to exist between the polymorphisms of SERCA/ATP2A2, Kir6.1/KCNJ8, and Kv1.5/KCNA5 and the presence of IHD;
7. All groups are comparable regarding the cardiovascular risk factors of T2DM and dyslipidemia, illustrating a potentially important implication of genetic polymorphisms in the susceptibility to IHD.

It is important to underline that the control group (Group 3) is a high-risk population, because of their cardiovascular risk factors

  • hypertension = 17 %,
  • T2DM = 34.1 %,
  • dyslipidemia = 41.4 %,

with an appropriate indication for coronary angiography, in accordance with current guidelines. Nevertheless, these patients were demonstrated to have both anatomically and functionally normal coronary arteries. Moreover, as shown in Tables 2 and 3, we observed that

  • rs5215_GG, rs5218_CT and rs5219_AA for Kir6.2/KCNJ11 had a higher prevalence in this group,compared to patients with CAD
  • and patients with microvascular dysfunction.

Moreover, as shown in Table 4, the presence of the rs5215_GG polymorphism for the Kir6.2 subunit was

  • inversely correlated with the prevalence of cardiovascular risk factors and CAD,whereas
  • rs5219_AA of the Kir6.2 subunit trended towards an inverse correlation with coronary microvascular dysfunction.

On the other hand, the SNP rs1799983_GT of eNOS was

  • confirmed to be an independent risk factor for microvascular dysfunction.

Our data suggest that the presence of certain genetic polymorphisms may represent a non-modifiable protective factor that could be used

  • to identify individuals at relatively low-risk for cardiovascular disease,
  • regardless of the presence of T2DM and dyslipidemia.

Current Clinical and Research Context

In normal coronary arteries, particularly the coronary microcirculation, there are several different mechanisms of CBFR, including

  • endothelial, neural, myogenic, and metabolic mediators [2, 8, 10, 12, 14, 15, 37, 55, 63, 64, 69].

In particular, endothelium-dependent vasodilation acts mainly via eNOS-derived nitric oxide (NO) in response to acetylcholine and shear stress.

  • NO increases intracellular cyclic guanosine monophosphate. It also causes vasodilation via
  • activation of both K-Ca channels and K-ATP channels.

Recent data suggested a pathophysiologically relevant role for the polymorphisms of eNOS/NOS3 in human coronary vasomotion [40–43]. Our data suggest that rs1799983_GT at exon 7 (Glu298Asp, GAG-GAT) of eNOS/NOS3 represents

  • an independent risk factor for coronary micro-vascular dysfunction, which agrees with a recent meta-analysis reporting an
  • association of this SNP with CAD in Asian populations [74]. In addition,
  • this SNP has been associated with endothelial dysfunction, although the mechanisms are not well defined [30].

Consistently, a recent study performed on 60 Indian patients with documented history of CAD reported a significantly higher frequency of rs1799983 (p.05) compared to control subjects, indicating that

  • variations in NOS3 gene may be useful clinical markers of endothelial dysfunction in CAD [54].
Interestingly, another association between rs1799983_GT and impaired collateral development has been observed in patientswith a

  • high-grade coronary stenosis or occlusion [19].
As is well known, the significance of the mechanisms of CBFR is partly determined by the location within the coronary vasculature. For instance, for vessels with a diameter of < 200 µm—which comprise the coronary microcirculation—metabolic regulation of coronary blood flow is considered the most important mechanism [24, 63]. Importantly, many of these mediators of metabolic regulation act through specific ion channels. In particular, in both coronary artery smooth muscle cells and endothelial cells
  • potassium channels determine the resting membrane potential (Em) and serve as targets of endogenous and therapeutic vasodilators [9, 27].
Several types of K+ channels are expressed in the coronary tree.
  • The K-ATP channels couple cell metabolic demand to conductance, via pore-forming (Kir6.1 and/or Kir6.2) subunits and regulatory
    [sulphonylurea-binding (SUR 1, 2A, or 2B)] subunits.
  • Kir6.x allows for channel inhibition by ATP, while SURx is responsible for channel activation by ADP and Mg2+.
K-ATP channel activation results in an outward flux of potassium and

  • consequent hyperpolarization, resulting in
  • voltage-gated calcium channel closure,
  • decreased Ca2+ influx, and ultimately
  • vasodilation [1, 5, 18, 20, 21, 33, 61, 62, 73, 75].

Our data do not support any significant difference regarding the Kir6.1 subunit of the K-ATP channel. On the other hand, this study suggests

  • an important role of specific SNPs for the Kir6.2 subunit (Tables 2, 3)—i.e., rs5215, rs5219, and rs5218—

in the susceptibility to IHD and microvascular dysfunction. These SNPs are among the most studied K-ATP channel polymorphisms, especially in the context of diabetes mellitus. In fact, in both Caucasian and Asian populations, these three SNPs as well as other genetic polymorphisms for the KCNJ11 gene have been associated with diabetes mellitus [34, 35, 44, 50, 57, 58, 70].

Nevertheless, the precise

  • structure–function impacts of the various amino acid substitutions remain unclear.

The rs5215 and rs5219 polymorphisms, also known as I337V and E23K, respectively, are highly linked with reported

  • concordance rates between 72 and 100 % [22, 23, 56].

The high concordance between rs5219 and rs5215 suggests that these polymorphisms

  • may have originated in a common ancestor, further indicating a
  • possible evolutionary advantage to their maintenance in the general population [49].

In our study, multivariate analysis suggests both an independent protective role of the

  • rs5215_GG against developing CAD and
  • a trend for rs5219_AA to be associated with protection against coronary microvascular dysfunction (Table 4a, b).
  • The variant rs5215_GG is a missense SNP located in the gene KCNJ11 at exon 1009 (ATC-GTC) and results in
    the substitution of isoleucine (I) residue with valine (V) [23].

Future studies are necessary to better understand the influence of this single amino acid variant on the function of the channel.

In humans, vasodilation of the coronary microvasculature in response to hypoxia and K-ATP channel opening
  • are both impaired in diabetes mellitus [39].
It is also described that gain-of-function mutations of the KCNJ11 gene cause neonatal diabetes mellitus, and loss-of-function mutations lead to congenital hyperinsulinism [43]. Our study is not discordant with previous studies about the correlation of SNPs of the Kir6.2 subunit and diabetes mellitus. Rather, our findings show that these SNPs are correlated with anatomically and functionally normal coronary arteries,
  • independent of the presence of either diabetes mellitus or dyslipidemia.
These data suggest the possibility that these particular SNPs may identify individuals with decreased risk for coronary microcirculatory dysfunction and IHD,
  • regardless of the presence of T2DM and/or dyslipidemia.

However, further studies are necessary to confirm these findings. In this context, to better investigate the implications of genetic variation in the K-ATP channel,

  • future studies should include ion channel’s functional modification due to the SNPs and analysis of SUR subunits.

More than 40-kV channel subunits have been identified in the heart, and sections of human coronary smooth muscle cells demonstrate Kv1.5 immunoreactivity [16, 17, 27, 38]. Through constant regulation of smooth muscle tone, Kv channels contribute to the control of coronary microvascular resistance [4, 7]. Pharmacologic molecules that inhibit Kv1.5 channels such as

  • pergolide [25],
  • 4-amino-pyridine [32], and
  • correolide [17]

lead to coronary smooth muscle cell contraction and block the coupling between

  • cardiac metabolic demand and
  • coronary blood flow.

However, no significant differences were identified between the study groups in terms of the particular polymorphisms for Kv1.5 that were analyzed in this study. Expression of

  • the voltage-dependent Na+ channel (Nav) has been demonstrated in coronary microvascular endothelia cells [3, 66].

Our analysis reveals a possible implication of the polymorphism rs1805124_GG for Nav1.5 channel with the presence of anatomically and functionally normal coronary arteries. This SNP leads to a homozygous 1673A-G transition, resulting in a His558-to-Arg (H558R) substitution. It is important to underline that

  • our data are the first to correlate the polymorphism rs1805124_GG with IHD.

Further research is necessary to confirm the observed implication.

Finally, we have analyzed the sarco/endoplasmic reticulum calcium transporting Ca2+-ATPase (SERCA), which is fundamental in the regulation of intracellular Ca2+ concentration [6].

SERCA is an intracellular pump that

  • catalyzes the hydrolysis of ATP coupled with the
  • translocation of calcium from the cytosol into the lumen of the sarcoplasmic reticulum.

Although this pump plays a critical role in regulation of the contraction/relaxation cycle, our analysis did not reveal any apparent association between

  • genetic variants of SERCA and the
  • prevalence of microvascular dysfunction or IHD.

Conclusions

This pilot study is the first to compare the prevalence of SNPs in genes encoding coronary ion channels between patients
  • with CAD or microvascular dysfunction and those with both anatomically and functionally normal coronary arteries.
Taken together, these results suggest the possibility of associations between SNPs and IHD and microvascular dysfunction, although

  • the precise manners by which specific genetic polymorphisms affect ion channel function and expression
have to be clarified by further research involving larger cohorts.

Limitations and future perspectives

Notable limitations of this pilot study are as follows:

1. Due to the lack of pre-existing data, the power calculation was performed in advance on the basis of assumptions of allele frequencies and the population at risk.
2. The sample size for each group is small, mainly due to both the difficulty in enrolling patients with normal coronary arteries and normal microvascular function (group 3) and the elevated costs of the supplies such as Doppler flow wires.
3. There is a lack of ethnic diversity of our cohort.
4. Currently, there is an absence of supportive findings in another independent cohort or population. However, our pilot study included patients within a well-defined, specific population and was aimed to identify the presence of statistical associations between selected genetic polymorphisms and the prevalence of a specific disease.
5. There is a lack of functional characterization of the described genetic polymorphisms.
6. We have not identified any correlation between novel SNPs and IHD. Nevertheless, we completely analyzed exon 3 of both KCNJ8 and KCNJ11 genes (Kir6.1 and Kir6.2 subunit, respectively) as well as the whole coding region of KCN5A gene (Kv1.5 channel).  Moreover, we examined previously described SNPs since there are no data in the literature regarding the possible association of the prevalences of those polymorphisms in the examined population.More extensive studies are necessary to confirm our  findings, possibly with a larger number of patients. Future investigations are also required to confirm the roles of ion  channels in the pathogenesis of coronary microvascular dysfunction and IHD. These studies should involve analysis of both other subunits of the K-ATP channels

  • sulfonylurea receptor, SURx and further coronary ion channels (e.g., calcium-dependent K channels), as well as
  • in vitro evaluation of ion channel activity by patch clamp and analysis of channel expression in the human cardiac tissue.

Moreover, to better address the significance of microvascular dysfunction in IHD, it could be interesting to analyze

  • typical atherosclerosis susceptibility genes (e.g., PPAP2B, ICAM1, et al.).

Methods

In this prospective, observational, single-center study – 242 consecutive patients admitted to our department were enrolled with

  • the indication to undergo coronary angiography .

All patients matched inclusion criteria

  1. age [18];
  2. suspected or documented diagnosis of acute coronary syndrome or stable angina
  3. with indication(s) for coronary angiography, in accordance with current guidelines [36, 68], and
  4. the same ethno-geographic Caucasian origin) and

Exclusion Criteria

  1. previous allergic reaction to iodine contrast,
  2. renal failure,
  3. simultaneous genetic disease,
  4. cardiogenic shock,
  5. non- ischemic cardiomyopathy

All patients signed an informed consent document  -

prior to participation in the study, which included

  • acknowledgement of the testing procedures to be performed
    (i.e., coronary angiography; intracoronary tests; genetic analysis, and processing of personal data).

The study was approved by the Institution’s Ethics Committee.
All clinical and instrumental characteristics were collected in a dedicated  database.

 Study Design

(a)  Standard therapies were administered, according to current guidelines [36, 68].
(b) An echocardiography was performed before and after coronary angiography
(c)  Coronary angiography was performed using radial artery or femoral artery
Judkins approach via sheath insertion.
(d) In patients showing normal epicardial arteries, intracoronary functional tests
were performed through Doppler flow wire to evaluate

  1. both endothelium-dependent microvascular function
    [via intracoronary (IC) infusion of acetylcholine (2.5–10 lg)] and
  2. nonendothelium-dependent microvascular function
    [via IC infusion of adenosine (5 lg)] [31]. 

(e) In all enrolled patients, a peripheral blood sample for genetic analysis was taken. 

On the basis  of the  coronary angiography and the intracoronary functional tests, 

  • the 242 patients were divided into three groups (see also Fig. 1).
  1. Group 1: 155 patients with anatomic coronary alteration
    (comprising patients with acute coronary syndrome and chronic stable angina).

    • microvascular dysfunction defined as coronary flow reserve (CFR) \ 2.5
    • after IC infusion of acetylcholine and adenosine].
  2. Group 2: 46 patients with functional coronary alteration
    [normal coronary arteries as assessed by angiography, and

    • as assessed by angiography and with normal functional tests
      (CFR C 2.5 after intracoronary infusion of acetylcholine and adenosine) (Fig. 1).
  3. Group 3: 41 patients with anatomically and functionally normal coronary arteries


BRC 2013 fedele genetic polymorphisms of ion channels.pdf_page_2

Fig. 1 Study design: 242 consecutive not randomized patients matching inclusion and exclusion criteria were enrolled.
In all patients, coronary angiography was performed, according to current ESC/ACC/AHA guidelines. In patients with
angiographically normal coronary artery, intracoronary functional tests were performed. In 242 patients
(155 with coronary artery disease, 46 patients with micro-vascular dysfunction, endothelium and/or non-endothelium
dependent, and 41 patients with anatomically and functionally normal coronary arteries) genetic analysis was performed.

Genetic Analysis

In conformity with the study protocol, ethylenediaminetetraacetic acid (EDTA) whole blood samples were collected according
to the international guidelines reported in the literature [48]. Samples were transferred to the Interinstitutional Multidisciplinary
BioBank (BioBIM) of IRCCS San Raffaele Pisana (Rome) and stored at -80 C until DNA extraction. Bibliographic research by
PubMed and web tools OMIM (http://www.ncbi.nlm.nih.gov/omim), Entrez SNP (http://www.ncbi.nlm.nih.gov/snp), and
Ensembl (http://www.ensembl.org/index.html) were used to select variants of genes involved in signaling pathways

  • related to ion channels and/or reported to be associated with
  • microvascular dysfunction and/or myocardial ischemia and/or
  • diseases correlated to IHD, such as diabetes mellitus.
Polymorphisms for the following genes were analyzed:
  1. NOS3 (endothelial nitric oxide synthase, eNOS),
  2. ATP2A2 (Ca2+/H+-ATPase pump, SERCA2),
  3. SCN5A (voltage-dependent Na+ channel,
  4. Nav1.5),
  5. KCNJ11 (ATP-sensitive K+ channel, Kir6.2 subunit),
  6. KCNJ8 (ATP-sensitive K+ channel, Kir6.1 subunit) and
  7. KCNA5 (voltage-gated K+ channel, Kv1.5).

In particular, we completely analyzed by direct sequencing

  • exon 3 of KCNJ8 (Kir6.1 subunit), which includes eight SNPs, as well as
  • the whole coding region of KCNA5 (Kv1.5 channel), which includes 32 SNPs and
  • four previously described variants [26, 47, 71, 72].
We also examined
  • the whole coding region of KCNJ11 (Kir6.2 subunit), for which sequence variants are described [26, 28].

All SNPs and sequence variants analyzed—a total of 62 variants of 6 genes—are listed in Table 1.

BRC 2013 fedele genetic polymorphisms of ion channels_page_004
BRC 2013 fedele genetic polymorphisms of ion channels_page_005

DNA was isolated from EDTA anticoagulated whole blood using the MagNA Pure LC instrument and theMagNA Pure LC
total DNA isolation kit I (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions. Standard
PCR was performed in a GeneAmp PCR System 9700 (Applied Biosystems, CA) using HotStarTaq Master Mix
(HotStarTaq Master Mix Kit, QIAGEN Inc, CA). PCR conditions and primer sequences are listed in Table 1.

In order to exclude preanalytical and analytical errors, all direct sequencing analyses were carried out on both
strands using Big Dye Terminator v3.1 Cycle Sequencing kit
(Applied Biosystems), run on an ABI 3130
Genetic Analyzer (Applied Biosystems), and repeated on PCR products obtained from new nucleic acid extractions.
All data analyses were performed in a blind fashion.

Statistical Analysis

This report, intended as pilot study, is the first to compare

  • the prevalence of SNPs in genes encoding  several effectors (including ion channels)
  • involved in CBFR between these groups of patients.

No definite sample size could be calculated to establish a power analysis. groups of patients. However, assuming

  • a 15 % prevalence of normal  macrovascular and microvascular coronary findings in unselected patients
    undergoing coronary angiography,

we estimated that

  • a sample size of at least 150 patients could enable the computation of two-sided 95 % confidence intervals for
    • such prevalence estimates ranging between -5.0 and + 5.0 %.

The significance of the differences of observed alleles and genotypes between groups, as well as

  • analysis of multiple inheritance models for SNPs were also tested
    (co-dominant, dominant, recessive, over-dominant and log-additive)
  • using a free web-based application (http://213. 151.99.166/index.php?module=Snpstats)
  • designed from a genetic epidemiology  point of view to analyze association studies.

Akaike Information Criterion (AIC) was used to determine the best-fitting inheritance model for analyzed SNPs,

  • with the model with the lowest AIC reflecting the best balance of  goodness-of-fit and parsimony.

Moreover,  the allelic frequencies were estimated by gene counting, and the genotypes were scored. For each gene,

  • the observed numbers of each genotype were compared with those expected for a population in Hardy–Weinberg (HW) equilibrium
  • using a free web-based application  (http://213.151.99.166/index.php?module=Snpstats) [59].

Linkage disequilibrium coefficient (D0) and  haplotype analyses were assessed using  the  Haploview 4.1 program.
Statistical analysis was performed using SPSS software package for Windows v.16.0 (SPSS Inc., Chicago, IL).

All categorical variables are expressed as percentages, and all continuous variables as mean ± standard deviation.
Differences between categorical variables

  • were analyzed by Pearson’s Chi-SQ test.

Given the presence of three groups, differences  between continuous variables, were calculated using
(including the number of SNPs tested),

  • one-way ANOVA; a post-hoc analysis with Bonferroni correction was made for multiple comparisons.

Univariate and multivariate logistic regression analyses

  • the independent impact of genetic polymorphisms on
    • coronary artery disease and microvascular dysfunction,

were performed to assess the independent impact of

  • genetic polymorphisms on coronary artery disease
    and microvascular dysfunction
    ,

while adjusting for other confounding variables.  The following parameters were entered into the model:

  • age,
  • male gender,
  • type 2 diabetes mellitus (T2DM),
  • systemic arterial hypertension,
  • dyslipidemia,
  • smoking status, and
  • family history of myocardial infarction (MI).

Only variables with a p value < 0.10 after univariate analysis were entered

  • into the multivariable model as covariates.

A two-tailed p < 0.05 was considered statistically significant.

Definition of Cardiovascular Risk Factors

Patients were classified as having T2DM if they had

  • fasting levels of glucose of >126 mg/dL in two separate measurements or
  • if they were taking hypoglycemic drugs.

Systemic arterial hypertension was defined as

  • systolic blood pressure  > 140 mmHg / diastolic blood pressure > 90 mmHg
  • in two separate measurements or
  • if the patient was currently taking antihypertensive drugs.

Dyslipidemia was considered to be present if

  • serum cholesterol levels were>220 mg/dL or
  • if the patient was being treated with cholesterol-lowering drugs.

Family history of MI was defined as a first-degree relative with MI before the age of 60 years.

Results

Sixty-two polymorphisms distributed among six genes coding for
  • nitric oxide synthase,
  • the SERCA pump, and
  • ion channels
    • were screened for sequence variations using PCR amplification and
    • direct DNA sequencing analysis

in the population of

  • 155 patients with CAD (group 1),
  • 46 patients with microvascular dysfunction (group 2), and
  • 41 patients with normal coronary arteries and
    • normal endothelium dependent and endothelium-independent vasodilation (group 3).
In Group 3, the genotype distribution of

  • SNP rs5215 (Kir6.2/KCNJ11) moderately deviates from the HW equilibrium (p = 0.05).
In Group 1 (CAD), the polymorphism

  • rs6599230 of Nav1.5/SCN5A showed deviation from HW equilibrium (p = 0.017).
The genotypic distribution of groups in terms of polymorphisms for
  • eNOS/NOS3, SERCA/ATP2A2, Nav1.5/SCN5A, Kir6.1/KCNJ8, or Kv1.5/KCNA5
were noticed. However, significant differences (p.05) for the SNPs
  • rs5215_GG, and
  • rs5219_AA of Kir6.2/KCNJ11 were observed,
as shown in Table 2. 

Table 3 displays 
significant differences between normal subjects (group 3) and
  • patients with either CAD (group 1) or microvascular dysfunction (group 2).

BRC 2013 fedele genetic polymorphisms of ion channels_page_006

When correcting for other covariates as risk factors, the rs5215_GG genotype of Kir6.2/KCNJ11 was found to be 

  • significantly associated with CAD after multivariate analysis (OR = 0.319, p = 0.047, 95 % CI = 0.100–0.991), evidencing
  • a ‘‘protective’’ role of this genotype, as shown in Table 4a.

Similarly, a trend that supports this role of Kir6.2/KCNJ11 was also observed

  • in microvascular dysfunction for rs5219 AA. In contrast,
  • rs1799983_GT for eNOS/NOS3 was identified as an independent risk factor

following multivariate analysis (Table 4b), which agrees with literature findings as described below. 

BRC 2013 fedele genetic polymorphisms of ion channels_page_007

SOURCE for TABLES

BasicResCardiol(2013)108:387   http//dx.dio.org/10.1007/s00395-013-0387-4

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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Mitochondrial Dysfunction and Cardiac Disorders

Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

Mitochondrial Metabolism and Cardiac Function

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix Identified

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

Mitochondrial Dynamics and Cardiovascular Diseases

Ritu Saxena, Ph.D.

http://pharmaceuticalintelligence.com/2012/11/14/mitochondrial-dynamics-and-cardiovascular-diseases/

Mitochondrial Damage and Repair under Oxidative Stress

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Nitric Oxide has a Ubiquitous Role in the Regulation of Glycolysis -with a Concomitant Influence on Mitochondrial Function

Larry H. Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Mitochondrial Mechanisms of Disease in Diabetes Mellitus

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2012/08/01/mitochondrial-mechanisms-of-disease-in-diabetes-mellitus/

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “Powerhouse of the Cell”

Ritu Saxena, PhD

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

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