Posts Tagged ‘Stanford University’

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP


  1. The Human Proteome Map Completed

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


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

Author and Curator, Larry H Bernstein, MD, FCAP


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

Author and Curator, Larry H Bernstein, MD, FCAP

https://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

https://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


6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator




  1. Extracellular evaluation of intracellular flux in yeast cells

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


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

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


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

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


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

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

https://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

https://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


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

Ritu Saxena, PhD


  1. Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena


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

Ritu Saxena


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

Curator: Larry H. Bernstein, MD, FCAP

https://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


  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

https://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

https://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


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

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

https://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:

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

12. Studies of Respiration Lead to Acetyl CoA


13. Lipid Metabolism

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


14. Carbohydrate Metabolism

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


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

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

https://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


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

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

https://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


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

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


20. Mitochondrial Metabolism and Cardiac Function

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


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

Curator: Larry H. Bernstein, MD, FCAP


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

Author and Curator: Stephen J. Williams, PhD

https://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

https://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


25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS


26. Overview of Posttranslational Modification (PTM)

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


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

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

https://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

https://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

https://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

https://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


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

https://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

https://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


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

Larry H Bernstein, MD, FCAP, Author and Curator

https://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

https://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

https://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

https://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

https://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

https://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


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

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


43. Problems of vegetarianism

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


44.  Amyloidosis with Cardiomyopathy

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


45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP


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

Curator and Author: Larry H Bernstein, MD, FACP


47. Nitric Oxide Function in Coagulation – Part II

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


48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP


49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP


50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS


51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS


52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP


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

Curator and Author: Larry H Bernstein, MD, FACP

https://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

https://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

https://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


57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP


58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.


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

https://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


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

Curator and Author: Larry H Bernstein, MD, FACP


Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

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


  1. RNA and the transcription the genetic code

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


  1. A Primer on DNA and DNA Replication

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


4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari


5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP


6. RNA and the transcription the genetic code

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


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

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


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

https://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


10. Regulation of somatic stem cell Function

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


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

Larry H. Bernstein, MD, FCAP, Reporter

https://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


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

Larry H Bernstein, MD, FCAP, Reporter


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

https://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

https://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


17. Silencing Cancers with Synthetic siRNAs

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


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

Reporter: Aviva Lev-Ari, PhD, RN


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

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

https://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


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

Reporter: Aviva Lev-Ari, PhD, RN

https://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

https://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


24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

https://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


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

Author and Curator, Larry H Bernstein, MD, FCAP

https://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

https://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


29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD


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

     Aviva Lev-Ari, PhD, RN

https://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


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

Aviva Lev-Ari, PhD, RN

https://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


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

A Lev-Ari, PhD, RN

https://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

https://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

https://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

https://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


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

Aviva Lev-Ari, PhD, RN

https://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

https://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

https://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


43. Directions for genomics in personalized medicine

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


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

Stephen J Williams, PhD

https://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


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

Aviva Lev-Ari, PhD, RD

https://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


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

Aviva Lev-Ari, PhD, RD

https://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

https://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

https://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


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

Aviva Lev-Ari, PhD, RD

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

Signaling Pathways

  1. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator


  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


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

Sudipta Saha, PhD

https://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

https://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

https://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


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

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

https://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


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

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

https://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


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

https://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

https://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


14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator


15.  Regulation of somatic stem cell Function

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


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

Larry H. Bernstein, MD, FCAP, Reporter


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Stanford Dropout is Already Drawing Comparisons with Steve Jobs

Larry H Bernstein, MD, Reporter

An interview by Eric Topol on Medscape of a 29 year-old Stanford University dropout is fascinating.

Editor’s Note:

If 29-year-old Elizabeth Holmes has her way, patients will no longer have to go to physicians’ offices, hospitals or laboratories to get high-complexity diagnostic blood tests. Nor will vial after vial of blood draws be necessary to do these tests.

Barely out of the gate after a decade of secrecy, the Stanford dropout is already drawing comparisons with Steve Jobs (she often wears the same black turtleneck). And her company, Theranos, Inc., which emerged from the shadows in September, just might be healthcare’s answer to Apple.[1] The so-called disruptive technology that Ms. Holmes, a former engineering major, and Theranos have created is said to have the potential to shake up and forever change the way laboratory medicine is conducted. Since forgoing college at 19, Ms. Holmes has secured millions of dollars in funding for her new venture, including $45 million in private equity funding in 2010.[2] The board of directors of her company is a Who’s Who of distinguished former and current technology, academic, and government officials.[2,3]

In an exclusive interview, Ms. Holmes talks to Medscape Editor-in-Chief Eric J. Topol, MD, about the decade she spent building her company; plans for the present and the future, including a recent deal with Walgreens drugstores; and whether she’s on the path to the creative destruction of laboratory medicine.

Leaving Stanford at Age 19

Dr. Topol: Hello. I’m Dr. Eric Topol, Editor-in-Chief of Medscape. Joining me today for Medscape One-on-One is Elizabeth Holmes, Founder, President, and CEO of Theranos.  We are here in Palo Alto, California, at the company’s headquarters. Elizabeth, welcome. This is going to be a fascinating discussion.

Ms. Holmes: Thank you. It’s wonderful to be here and have you here.

Dr. Topol: This is a story that has been brewing for a long time. You were at Stanford University, and at age 19 you decided to change your path. Is that right?

Ms. Holmes: Yes.

Dr. Topol: What made you think, “I’m on to something, and I don’t want to do college; I’ve got something else that’s  probably bigger than that”?

Ms. Holmes: I knew that I wanted to do something that could make a difference in the world.

To me, there was nothing greater that I could build than something that would change the reality in our healthcare system today, which is that when someone you love gets really, really sick, usually by the time you find that out, it’s too late to be able to do something about it. And in those moments it’s heartbreaking, because there is nothing you wouldn’t do.


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Four Startups After One Year: Biodesign entrepreneurship program @ Hebrew University-Hadassah Medical Center

Reporter: Aviva Lev-Ari, PhD, RN


Israel’s First Biodesign Program Produces Four Startups After One Year

August 6, 2013

Students in Hebrew University-Hadassah Medical Center program develop “science fiction gadgets”

Biodesign entrepreneurship program is Israel’s first medical innovation accelerator

Jerusalem — As health costs spiraled over the last decade, the need for more cost-effective health care systems has become increasingly urgent. Medical innovation plays a vital role in making medicine both efficient and affordable — not to mention improving the quality of patient care and ensuring positive outcomes. However, the process of creating new medical devices requires an in-depth understanding of multiple disciplines including medicine, engineering, and finance that few could master alone. As a result, most aspiring medical innovators face disappointment as the vast majority of ideas fail before reaching the market.

According to Dr. Yaakov Nahmias, the director of The Hebrew University of Jerusalem’s Center for Bioengineering, “When it comes to bringing an idea to market, there is a huge disparity between Hi-Tech, where a few programmers can succeed, and Bio-Tech, where clinicians, engineers, and business experts must all work together to bring a product to the market.”

To solve this problem, Nahmias partnered with Professor Chaim Lotan, the director of Hadassah Medical Center’s Heart Institute and an expert in clinical innovation. According to Prof. Lotan, “We knew that Stanford University’s Biodesign program was the most successful medical innovation program to date, and considering the outstanding students at The Hebrew University and Hadassah we were certain we could give them a run for their money.”

Developing “science fiction gadgets” GuideIN Tube, MetaboShield, SAGIV, and DCDI at the Biodesign program of the Hebrew University of Jerusalem and Hadassah Medical Center

The two partnered with Professor Dan Galai, the former Dean of the Business School at The Hebrew University, and with the help of Dr. Todd Brighton, a Biodesign program director at Stanford University, established The Hebrew University’s Biodesign Medical Innovation Program, the first academic medical innovation accelerator in Israel.

View videos on the innovations

Biodesign is a multi-disciplinary, team-based approach to medical innovation. The program takes outstanding medical fellows, bioengineering and business graduate students, and tutors them in the science and practice of bringing a medical innovation to the market. The teams receive a list of clinical problems, collected from Israeli and American hospitals, and critically evaluate their commercial potential. Once they identify a clinical need with commercial potential, they find an engineering solution that can be protected by a patent application.

Developing “science fiction gadgets” GuideIN Tube, MetaboShield, SAGIV, and DCDI at the Biodesign program of The Hebrew University of Jerusalem and Hadassah Medical Center

The students are mentored by some of Israel’s best and brightest academic and industrial experts, who bring their experience in scientific discovery, clinical applications, and business development.

According to the Hebrew University’s Nahmias, “This isn’t a pure academic exercise. We have students and clinicians who are eager to bring innovation to the market. The program generated quite of lot of excitement with the business and academic environment. It is exactly this drive that makes Israel a start-up nation.”

One year after starting with 20 students and medical fellows, the program has already produced four projects that passed through the proof-of-concept stage, are protected by provisional patent applications, and are showing excellent market potential.

One of the projects, called SAGIV, is a semi-automatic handheld device for rapid and safe IV insertion, using infrared sights and electrical sensing. SAGIV targets a $900 million market with elements already tested on difficult IV insertion cases at the Hadassah Medical Center.

Another project, called GuideIN Tube, is a robotic intubation device which automatically navigates towards the lungs, targeting a $3 billion market.

“The projects really look like science fiction gadgets,” said Dr. Nahmias. “Even if just a few Biodesign companies succeed, they can completely transform the Israeli medical device sector.”

“We have incredibly driven students at The Hebrew University, and Biodesign gives them critical tools they need to succeed,” added Prof. Lotan. Both directors noted that students accomplished in one academic year what many start-up companies take 2 to 3 years to complete, advancing to the point of having proof-of-principle prototypes.

Yehuda Zisapel, president of RAD-Bynet Group, one of the largest investment groups in Israel, said: “Biodesign is a truly innovative approach to generate and accelerate new ideas. The cooperative efforts of physicians, scientists, engineers and business development people allows for a multidimensional approach which encourages the creation and development of new ideas. I was really impressed by the team work and the spirit created by the program, and also by the impressive achievements of the projects.”

Hadassah Medical Center’s Prof. Lotan attributes the program’s success to several additional factors: “We are based in Jerusalem, where biotechnology ventures are buoyed by sustained government support. We are backed by the strong track record of Yissum and Hadasit, the technology transfer companies of The Hebrew University and Hadassah Medical Center. And we have an important relationship with Stanford’s Biodesign program, which offers knowledge, experience and course materials. The Biodesign program has increased Stanford University biomed startup success rates by 4 to 5 folds over the last decade. We envision a similar revolution in Jerusalem, where 50% of the medical research in Israel is already taking place.”


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Medscape Update on Calcium and Cardiovascular Risk

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

New Data Dispute Calcium Cardiovascular Risk in Both Sexes

Nancy A. Melville   Oct 08, 2013

Medscape Medical News from the American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting

BALTIMORE — Two new studies contribute further to the debate over the cardiovascular risk associated with supplementary or dietary calcium, each decidedly coming down on the side of no significant risk — to men or women.

“[Based on these findings], clinicians should continue to evaluate calcium intake, encourage adequate dietary intake, and if necessary, use supplements to reach but not exceed recommended intakes,” Douglas C. Bauer, MD, from the University of California, San Francisco, the lead author of the first study, told Medscape Medical News.

Results of both studies were reported at the recent American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting.

Dr. Bauer’s observational trial is one of few contemporary studies to evaluate the level of risk among men, who are often poorly represented in calcium studies, he noted. The results showed no association between calcium dietary intake or supplementation and total or cardiovascular mortality. The second study was an updated meta-analysis of calcium supplementation among women and similarly demonstrated no increased risk for ischemic heart disease (with adjudicated outcomes) or total mortality in elderly women. It did draw some criticism for potential bias and contamination, however.

Nevertheless, says Robert Marcus, MD, a retired Stanford University bone specialist, the 2 studies are “powerful. The one involving men had very elegant, accurate reports of death and validated diagnosis of myocardial infarction, and the [study involving women] was also excellent work,” he commented.

“This field has been the subject of an enormous amount of controversy, ambiguity, and confusion for the past several years, and I think the most important thing is to help us come up with what is true,” he said. The quality of data to suggest an adverse effect of calcium is “very poor,” and there is now compelling evidence that there is little to substantiate this, he noted. But despite these reassuring new findings, public anxiety over a potential risk with calcium is unlikely to go away, he believes.

In recommendations issued in 2010, the ASBMR said that most adults 19 years of age and older require about 600 to 800 IUs of vitamin D daily and 1000 to 1200 mg of calcium daily through food and with supplements, if needed.

Contemporary Data on Calcium Intake in Men

The use of calcium supplements, predominantly with vitamin D, is an important therapy for the prevention of osteoporosis and its clinical consequences. But concerns about the cardiovascular safety of calcium have emerged periodically; in 2 alarming meta-analyses published in 2010 and 2011 by Dr. Mark Bolland and colleagues, for example, there was a 27% increase in MI among individuals allocated to calcium supplements in the first study and a 24% increased risk in the second.

More recently, a 40% increase in total mortality and up to a 50% increase in cardiovascular mortality was seen among women from a Swedish mammography cohort with a calcium intake exceeding 1400 mg per day. In that study, the effect on mortality appeared to be especially strong if a high dietary intake of calcium was combined with calcium supplements.

In their new study, Dr. Bauer and his colleagues set out to assess rates of dietary calcium intake, use of supplements, and mortality in a prospective cohort of 5967 men over the age of 65 years in the Osteoporotic Fractures in Men (MrOS) study.

The participants completed extensive surveys at baseline on their dietary calcium intake, and supplementation was verified by a review of pill bottles by trained staff.

Mean dietary calcium intake was 1142 ± 590 mg/day, with more than half — 65% — of participants reporting use of calcium supplements.

Over the 10-year follow-up, among 2022 men who died, 687 deaths were caused by cardiovascular disease. The highest mortality for CVD was seen in the quartile with the lowest intake from calcium supplementation.

And in models that adjusted for age, energy intake, and calcium use, men in the lowest quartile of total calcium intake (less than 621 mg per day) had higher total mortality compared with those in the highest quartile (more than 1565 mg of calcium per day).

Adjustment for additional confounding factors showed no association between calcium dietary intake and total or cardiovascular mortality (P for trend .51 and .79, respectfully). Likewise, there was no association between calcium supplementation and total or cardiovascular mortality.

The authors also conducted an additional analysis of calcium intake and adjudicated cardiovascular disease events in a subcohort of the study, MrOS Sleep, involving 3120 patients who took part in a 7-year follow-up, and again there was no higher risk for cardiovascular events associated with calcium intake.

The study did have is limitations, Dr. Bauer acknowledged, including the observational design, calcium intake being assessed with a food frequency questionnaire, and cause of death not being formally adjudicated. Nevertheless, the findings are important in demonstrating the level of risk among men in a contemporary setting, he pointed out.

“Contrary to the Swedish study of women, we found no evidence that calcium supplementation is harmful to men, even among those with the highest dietary calcium intake,” he concluded, recommending that future studies should include adjudicated outcomes.

Study in Men as Expected, but Female Research Questioned

In the second study reported at the ASBMR meeting, Joshua Lewis, MD, PhD, from the University of Western Australia, Perth, and colleagues reported a meta-analysis of 19 randomized controlled trials involving women over the age of 50 years who had received calcium supplementation for more than a year.

Importantly, the analysis included reports of adjudicated cardiovascular outcomes, which the researchers note is important because gastrointestinal events can be misreported as cardiac ones. They also assessed all-cause mortality.

Among 59,844 participants in the studies, there were 4646 deaths, and the relative risk for death among those randomized to calcium supplements was 0.96 (P = .18).

The relative risk for 3334 ischemic heart disease events among 46,843 participants was 1.02 (P = .053), and the risk for 1097 MI events among 49,048 participants was 1.09 (P =.21).

“The data from this meta-analysis does not support the concept that calcium supplementation with or without vitamin D increases the risk of ischemic heart disease or total mortality in elderly women,” concluded Dr. Lewis.

But bone specialist Ian Reid, MD, from the University of Auckland, New Zealand, who was a coauthor on some of the Bolland studies, said this analysis essentially repeats previous ones, but with the inclusion of 20,000 patients from the Women’s Health Initiative (WHI), many of whom continued to take their own calcium tablets, regardless of whether they were randomized to calcium or placebo.

These “contaminated” WHI data have the potential to mask the effect of calcium, he told Medscape Medical News. In addition, in a study from Denmark also included in the meta-analysis, subjects were not properly blinded to treatment assignment and the calcium and control groups were not comparable at baseline for cardiovascular risk, which introduced “major potential bias,” he added.

Regarding the results from the study in men by Dr. Bauer and colleagues, Dr. Reid said they were not surprising to him. “Generally, people who take calcium supplements have more health-conscious behaviors than those who do not and so have a lower baseline risk of heart disease” that can “obscure small adverse effects of drugs such as calcium,” he observed.

An effect has to be “very substantial” before it can be picked up in an observational study, because of the many confounders that can obscure such an effect, he concluded.

Dr. Bauer, Dr. Lewis, Dr. Reid, and Dr. Marcus have reported no financial relationships. MrOS is supported by funding from the National Institutes of Health.

American Society for Bone and Mineral Research 2013 Annual Meeting. Abstracts 1001 and 1002, presented October 4, 2013.

Related article in Pharmaceutical Intelligence:

Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women
Aviva Lev-Ari, PhD. RN

Read Full Post »

Nobel Prize in Physiology or Medicine 2013 for Cell Transport: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University

Reporter: Aviva Lev-Ari, PhD, RN

Comments by Graduate Students of the nobel Prize Recipients and other in NYT, 10/7/2013:

I had the privilege of meeting Randy Schekman a few times when I was a postdoc at Berkeley. In addition to pioneering the understand of cellular trafficking, he was also a great colleague and educator (of undergrads, grad students, postdocs). Hats off to a wonderful scientist who also pays it forward to future generations as a mentor!

Last couple years, including this year, the Nobel for Physiology or Medicine Award has been dominated by Cell Biologists. I think this highlights how understanding cells is really the key to most medicine.
Paul Knoepfler

I guess UC Berkeley will have to add a few more Nobel Laureate Parking Spots on their campus now!
Yes, in parking-challenged Berkeley campus, some of the best parking spots are reserved for the Nobel Laureate Faculty. They have so many winners, and rather spotty on-campus parking, so they don’t want such brains to go hunt for parking. They reason that the Laureates should be doing better things, like more research, or assisting newer researchers and students. A most elegant solution!
I don’t think there is any other institution anywhere in the world that has dedicated parking for their Nobel-winning employees. Or has so many Nobels on the payroll. But then, there is just one Cal.
This prize is another testament to UC Berkeley’s standing.
Congratulations to the scientists, and a big thank you to their institutions that allowed them the freedom and resources to pursue their ideas.

Randy Schekman awarded 2013 Nobel Prize in Physiology or Medicine

By Robert Sanders, Media Relations | October 7, 2013


ScheckmanRandy Schekman, who will share the 2013 Nobel Prize in Physiology or Medicine (Peg Skorpinski photo)

Randy W. Schekman, professor of molecular and cell biology at the University of California, Berkeley, has won the 2013 Nobel Prize in Physiology or Medicine for his role in revealing the machinery that regulates the transport and secretion of proteins in our cells. He shares the prize with James E. Rothman of Yale University and Thomas C. Südhof of Stanford University.

Discoveries by Schekman about how yeast secrete proteins led directly to the success of the biotechnology industry, which was able to coax yeast to release useful protein drugs, such as insulin and human growth hormone. The three scientists’ research on protein transport in cells, and how cells control this trafficking to secrete hormones and enzymes, illuminated the workings of a fundamental process in cell physiology.

Schekman is UC Berkeley’s 22nd Nobel Laureate, and the first to receive the prize in the area of physiology or medicine.

In a statement, the 50-member Nobel Assembly lauded Rothman, Schekman and Südhof for making known “the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.”

“My first reaction was, ‘Oh, my god!’ said Schekman, 64, who was awakened at his El Cerrito home with the good news at 1:30 a.m. “That was also my second reaction.”

Be part of our developing story on Storify and Twitter: Tweet your congratulations to Professor Schekman, using hashtag #BerkeleyNobel.

Also see:

Happy ending for Berkeley’s newest Nobel winner

Schekman and Rothman separately mapped out one of the body’s critical networks, the system in all cells that shuttles hormones and enzymes out and adds to the cell surface so it can grow and divide. This system, which utilizes little membrane bubbles to ferry molecules around the cell interior, is so critical that errors in the machinery inevitably lead to death.

“Ten percent of the proteins that cells make are secreted, including growth factors and hormones, neurotransmitters by nerve cells and insulin from pancreas cells,” said Schekman, a Howard Hughes Medical Institute Investigator and a faculty member in the Li Ka Shing Center for Biomedical and Health Sciences.

Schekman on the phoneSchekman takes a call at home after getting the news. (Carol Ness photo)

In what some thought was a foolish decision, Schekman decided in 1976, when he first joined the College of Letters and Science at UC Berkeley, to explore this system in yeast. In the ensuing years, he mapped out the machinery by which yeast cells sort, package and deliver proteins via membrane bubbles to the cell surface, secreting proteins important in yeast communication and mating. Yeast also use the process to deliver receptors to the surface, the cells’ main way of controlling activities such as the intake of nutrients like glucose.

In the 1980s and ’90s, these findings enabled the biotechnology industry to exploit the secretion system in yeast to create and release pharmaceutical products and industrial enzymes. Today, diabetics worldwide use insulin produced and discharged by yeast, and most of the hepatitis B vaccine used around the world is secreted by yeast. Both systems were developed by Chiron Corp. of Emeryville, Calif., now part of Novartis International AG, during the 20 years Schekman consulted for the company.

Various diseases, including some forms of diabetes and a form of hemophilia, involve a hitch in the secretion system of cells, and Schekman is now investigating a possible link to Alzheimer’s disease.

“Our findings have aided people in understanding these diseases,” said Schekman.

Based on the machinery discovered by Schekman and Rothman, Südhof subsequently discovered how nerve cells release signaling molecules, called neurotransmitters, which they use to communicate.

For his scientific contributions, Schekman was elected to the National Academy of Sciences in 1992, received the Gairdner International Award in 1996 and the Lasker Award for basic and clinical research in 2002. He was elected president of the American Society for Cell Biology in 1999. On Oct. 3, Schekman received the Otto Warburg Medal of the German Society for Biochemistry and Molecular Biology, which is considered the highest German award in the fields of biochemistry and molecular biology.

Schekman, formerly editor of the journal Proceedings of the National Academy of Sciences, currently is editor-in-chief of the new open access journal eLife.

Schekman and his wife, Nancy Walls, have two adult children.



tanford Report, October 7, 2013

Thomas Südhof wins Nobel Prize in Physiology or Medicine

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.


Steve FischThomas SudhofThomas Sudhof won the 2013 Nobel Prize in Physiology or Medicine.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.

He shared the prize with James Rothman, PhD, a former Stanford professor of biochemistry, andRandy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine.

The three were awarded the prize “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

“I’m absolutely surprised,” said Südhof, who was in the remote town of Baeza in Spain to attend a conference and give a lecture. “Every scientist dreams of this. I didn’t realize there was chance I would be awarded the prize. I am stunned and really happy to share the prize with James Rothman and Randy Schekman.”

The three winners will share a prize that totals roughly $1.2 million, with about $413,600 going to each.

Robert Malenka, MD, Stanford’s Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, is at the conference with Südhof, a close collaborator. “He’s dazed, tired and happy,” Malenka said by phone. “The only time I’ve seen him happier was when his children were born.”

Südhof, the Avram Goldstein Professor in the School of Medicine, received the award for his work in exploring how neurons in the brain communicate with one another across gaps called synapses. Although his work has focused on the minutiae of how molecules interact on the cell membranes, the fundamental questions he’s pursuing are large.

“The brain works by neurons communicating via synapses,” Südhof said in a phone conversation this morning. “We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?” In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice’s synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Lloyd Minor, MD, dean of the School of Medicine, said, “Thomas Südhof is a consummate citizen of science. His unrelenting curiosity, his collaborative spirit, his drive to ascertain the minute details of cellular workings, and his skill to carefully uncover these truths — taken together it’s truly awe-inspiring.

“He has patiently but relentlessly probed one of the fundamental questions of medical science — perhaps the fundamental question in neuroscience: How nerve cells communicate with each other. The answer is at the crux of human biology and of monumental importance to human health. Dr. Südhof’s receipt of this prize is inordinately well-deserved, and I offer him my heartfelt congratulations. His accomplishment represents what Stanford Medicine and the biomedical revolution are all about.”

The Nobel committee called Südhof on his cell phone after trying his home in Menlo Park, Calif. His wife, Lu Chen, PhD, associate professor of neurosurgery and of psychiatry and behavioral sciences, then gave the committee his cell phone number to reach him in Spain.

“The phone rang three times before I decided to go downstairs and pick it up,” Chen said. “I thought it was one of my Chinese relatives who couldn’t figure out the time zone.”

Chen and Südhof have two young children, and Südhof has four adult children from a previous marriage. “I was very surprised,” Chen said, “but he’s more concerned about how I’ll get the kids up this morning in time for school.”

“I was expecting a call from a colleague about the conference I’m here to attend, so I pulled off in a parking lot,” said Südhof, who was driving from Madrid to Baeza at the time he received the announcement. “I hadn’t slept at all the previous night, and I certainly wasn’t expecting a call from the Nobel committee.”

On the day he got the call from the Nobel committee, he was scheduled to give a talk at a conference, Membrane Traffic at the Synapse: The Cell Biology of Synaptic Plasticity, held in a 17th-century building that now serves as a conference center.

“Professor Sudhof’s contributions to the understanding of how cells operate have been of enormous importance to medicine, and to his own work in understanding how connections form within the human brain,” said Stanford President John Hennessy. “The recognition by the Nobel committee is a remarkable achievement.”

Südhof, who is also a Howard Hughes Medical Institute investigator, has spent the past 30 years prying loose the secrets of the synapse, the all-important junction where information, in the form of chemical messengers called neurotransmitters, is passed from one neuron to another. The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of taking a step forward, experiencing a fleeting twinge of regret, recalling an incident from the morning commute or tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and peripheral nervous system.

Even a moment’s consideration of the total number of synapses in the typical human brain adds up to instant regard for that organ’s complexity. Coupling neuroscientists’ ballpark estimate of 200 billion neurons in a healthy adult brain with the fact that any single neuron may share synaptic contacts with as few as one or as many as 1 million other neurons (the median is somewhere in the vicinity of 10,000) suggests that your brain holds perhaps 2 quadrillion synapses — 10,000 times the number of stars in the Milky Way.

“The computing power of a human or animal brain is much, much higher than that of any computer,” said Südhof. “A synapse is not just a relay station. It is not even like a computer chip, which is an immutable element. Every synapse is like a nanocomputer all by itself. The amount of neurotransmitter released, or even whether that release occurs at all, depends on that particular synapse’s previous experience.”

Much of a neuron can be visualized as a long, hollow cord whose outer surface conducts electrical impulses in one direction. At various points along this cordlike extension are bulbous nozzles known as presynaptic terminals, each one housing myriad tiny, balloon-like vesicles containing neurotransmitters and each one abutting a downstream (or postsynaptic) neuron.

When an electrical impulse traveling along a neuron reaches one of these presynaptic terminals, calcium from outside the neuron floods in through channels that open temporarily, and a portion of the neurotransmitter-containing vesicles fuse with the surrounding bulb’s outer membrane and spill their contents into the narrow gap separating the presynaptic terminal from the postsynaptic neuron’s receiving end.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion: As a result, synaptic transmission is today one of the best-understood phenomena in neuroscience.

Südhof, who was born in Germany in 1955, received an MD in 1982 from Georg-August-Universität in Göttingen. He came to Stanford in 2008 after 25 years at the University of Texas Southwestern Medical Center at Dallas, where he first worked as a postdoctoral fellow at the laboratories of Michael Brown, MD, and Joseph Goldstein, MD.. Brown and Goldstein were awarded the Nobel Prize in Physiology or Medicine in 1985 for their work in understanding the regulation of cholesterol metabolism. In 1986, Südhof established his own laboratory at the university.

Südhof became an HHMI investigator in 1991, and moved to Stanford as a professor in molecular and cellular physiology in 2008.

The proteins Südhof has focused on for close to three decades are disciplined specialists. They recruit vesicles, bring them into “docked” positions near the terminals, herd calcium channels to the terminal membrane, and, cued by calcium, interweave like two sides of a zipper and force the vesicles into such close contact with terminal membranes that they fuse with them and release neurotransmitters into the synaptic gap. Although these specialists perform defined roles at the synapses, similar proteins, discovered later by Südhof and others, play comparable roles in other biological processes ranging from hormone secretion to fertilization of an egg during conception to immune cells’ defense against foreign invaders.

“We’ve made so many major advances during the past 50 years in this field, but there’s still much more to learn,” said Südhof, who in a 2010 interview with The Lancet credited his bassoon instructor as his most influential teacher for helping him to learn the discipline to practice for hours on end. “Understanding how the brain works is one of the most fundamental problems in neuroscience.”

Südhof’s accomplishments also earned him the 2013 Lasker Basic Medical Research Award. He is a member of the National Academy of Sciences, the Institute of Medicine and the American Academy of Arts & Sciences. He also is a recipient of the 2010 Kavli Prize in neuroscience.

In the Lancet interview, Südhof defined basic research as an approach often neglected in the pursuit of medicine. “This ‘solid descriptive science,’ like neuroanatomy or biochemistry, [are] disciplines that cannot claim to immediately understand functions or provide cures, but which form the basis for everything we do.”

Südhof said this morning he is excited to speak with his family about the prize, although it may be too much for his youngest children, ages 3 and 4, to grasp. “I will try to explain it to them,” he said. “It will be a wonderful occasion.” He noted that he has already received congratulatory calls from two of his four adult children. For them, the news may have come as less of a surprise.

“The Nobel prize became an inevitable topic of conversation when Tom won the Lasker award,” Chen said. “But the two of us share a feeling that one should never work for prizes.”

“Everyone has pegged him as a potential Nobel prize winner for many years,” said Malenka, who described the scene at the conference during the lunch hour. “It was just a matter of time. The attendees were clapping and cheering for him.”

Although he plans to return to the United States as soon as possible, Südhof has no plans to let the award slow his research — or even his plans for the day. He responded to an inquiry with a characteristically low-key reply. “Well, I think I’ll go ahead and give my talk.”


Rothman Lab

Membrane fusion is a fundamental biological process for organelle formation, nutrient uptake, and the secretion of hormones and neurotransmitters.

It is central to vesicular transport, storage, and release in many areas of endocrine and exocrine physiology, and imbalances in these processes give rise to important diseases, such as diabetes.

We employ diverse biophysical, biochemical, and cell biological approaches to characterize the fundamental participants in intracellular transport processes.

Time lapse images of fusing flipped-SNARE cells.

SNARE Overview

Over 30 years ago, we observed what we interpreted to be vesicular transport in crude extracts of tissue culture cells. In subsequent years we found that we had reconstituted vesicle trafficking in the Golgi, including the process of membrane fusion. Using this assay as a guide, we purified as a required factor the NEM-Sensitive Fusion protein (NSF). This led to the purification of the Soluble NSF Attachment Factor (SNAP), which bound NSF to Golgi membranes, and then with these tools discovered that the receptors for SNAP in membranes were actually complexes of proteins (which we called SNAREs) which we envisioned could potentially partner as a bridge between membranes to contribute to the process of membrane fusion and provide specificity to it (as captured in the ‘SNARE hypothesis’ proposed at the time).

We now know that organisms have a large family of SNARE proteins that indeed form cognate partnerships in just this way, and that NSF is an ATPase that (using SNAP as an adaptor protein) disrupts the SNARE complex after fusion is complete so its subunits can be recycled for repeated use. Recombinant cognate SNAREs introduced into artificial bilayers or expressed ectopically on the outside of cells ( “flipped SNAREs”) spontaneously and efficiently result in membrane (or cell) fusion, demonstrating that the SNARE complex is not only necessary but is sufficient for fusion. There are many proteins known and rapidly being discovered which closely regulate this vital process, but the muscle – if not always the brains – is in the SNAREs. Compartmental specificity is encoded to a remarkable degree in the functional partnering of SNARE proteins, a fact which is in no way inconsistent with the emerging contribution of upstream regulatory components (like rabGTPases and tethering complexes) to domain/compartment specificity.

Current Research & Projects

Our lab is working to elucidate the underlying mechanisms of vesicular transport within cells and the secretion of proteins and neurotransmitters.

Projects include:

  1. The biochemical and biophysical mechanisms of vesicle budding and fusion;
  2. Cellular regulation of vesicle fusion in exocytosis and synaptic transmission;
  3. Structural and functional organization of the Golgi apparatus from a cellular systems view.

We take an interdisciplinary approach which includes cell-free biochemistry, single molecule biophysics, high resolution optical imaging of single events/single molecules in the cell and in cell-free formats.

The overall goal is to understand transport pathways form structural mechanism to cellular physiology. The latter is facilitated by high throughput functional genomics at the cellular level (see Yale Center for High Throughput Cell Biology).


We have a strong interest in new lab members who bring backgrounds in chemistry, physics, and engineering.



3 Americans Win Joint Nobel Prize in Medicine


From left: Randy W. Schekman, Thomas C. Südhof and James E. Rothman.


Published: October 7, 2013 151 Comments

Three Americans won the Nobel Prize in Physiology or Medicine Monday for discovering the machinery that regulates how cells transport major molecules in a cargo system that delivers them to the right place at the right time in cells.

Science Twitter Logo.

The Karolinska Institute in Stockholmannounced the winners: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University.

The molecules are moved around cells in small packages called vesicles, and each scientist discovered different facets that are needed to ensure that the right cargo is shipped to the correct destination at precisely the right time.

Their research solved the mystery of how cells organize their transport system, the Karolinska committee said. Dr. Schekman discovered a set of genes that were required for vesicle traffic. Dr. Rothman unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Dr. Südhof revealed how signals instruct vesicles to release their cargo with precision.

The tiny vesicles, which have a covering known as membranes, shuttle the cargo between different compartments or fuse with the membrane. The transport system activates nerves. It also controls the release of hormones.

Disturbances in this exquisitely precise control system cause serious damage that, in turn, can contribute to conditions like neurological diseases, diabetes and immunological disorders.

Dr. Schekman, 64, who was born in St. Paul, used yeast cells as a model system when he began his research in the 1970s. He found that vesicles piled up in parts of the cell and that the cause was genetic. He went on to identify three classes of genes that control different facets of the cell’s transport system. Dr. Schekman studied at the University of California in Los Angeles and at Stanford University, where he obtained his Ph.D. in 1974.

In 1976, he joined the faculty of the University of California, Berkeley, where he is currently professor in the Department of Molecular and Cell Biology. Dr. Schekman is also an investigator at the Howard Hughes Medical Institute.

Dr. Rothman, 63, who was born in Haverhill, Mass., studied vesicle transport in mammalian cells in the 1980s and 1990s. He discovered that a protein complex allows vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location.

The same principle operates inside the cell and when a vesicle binds to the cell’s outer membrane to release its contents. Dr. Rothman received a Ph.D. from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University, where he started his research on the vesicles of the cell. Dr. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University.

In 2008, he joined the faculty of Yale University where he is currently professor and chairman in the Department of Cell Biology. Some of the genes Dr. Schekman discovered in yeast coded for proteins correspond to those Dr. Rothman identified in mammals. Collectively, they mapped critical components of the cell´s transport machinery.

Dr. Südhof, 57, who was born in Göttingen, Germany, studied neurotransmission, the process by which nerve cells communicate with other cells in the brain. At the time he set out to explore the field 25 years ago, much of it was virgin scientific territory. Researchers had not identified a single protein in the neurotransmission process.

Dr. Südhof helped transform what had been a rough outline into a number of molecular activities to provide insights into the elaborate mechanisms at the crux of neurological activities, from the simplest to the most sophisticated. He did so by systematically identifying, purifying and analyzing proteins that can rapidly release chemicals that underlie the brain’s activities. The transmission process can take less than a thousandth of a second.

Dr. Südhof studied at the Georg-August-Universität in Göttingen, where he received a medical degree in 1982 and a doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas. Dr. Südhof, who has American citizenship, became an investigator at the Howard Hughes Medical Institute in 1991 and was appointed professor of molecular and cellular physiology at Stanford University in 2008.

All three scientists have won other awards, including the Lasker Prize, for their research.


This article has been revised to reflect the following correction:

Correction: October 7, 2013

An earlier version of this article misstated Randy W. Schekman’s age. He is 64, not 65.



Nobel for Cell Transport

October 07, 2013

This year’s Nobel Prize in Physiology or Medicine is going jointly to three scientists for their work figuring out how cells transport their cargo, according to the Karolinska Institute. They will share the $1.25 million prize.

“Imagine hundreds of thousands of people who are traveling around hundreds of miles of streets; how are they going to find the right way? Where will the bus stop and open its doors so that people can get out?” says Nobel committee secretary Goran Hansson, according to the Associated Press. “There are similar problems in the cell.”

By studying yeast cells with defective vesicles, Randy Schekman from the University of California, Berkeley, uncovered three classes of genes that control transportation within the cell, the New York Times adds. Schekman was awakened in California by the call from Stockholm. “I wasn’t thinking too straight. I didn’t have anything elegant to say,” he tells the AP. “All I could say was ‘Oh my God,’ and that was that.” Schekman adds that he called his lab manager to arrange a celebration in the lab.

Meanwhile, Yale University’s James Rothman discovered a protein complex that allows vesicles to bind to their intended membrane targets, getting the vesicle contents to a specific location. Rothman notes that he recently lost funding for work building on his discovery, and says that he hopes that having won the Nobel will help him when he reapplies.

And Thomas Südhof at Stanford University systematically studied how nerve cells communicate, finding that vesicles full of neurotransmitters bind to cell membranes to release their contents through a molecular mechanism that responds to the presence of calcium ions. He was on his way to a give a talk when he got his call. “I got the call while I was driving and like a good citizen I pulled over and picked up the phone,” Südhof says to the AP. “To be honest, I thought at first it was a joke. I have a lot of friends who might play these kinds of tricks.”


Other related articles published on these Open Access Online Scientific Journal include the following:

The Series on Cardiovascular Disease and the role of Calcium Signaling consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP


Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

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


Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

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


Part IV: 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

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


Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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


Part VI: 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


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmiasand Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

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


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

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


Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

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

Part X: 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


Read Full Post »

Calcium-Channel Blocker, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

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


Author: Larry H Bernstein, MD, FACC  

This Chapter is one of a series of articles on calcium activation, in this case, in the signaling of smooth muscle cells by the interacting neural innervation.    The process occurs by calcium triggering neurotransmitter release by initiating synaptic vesicle fusion.   The mechanism by which this occurs is addressed in detail, and involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, the discovery of a calcium-dependsent Syt1 (C) domain of protein- kinase C isoenzyme, which binds to phospholipids.
The 2013 Lasker Prize was awarded to Richard Schell (Genentech) and Thomas Sudolf (Stanford University) for their discoveries concerning the molecular machinery and regulatory mechanism that underlie the rapid release of neurotransmitters, a process that underlies all of the brain’s activities. They identified and isolated many of this reaction’s key elements, unraveled central aspects of its fundamental mechanism, and deciphered how cells govern it with extreme precision. These advances have provided a molecular framework for understanding some of the most devastating disorders that afflict humans as well as normal functions such as learning and memory, explaining unresolved hypotheses derived from the earlier work in the 1950sof the late Bernard Katz.  We also see that the work clarifies the debates initiated by the Nobelist Santiago Ramon y Cajal (1891) concerning the development of neural networks.  A biological relay system achieves these feats. Neurotransmission kicks off with an electrical pulse that runs down a nerve cell, or neuron. When that signal reaches the tip, calcium enters the cell. In response, the neuron liberates chemical messengers—neurotransmitters.
In the 1950s, the late Bernard Katz figured out that cells eject neurotransmitters in fixed amounts.  Balloon-like containers—vesicles—each hold set quantities of the chemicals. Calcium incites these lipid-bound sacs to fuse with the membrane that encases the cell, and their contents spill out. The picture that emerges from the later work is that synaptic vesicle exocytosis operates by a general mechanism of membrane fusion that revealed itself to be a model for all membrane fusion, but that is uniquely regulated by a calcium-sensor protein called synaptotagmin. The general membrane-fusion mechanism thus identified is mediated by SNARE- (for soluble NSF-receptors) and SM-proteins (for Sec1/Munc18-like proteins), largely discovered at the synapse, with synaptotagmin acting together with a molecular assistant called complexin as a clamp and activator of the membrane fusion mediated by the SNARE- and SM-proteins. Strikingly, the biochemical properties of synaptotagmin were found to precisely correspond to the extraordinary calcium-triggering properties of release, and to account for a regulatory pathway that also applies to other types of calcium-triggered fusion, for example fusion observed in hormone secretion and fertilization. At the synapse, finally, these interdependent machines — the fusion apparatus and its synaptotagmin-dependent control mechanism — are embedded in a proteinaceous active zone that links them to calcium channels, and regulates the docking and priming of synaptic vesicles for subsequent calcium-triggered fusion. Thus, work on neurotransmitter release revealed a hierarchy of molecular machines that mediate the fusion of synaptic vesicles, the calcium-control of this fusion, and the embedding of calcium-controlled fusion in the context of the presynaptic terminal at the synapse.
This portion of the discussion deals with the interaction of the neuronal endings interwoven into smooth muscle.   The calcium triggering of smooth muscle contractions is similar with respect to airways and arteries, urinary bladder, uterine contraction, and gastrointestinl tract.
The basic mechanism that underlie this MOTIF taken as variations of that described above are well described  by Michael J. Berridge in ‘Smooth muscle cell calcium activation mechanisms’. (J Physiol. 2008 Nov 1;586(Pt 21):5047-61.
http://dx.doi.org/10.1113/jphysiol.2008.160440.  Epub 2008 Sep 11.)
This is illustrated in his graphical examples.
Figure 1. The three main mechanisms responsible for generating the Ca2+ transients that trigger smooth muscle cell (SMC) contraction. From: Smooth muscle cell calcium activation mechanisms.
 Fig 1 Ca2+
A, receptor-operated channels (ROCs) or a membrane oscillator induces the membrane depolarization (ΔV) that triggers Ca2+ entry and contraction.
B, a cytosolic Ca2+ oscillator induces the Ca2+ signal that drives contraction.
C, a cytosolic Ca2+ oscillator in interstitial cells of Cajal (ICCs) or atypical SMCs induces the membrane depolarization that spreads through the gap junctions to activate neighbouring SMCs. Reproduced from Berridge (2008), with permission.
Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061.  http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f1.jpg

Figure 5. Vascular or airway SMCs are driven by a cytosolic oscillator that generates a periodic release of Ca2+ from the endoplasmic reticulum that usually appears as a propagating Ca2+ wave. From: Smooth muscle cell calcium activation mechanisms.

tjp0586-5047-f5   Vascular or airway SMCs are driven by a cytosolic oscillator that generates a periodic release of Ca2+ from the endoplasmic reticulum

The oscillator is induced/modulated by neurotransmitters such as acetylcholine (ACh), 5-hydroxytryptamine (5-HT), noradrenaline (NA) and endothelin-1 (ET-1), which act through inositol 1,4,5-trisphosphate (InsP3) that initiates the oscillatory mechanism. The sequence of steps 1–9 is described in the text. Reproduced from Berridge (2008), with permission.
Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061.    http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f5.jpg

Figure 7. The cytosolic Ca2+ oscillator responsible for pacemaker activity in interstitial cells of Cajal releases periodic pulses of Ca2+ that form a Ca2+ wave. From: Smooth muscle cell calcium activation mechanisms.

tjp0586-5047-f7 The cytosolic Ca2+ oscillator responsible for pacemaker activity in interstitial cells of Cajal releases periodic pulses of Ca2+ that form a Ca2+ wave.

The increase in Ca2+ activates Cl− channels (CLCA) to give the spontaneous transient inward currents (STICs) that sum to form the spontaneous transient depolarizations (STD) resulting in the slow waves of membrane depolarization (see inset). Current flow through gap junctions allows these waves to spread into neighbouring smooth muscle cells to activate contraction. See text for a description of the oscillator that drives this activation process. Reproduced from Berridge (2008), with permission.
Michael J Berridge. J Physiol. 2008 November 1;586(Pt 21):5047-5061.  http://www.ncbi.nlm.nih.gov/pmc/articles/instance/2652144/bin/tjp0586-5047-f7.gif

This article is the Part IX in a series of articles on Activation and Dysfunction of the Calcium Release Mechanisms in Cardiomyocytes and Vascular Smooth Muscle Cells.

The Series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP


Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

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


Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

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


Part IV: 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

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


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

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


Part VI: 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


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmiasand Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

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


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

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


Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

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

Part X: 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


Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP


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

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


This article has FIVE Sections:

Section One

Innovations in Combination Drug Therapy: Calcium-Channel Blocker –  Amlodipine (Norvasc) in single-pill combinations (SPCs) of drugs

Section Two

Calcium-Channel Blockers: Drug Class and Indications

Section Three

Brand and Generic Calcium Channel Blocking Agents

Section Four

Dysfunction of the Calcium Release Mechanism

Section Five

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

 Section One

Innovations in Combination Drug Therapy:

Calcium-Channel Blocker, Amlodipine (Norvasc) in Single-Pill Combinations (SPCs) of Drugs

Latest development on Cardiovascular Pharmacotherapy relates to the development of a Duo Combination Therapy to include a leading  Calcium-Channel Blocker, Amlodipine (Norvasc), as one of the two drug classes in one pill:The research investigated the therapeutic efficacy achieved via a comparison of a two single-pill combinations (SPCs) of drugs:

  • telmisartan/amlodipine (T/A) [ARB/CCB]


  • telmisartan/hydrochlorothiazide (T/H) [ARB/Diuterics]
Drug classes:
ARB – telmisartan
CCB – amlodipine
Diuretics – hydrochlorothiazide

A review of the benefits of early treatment initiation with single-pill combinations of telmisartan with amlodipine or hydrochlorothiazide

Authors: Segura J, Ruilope LM

Published Date September 2013 Volume 2013:9 Pages 521 – 528


Published: 16 September 2013, Dovepress Journal: Vascular Health and Risk Management

Julian Segura, Luis Miguel Ruilope

Department of Nephrology, Hospital 12 de Octubre, Madrid, Spain


This review discusses the rationale for earlier use of single-pill combinations (SPCs) of antihypertensive drugs, with a focus on telmisartan/amlodipine (T/A) and telmisartan/hydrochlorothiazide (T/H) SPCs.
  • Compared with the respective monotherapies, the once-daily T/A and T/H SPCs have been shown to result in significantly higher blood pressure (BP) reductions, BP goal rates, and response rates in patients at all stages of hypertension.
  • As expected, BP reductions are highest with the highest dose (T80/A10 and T80/H25) SPCs. Subgroup analyses of the telmisartan trials have reported the efficacy of both SPCs to be consistent, regardless of the patients’ age, race, and coexisting diabetes, obesity, or renal impairment.
  • In patients with mild-to-moderate hypertension, the T/A combination provides superior 24-hour BP-lowering efficacy compared with either treatment administered as monotherapy.
  • Similarly, the T/H SPC treatment provides superior 24-hour BP-lowering efficacy, especially in the last 6 hours relative to other renin–angiotensin system inhibitor-based SPCs.
  • The T/A SPC is associated with a lower incidence of edema than amlodipine monotherapy, and
  • The T/H SPC with a lower incidence of hypokalemia than hydrochlorothiazide monotherapy
  • Existing evidence supports the use of the T/A SPC for the treatment of hypertensive patients with prediabetes, diabetes, or metabolic syndrome, due to the metabolic neutrality of both component drugs, and the use of the T/H SPC for those patients with edema or in need of volume reduction.
Keywords: angiotensin receptor blockers, or ARBs, calcium-channel blocker, or CCBs, essential hypertension, diuretic, , renin-angiotensin system inhibitor, or ACEI
We reported on 5/29/2012

Triple Combination Therapy: ARB and Calcium Channel Blocker and Diuretics

In July 2010, a triple combination drug for hypertension was approved by the US Food and Drug Administration. Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide, according to Monthly Prescribing Reference.

TRIBENZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker and Diuretic


Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. TRIBENZOR can help your blood vessels relax and reduce the amount of fluid in your blood. This can make your blood pressure lower. Medicines that lower blood pressure may lower your chance of having a stroke or a heart attack.

Some people may need more than 1—or even more than 2—medicines to help control their blood pressure. TRIBENZOR combines 3 effective medicines in 1 convenient pill. Read the following chart to learn how each medicine works in its own way to help lower blood pressure.

TRIBENZOR: 3 effective medicines in 1 pill

The medicine in TRIBENZOR How it works What it does
Angiotensin II receptor blocker Blocks a natural chemical in your body that causes blood vessels to narrow.





Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.
Diuretic (water pill) Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood.


            Effectively lower blood pressure. People taking the 3 medicines in TRIBENZOR had greater reductions in blood pressure than did people taking any 2 of the medicines combined

            Start to work quickly. People taking TRIBENZOR saw results in as little as 2 weeks

AZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker

How AZOR work

AZOR relaxes and widens blood vessels to help lower blood pressure.

You may have already tried another blood pressure medicine that works a certain way to lower blood pressure. But 1 blood pressure medicine may not be enough for you. You may find the help you need with the 2 effective medicines in AZOR.

AZOR combines 2 effective medicines in 1 convenient pill.

Learn how each medicine in AZOR works in its own way to help lower blood pressure.

The medicine in AZOR How it works What it does
Angiotensin II receptor blocker (ARB) Blocks a natural chemical in your body that causes blood vessels to narrow. This helps your blood vessels relax and widen.





Calcium channel blocker Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax.


Section Two

Calcium-Channel Blockers: Drug Class and Indications

In Sudhof’s Lasker Award presentation he refers to the biochemical properties of synaptotagmin were found to precisely correspond to the extraordinary calcium-triggering properties of release, and to account for a regulatory pathway that also applies to other types of calcium-triggered fusion, for example fusion observed in hormone secretion.  A CCB would have to block the calcium-triggering properties of release, and consequently, would block the release of neurohormones.  This is because the fusion apparatus and its synaptotagmin-dependent control mechanism linked to the calcium channels, docking and priming synaptic vesicles, being blocked, disables the calcium-control of the vesicle fusion that is necessary for neurotransmitter release. Consequently, the end result would be increased vascular flow from the inhibition.

What are calcium channel blockers and how do they work?

In order to pump blood, the heart needs oxygen. The harder the heart works, the more oxygen it requires. Angina (heart pain) occurs when the supply of oxygen to the heart is inadequate for the amount of work the heart must do. By dilating the arteries, CCBs reduce the pressure in the arteries. This makes it easier for the heart to pump blood, and, as a result, the heart needs less oxygen. By reducing the heart’s need for oxygen, CCBs relieve or prevent angina. CCBs also are used for treating high blood pressure because of their blood pressure-lowering effects. CCBs also slow the rate at which the heart beats and are therefore used for treating certain types of abnormally rapid heart rhythms.

For what conditions are calcium channel blockers used?

CCBs are used for treating high blood pressure, angina, and abnormal heart rhythms (for example, atrial fibrillationparoxysmal supraventricular tachycardia).

They also may be used after a heart attack, particularly among patients who cannot tolerate beta-blocking drugs, have atrial fibrillation, or require treatment for their angina.

Unlike beta blockers, CCBs have not been shown to reduce mortality or additional heart attacks after a heart attack.

CCBs are as effective as ACE inhibitors in reducing blood pressure, but they may not be as effective as ACE inhibitors in preventing the kidney failure caused by high blood pressure or diabetes.

They also are used for treating:

CCBs are also used in the prevention of migraine headaches.

Are there any differences among calcium channel blockers?

CCBs differ in their duration of action, the process by which they are eliminated from the body, and, most importantly, in their ability to affect heart rate and contraction. Some CCBs [for example, amlodipine (Norvasc)] have very little effect on heart rate and contraction so they are safer to use in individuals who have heart failure or bradycardia (a slow heart rate). Verapamil (Calan, Isoptin) and diltiazem (Cardizem) have the greatest effects on the heart and reduce the strength and rate of contraction. Therefore, they are used in reducing heart rate when the heart is beating too fast.

What are the side effects of calcium channel blockers?

  • The most common side effects of CCBs are constipationnausea,headacherashedema (swelling of the legs with fluid), low blood pressure, drowsiness, and dizziness.
  • Liver dysfunction and over growth of gums may also occur. When diltiazem (Cardizem) or verapamil (Calan, Isoptin) are given to individuals with heart failure, symptoms of heart failure may worsen because these drugs reduce the ability of the heart to pump blood.
  • Like other blood pressure medications, CCBs are associated with sexual dysfunction.


Section Three

Brand and Generic Calcium Channel Blocking Agents

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Calcium channel blockers block voltage gated calcium channels and inhibits the influx of calcium ions into cardiac and smooth muscle cells. The decrease in intracellular calcium reduces the strength of heart muscle contraction, reduces conduction of impulses in the heart, and causes vasodilatation.

Decrease in intracellular calcium in the heart decreases cardiac contractility. Decreased calcium in the vascular smooth muscle reduces its contraction and therefore causes vasodilatation.

Decrease in cardiac contractility decreases cardiac output and vasodilatation decreases total peripheral resistance, both of which cause a drop in blood pressure.

Calcium channel blocking agents are used to treat hypertension.

Filter by: — all conditions –AnginaAngina Pectoris ProphylaxisArrhythmiaAtrial FibrillationAtrial FlutterBipolar DisorderCluster HeadachesCoronary Artery DiseaseHeart FailureHigh Blood PressureHypertensive EmergencyHypertrophic CardiomyopathyIdiopathic Hypertrophic Subaortic StenosisIschemic StrokeMigraine PreventionNocturnal Leg CrampsPremature LaborRaynaud’s SyndromeSubarachnoid HemorrhageSupraventricular Tachycardia

Drug Name ( View by: Brand | Generic )
Afeditab CR (Pro, More…)generic name: nifedipine
Diltia XT (Pro, More…)generic name: diltiazem
Diltiazem Hydrochloride SR (More…)generic name: diltiazem
Nimotop (Pro, More…)generic name: nimodipine
Verelan PM (Pro, More…)generic name: verapamil
Cartia XT (Pro, More…)generic name: diltiazem
Adalat (More…)generic name: nifedipine
Calan SR (Pro, More…)generic name: verapamil
Cardizem (Pro, More…)generic name: diltiazem
Diltiazem Hydrochloride CD (More…)generic name: diltiazem
Isoptin SR (Pro, More…)generic name: verapamil
Nifediac CC (Pro, More…)generic name: nifedipine
Tiazac (Pro, More…)generic name: diltiazem
Procardia (Pro, More…)generic name: nifedipine
Adalat CC (Pro, More…)generic name: nifedipine
Cardizem LA (Pro, More…)generic name: diltiazem
Calan (Pro, More…)generic name: verapamil
Procardia XL (Pro, More…)generic name: nifedipine
Isoptin (More…)generic name: verapamil
Nifedical XL (Pro, More…)generic name: nifedipine
Plendil (Pro, More…)generic name: felodipine
Taztia XT (Pro, More…)generic name: diltiazem
Cardizem CD (Pro, More…)generic name: diltiazem
Norvasc (Pro, More…)generic name: amlodipine
Verelan (Pro, More…)generic name: verapamil
Cardene SR (Pro, More…)generic name: nicardipine
DynaCirc CR (Pro, More…)generic name: isradipine
Sular (Pro, More…)generic name: nisoldipine
Cardene (Pro, More…)generic name: nicardipine
Cardene IV (Pro, More…)generic name: nicardipine
Cleviprex (Pro, More…)generic name: clevidipine
Covera-HS (Pro, More…)generic name: verapamil
Dilacor XR (Pro, More…)generic name: diltiazem
Dilt-XR (Pro, More…)generic name: diltiazem
Diltiazem Hydrochloride XR (More…)generic name: diltiazem
Diltiazem Hydrochloride XT (More…)generic name: diltiazem
Diltzac (Pro, More…)generic name: diltiazem
Dynacirc (Pro, More…)generic name: isradipine
Matzim LA (Pro, More…)generic name: diltiazem
Nymalize (Pro, More…)generic name: nimodipine
Vascor (More…)generic name: bepridil

Section Four

Dysfunction of the Calcium Release Mechanism

For Disruption of Calcium Homeostasis in Vascular Smooth Muscle Cells, see

Part IV: 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

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


Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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


For Disruption of Calcium Homeostasis in Cardiomyocyte Cells, see

Part VI: 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


Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

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


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

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


Section Five

The Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

This topic is covered in

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


Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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



Work on neurotransmitter release revealed a hierarchy of molecular machines that mediate the fusion of synaptic vesicles, the calcium-control of this fusion, and the embedding of calcium-controlled fusion in the context of the presynaptic terminal at the synapse. The neural transmission is described as a biological relay system. Neurotransmission kicks off with an electrical pulse that runs down a nerve cell, or neuron. When that signal reaches the tip, calcium enters the cell. In response, the neuron liberates chemical messengers—neurotransmitters.  When the calcium-controlled fusion at the presynaptic junction is blocked, as with a CCB, neurotransmitters are not released.  The activity of the neurotransmitters would be to cause smaooth muscle contraction of the vessel.  The CCB would cause relaxation and flow.


Part IX of this series of articles discussed the mechanism of the signaling of smooth muscle cells by the interacting parasympathetic neural innervation that occurs by calcium triggering neurotransmitter release by initiating synaptic vesicle fusion. It involves the interaction of soluble N-acetylmaleimide-sensitive factor (SNARE) and SM proteins, and in addition, the discovery of a calcium-dependent Syt1 (C) domain of protein- kinase C isoenzyme, which binds to phospholipids. It is reasonable to consider that it differs from motor neuron activation of skeletal muscles, mainly because the innervation is in the involuntary domain. The cranial nerve rooted innervation has evolved comes from the spinal ganglia at the corresponding level of the spinal cord. It is in this specific neural function that we find a mechanistic interaction with adrenergic hormonal function, a concept intimated by the late Richard Bing. Only recently has there been a plausible concept that brings this into serious consideration. Moreover, the review of therapeutic drugs that are used in blocking adrenergic receptors are closely related to the calcium-channels. Interesting too is the participation of a phospholipid bound protein-kinase isoenzyme C calcium-dependent domain Syt1. The neurohormonal connection lies in the observation by Katz in the 1950’s that the vesicles of the neurons hold and eject fixed amounts of neurotransmitters.  The mechanism of this action will be futher discussed in Part X.

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Reporter: Aviva Lev-Ari, PhD, RN

Stanford University and NIST, Launch Biomedical Measurement Science Program; Partners Include Life Tech and Agilent

June 21, 2013

NEW YORK (GenomeWeb News) – Stanford University and the National Institute of Standards and Technology have launched a new program that aims to develop methods for measuring the accuracy and comparability of life sciences and genomics technologies, particularly tools that are expanding beyond the lab and into clinical medicine.

The Advances in Biomedical Measurement Science (ABMS) program will use funding and resources from Stanford and NIST, as well as from commercial partners Life Technologies and Agilent Technologies, to develop industry consensus standards and standard reference materials for a range of genomics and imaging technologies, Marc Salit, leader of NIST’s Multiplexed Biomolecular Science Group, Biosystems and Biomaterials Divisions, told GenomeWeb Daily News today.

The ABMS partners plan to focus on technology areas that are edging their way into clinical medicine and other applications, including the use of high-throughput sequencing for HLA typing; stem cell phenotyping and genotyping; quantitative imaging for non-invasive cancer diagnosis and for drug response and screening; synthetic biology; and multiparameter protein measurement.

The partners expect that improving the accuracy and comparability of data from these tools will make it easier and faster to make decisions about how they will be used in research and in the clinic, and how they might be regulated.

The initiative is part of an effort by NIST to expand its presence in biotechnology, healthcare, and biomedicine, particularly through partnerships with universities that have competencies, medical facilities, and expertise in areas that the institute lacks.

“Stanford has a critical mass of some of these assets, and NIST thought [the ABMS program] would be an efficient way to expand its presence in the healthcare and biomedical areas,” Salit said.

“NIST was a spectacular resource for the century of physics in the 20th Century; we want to be that resource for the century of biology, this century,” he told GWDN. “We wanted to see if we could take what we had developed in chemistry — in terms of measurement assurance and the kinds of things that bring confidence to measurement results — and transfer it into genomic measurement.”

Several NIST researchers have relocated to Stanford from their offices in Gaithersburg, Md., and will work directly with established Stanford investigators and postdocs, while around half of Salit’s team will remain at the Maryland lab, he said.

Another selling point of this partnership for NIST is that it enables the agency to establish “a permanent presence” on the West Coast, near Silicon Valley, Salit said.

NIST has other well-established joint institutes at US universities, and the long-term aim is that the ABMS will be “a seed from which such a joint institute could grow,” Salit explained.

The program will operate as a virtual center at first, where investigators from NIST, Stanford, and the industry partners will “work shoulder to shoulder” to study genomics and imaging technologies that are working their way into clinical care, he added.

“Some of these [Stanford and industry] research groups have instruments and technologies that exist commercially which would benefit from a real thorough study, from a measurement science perspective” said Salit.

Tom Baer, director of the Advances in Biomedical Measurement Science Program, told GWDN that the life sciences companies involved in the program have a strong interest in working with partners to test, measure, and analyze their technologies in new ways. The two companies already involved, and any future industry partners, will pay annual fees to help support the program, he noted.

“We expect that there will be significant standards reference materials and protocols that will come out of the joint research here with Mark’s group on campus. And [Life Technologies and Agilent] are going to benefit because there will be some really first-class scientists working with their instrumentation, studying how well they perform now and coming up with ways that they could potentially be improved,” said Baer, who also is executive director of the Stanford Photonics Research Center.

Salit noted that NIST does not develop government regulations but informs their development, and added that in working with tech companies its mission is to help “grow the whole pie bigger,” and to support the US technology industry enterprise broadly.

This kind of partnership, he said, also will engage experts from the Food and Drug Administration, which will “bring real value” to these companies.

The HLA typing project, which will study the use of high-throughput sequencing and other nucleic acid-based technologies for identifying immune responses to bone marrow and stem cell transplantation, is a “perfect example” of the kind of program the partners will pursue, Baer explained. “This has great resonance with at least one of the commercial partners, who is trying to develop methods and products around HLA typing,” he added.

“We’re looking to identify areas of great medical need in the whole area of tissue transplants, both as it exists today and as it is going to grow with the stem cell and regenerative medicines initiatives that are underway,” said Baer. “This is an area of critical medical need where measurement science can play a very important role with the new quantitative technologies that are currently available.”

He said the HLA typing effort is “a prototype of how we’re developing the research programs at ABMS.” The goal is “to look not just at the concept of how you do this measurement, but what is the problem, where is measurement playing a role, and how we can improve the performance of the systems and technologies through both standards development, better understanding, and measurement science,” Baer said.

Baer also said that he expects this project will serve to educate regulatory agencies about “what is legitimate scientific data with a legitimate use of particular instrumentation, and what protocols have intellectual or scientific merit or not.”

He noted that NIST wasn’t aware of this need prior to beginning a dialogue with the Stanford researchers. “By coming here and interacting directly with groups that have patient contact, and dealing with developing solutions to significant medical problems, we are able to focus NIST on these areas and bring the resources of the medical community here at Stanford to bear with NIST, as well as with the companies that are supplying the instrumentation,” said Baer.

Matt Jones is a staff reporter for GenomeWeb Daily News. He covers public policy, legislation, and funding issues that affect researchers in the genomics field, as well as the operations of research institutes. E-mail Matt Jones or follow GWDN’s headlines at @DailyNewsGW.

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CD47: Target Therapy for Cancer

Author/Curator: Tilda Barliya

“A research team from Stanford University’s School of Medicine is now one step closer to uncovering a cancer treatment that could be applicable across the board in killing every kind of cancer tumor” (1). It appeared that their antibody-drug against the CD47 protein, enabled the shrinking of all tumor cells. After completing their animal studies the researchers now move into a human phase clinical trials. CD47 has been previously studied and evaluated for its role in multiple cells, some of this data however, is somewhat controversy. So where do we stand?


CD47 (originally named integrin-associated protein (IAP)) is a cell surface protein of the immunoglobulin (Ig) superfamily, which is heavily glycosylated and expressed by virtually all cells in the body and overexpressed in many types of cancer  including breast, ovarian, colon, prostate and others (3). CD47 was first recognized as a 50 kDa protein associated and copurified with the  Alpha-v-Beta-3 integrin in placenta and neutrophil granulocytes and later shown to have the capacity to regulate integrin function and the responsiveness of leukocytes to RGD-containing extracellular matrix proteins. CD47 has also been shown to be identical to the OA-3/OVTL3 antigen highly expressed on most ovarian carcinomas (4,5).

CD47 consists of an extracellular IgV domain, a five times transmembrane-spanning domain, and a short alternatively spliced cytoplasmic tail. In both humans and mice, the cytoplasmic tail can be found as four different splice isoforms ranging from 4 to 36 amino acids, showing different tissue expression patterns (3).

CD47 interactions (3, 6):

  • Thrombospondin-1 (TSP-1) – a secreted glycoprotein that plays a role in vascular development and angiogenesis. Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.
  • Signal-regulatory protein-alpha (SIRPα) – an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.
  • Integrins – several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that effect a range of cell functions including adhesion, spreading and migration

These interactions with multiple proteins and cells types create several important functions, which include:

  • Cell proliferation – cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation. For example, activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors. In cancer cells however, activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma. it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells (7).  Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters (8).
  • Apoptosis – Ligation of CD47 by anti-CD47 mAbs was found to induce apoptosis in a number of different cell types (3). For example: Of the two SIRP-family members known to bind the CD47 IgV domain (SIRPα and SIRPγ), SIRPα as a soluble Fc-fusion protein does not induce CD47-dependent apoptosis, hile SIRPα or SIRPγ bound onto the surface of beads induces apoptosis through CD47 in Jurkat T cells and the myelomonocytic cell line U937.
  • Migration – CD47  role on cell migration was first demonstrated in neutrophils, these effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. In cancer, Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanomaprostate cancer and ovarian cancer-derived cells (9).
  • Angiogenesis – The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells (10). More so, CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis (11). (12)
  • Inflammatory response – Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Tumor cells can also evade macrophage phagocytosis through the expression of CD47 (2, 13).

It appears that CD47 ligation induce different responses, depending on cell type and partner for ligation.

Therapeutic and clinical aspect of CD47 in human cancer:

CD47 is overexpressed in many types of human cancers  and its known function as a “don’t eat me” signal, suggests the potential for targeting the CD47-SIRPα pathway as a common therapy for human malignancies (2,13). Upregulation of CD47 expression in human cancers also appears to influence tumor growth and dissemination. First, increased expression of CD47 in several hematologic malignancies was found to be associated with a worse clinical prognosis, and in ALL to predict refractoriness to standard chemotherapies (13, 14-16). Second, CD47 was demonstrated to regulate tumor metastasis and dissemination in both MM and NHL (13, 17).

Efforts have been made to develop therapies inhibiting the CD47-SIRPα pathway, principally through blocking monoclonal antibodies directed against CD47, but also possibly with a recombinant SIRPα protein that can also bind and block CD47.

Figure 2

Chao MP et al. 2012 Combination strategies targeting CD47 in cancer

While monotherapies targeting CD47 were efficacious in several pre-clinical tumor models, combination strategies involving inhibition of the CD47-SIRPα pathway offer even greater therapeutic potential. Specifically, antibodies targeting CD47-SIRPα can be included in combination therapies with other therapeutic antibodies, macrophage-enhancing agents, chemo-radiation therapy, or as an adjuvant therapy to inhibit metastasis (13).

For example, anti-SIRPα antibody was found to potentiate  antibody-dependent cellular cytotoxicity (ADCC) mediated by the anti-Her2/Neu antibody trastuzumab against breast cancer cells (18).  CD47–SIRPα interactions and SIRPα signaling negatively regulate trastuzumab-mediated ADCC in vitro and antibody-dependent elimination of tumor cells in vivo

More so, chemo-radiation therapy-mediated upregulation of cell surface calreticulin may potentially augment the activity of anti-CD47 antibody. However, this approach may also lead to increased toxicity as cell surface calreticulin is expressed on non-cancerous cells undergoing apoptosis, a principle effect of chemo-radiation therapy (19).


  • Phagocytic cells, macrophages, regulate tumor growth through phagocytic clearance
  • CD47 binds SIRPα on phagocytes which delivers an inhibitory signal for phagocytosis
  • A blocking anti-CD47 antibody enabled phagocytic clearance of many human cancers
  • Phagocytosis depends on a balance of anti-(CD47) and pro-(calreticulin) signals
  • Anti-CD47 antibody synergized with an FcR-engaging antibody, such as rituximab


Evasion of immune recognition is a major mechanism by which cancers establish and propagate disease. Recent data has demonstrated that the innate immune system plays a key role in modulating tumor phagocytosis through the CD47-SIRPα pathway. Careful development of reagents that can block the CD47/SIRPα interaction may indeed be useful to treat many forms of cancer without having too much of a negative side effect in terms of inducing clearance of host cells. Therapeutic approaches inhibiting this pathway have demonstrated significant efficacy, leading to the reduction and elimination of multiple tumor types.

Dr. Weissman says: “We are now hopeful that the first human clinical trials of anti-CD47 antibody will take place at Stanford in mid-2014, if all goes wellClinical trials may also be done in the United Kingdom”. These clinical trials must be designed so that the data they generate will produce a valid scientific result!!!


1. By Sara Gates:  Cancer Drug That Shrinks All Tumors Set To Begin Human Clinical Trials. http://www.huffingtonpost.com/2013/03/28/cancer-drug-shrinks-tumors_n_2972708.html

2. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-6667. http://www.pnas.org/content/early/2012/03/20/1121623109

3. Oldenborg PL. CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN Hematology Volume 2013 (2013), Article ID 614619, 19 pages.  http://www.hindawi.com/isrn/hematology/2013/614619/

4. G. Campbell, P. S. Freemont, W. Foulkes, and J. Trowsdale, “An ovarian tumor marker with homology to vaccinia virus contains an IgV- like region and multiple transmembrane domains,”Cancer Research, vol. 52, no. 19, pp. 5416–5420, 1992. http://cancerres.aacrjournals.org/content/52/19/5416.long

5. L. G. Poels, D. Peters, Y. van Megen et al., “Monoclonal antibody against human ovarian tumor-associated antigens,” Journal of the National Cancer Institute, vol. 76, no. 5, pp. 781–791, 1986. http://www.ncbi.nlm.nih.gov/pubmed/3517452

6. CD47. Wikipedia. http://en.wikipedia.org/wiki/CD47

7. Sick E, Boukhari A, Deramaudt T, Rondé P, Bucher B, André P, Gies JP, Takeda K (February 2011). “Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway”. Glia 59 (2): 308–319. http://www.ncbi.nlm.nih.gov/pubmed/21125662

8. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD.  “Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors”Sci Rep 2013: 3: 1673. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628113/

9. Shahan TA, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. “Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca(2+)-dependent mechanism requiring CD47 and the integrin alpha(V)beta(3)”. J. Biol. Chem 2000. 275 (7): 4796–4802. http://www.jbc.org/content/275/7/4796

10. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD. “CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1”. J. Biol. Chem  2006. 281 (36): 26069–26080.  http://www.jbc.org/content/281/36/26069

11. Smadja DM, d’Audigier C, Bièche I, Evrard S, Mauge L, Dias JV, Labreuche J, Laurendeau I, Marsac B, Dizier B, Wagner-Ballon O, Boisson-Vidal C, Morandi V, Duong-Van-Huyen JP, Bruneval P, Dignat-George F, Emmerich J, Gaussem P. “Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties”. Arterioscler. Thromb. Vasc. Biol  2011. 31 (3): 551–559. http://atvb.ahajournals.org/content/31/3/551

12. G. D. Grossfeld, D. A. Ginsberg, J. P. Stein et al., “Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression,” Journal of the National Cancer Institute 1997 vol. 89, no. 3, pp. 219–227. http://www.scopus.com/record/display.url?eid=2-s2.0-18744423089&origin=inward&txGid=9C86356DDB0B6816ACCBF90F9CA44E92.WlW7NKKC52nnQNxjqAQrlA%3a2

13. Chao MP, Weissman IL, Majeti R. “The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications”Curr. Opin. Immunol 2012. 24 (2): 225–32. http://www.sciencedirect.com/science/article/pii/S095279151200012Xhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319521/

14. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Jr, van Rooijen N, Weissman IL. Cd47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726837/

15. Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of cd47 eliminates human acute lymphoblastic leukemia.Cancer Res. 2011;71 (4):1374–1384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041855/

16. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, et al. Anti-cd47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell. 2010;142(5):699–713. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943345/

17. Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-hodgkin lymphoma requires cd47 and is inhibited by anti-cd47 antibody therapy. Blood.2011;118(18):4890–4901. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208297/

18. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, et al. Cd47-signal regulatory protein-alpha (sirpalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A.2011;108(45):18342–18347. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215076/

19. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61. http://www.ncbi.nlm.nih.gov/pubmed/17187072

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Larry Bernstein MD. Treatment for Metastatic HER2 Breast Cancer https://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/

II. By: Tilda Barliya PhD. Colon Cancer.  https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

III. By: Ritu Saxena PhD. In focus: Triple Negative Breast Cancer. https://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

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News from the National Academy of Sciences

Date: April 30, 2013


National Academy of Sciences Members and Foreign Associates Elected

The National Academy of Sciences announced today the election of 84 new members and 21 foreign associates from 14 countries in recognition of their distinguished and continuing achievements in original research.

Those elected today bring the total number of active members to 2,179 and the total number of foreign associates to 437. Foreign associates are nonvoting members of the Academy, with citizenship outside the United States.

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We congratulate OUR BOARD MEMBER for being elected 

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Director, Morrison Institute for Population and Resource Studies, and Burnet C. and Mildred Finley Wohlford Professor of Biological Sciences, department of biological sciences, Stanford University, Stanford, Calif.


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Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New Center (CEGS) on the Brain: Mental Disorders and the Nervous System

April 16, 2013

NEW YORK (GenomeWeb News) – The National Human Genome Research Institute plans to fund new Centers of Excellence in Genomic Sciences, or CEGS, to create interdisciplinary teams that pursue innovative genome-based approaches to address biomedical problems and to understanding the basis of biological systems.

NHGRI, along with support from the National Institute of Mental Health, expects to provide up to $2 million per year for each of the new CEGS it funds, and plans to award up to four new awards each year.

Although these CEGS may pursue a wide range of research objectives, NIMH will support the program because it wants to fund research using novel genomic approaches that can accelerate the understanding of the genetic basis of mental disorders and the nervous systemNHGRI said on Friday.

The CEGS program was created to use the new knowledge and technologies that resulted from the Human Genome Project and subsequent genomics research to develop new tools, methods, and concepts that apply to human biology and disease.
CEGS grantees are expected to be innovative, to focus on a critical issue in genomic science, to use multiple investigators working under one leader, to work toward a specific outcome, and to tackle challenging aspects of problems that may have impeded previous research efforts.

Further, they are supposed to bolster the pool of professional scientists and engineers who are trained in genomics through offering educational programs, and they are expected to address the shortage of scientists from underrepresented minority communities by developing recruiting programs that encourage minority community members to become independent genomics investigators.

The technologies and methods the CEGS investigators develop should be applicable to a wide range of cell types and organisms, and they should be scalable and expandable so they may apply to other model systems, according to NHGRI’s funding opportunity announcement.

Recent CEGS centers include

  • Caltech’s Center for In Toto Genomic Analysis of Vertebrate Development;
  • Harvard University’s Center for Transcriptional Consequences of Human Genetic Variation;
  • Johns Hopkins University’s Center for the Epigenetics of Common Human Disease;
  • Stanford University’s Center for the Genomic Basis of Vertebrate Diversity;
  • Arizona State University’s Microscale Life Sciences Center;
  • Medical College of Wisconsin, Milwaukee’s Center of Excellence in Genomics Science;
  • The University of North Carolina at Chapel Hill‘s CISGen center;
  • The Broad Institute’s Center for Cell Circuits;
  • Yale University’s Center for the Analysis of Human Genome Using Integrated Technologies; and
  • Dana-Farber Cancer Institute‘s Center for Genomic Analysis of Network Perturbations in Human Disease.


Center for In Toto Genomic Analysis of Vertebrate Development

P50 HG004071
Marianne Bronner-Fraser
California Institute of Technology, Pasadena, Calif.

This Center of Excellence in Genomic Science (CEGS) assembles a multidisciplinary group of investigators to develop innovative technologies with the goal of imaging and mutating every developmentally important vertebrate gene. Novel “in toto imaging” tools make it possible to use a systems-based approach for analysis of gene function in developing vertebrate embryos in real time and space. These tools can digitize in vivo data in a systematic, high-throughput, and quantitative fashion. Combining in toto imaging with novel gene traps permits a means to rapidly screen for developmentally relevant expression patterns, followed by the ability to immediately mutagenize genes of interest. Initially, key technologies will be developed and tested in the zebrafish embryo due to its transparency and the ability to obtain rapid feedback. Once validated, these techniques will be applied to an amniote, the avian embryo, due to several advantages including accessibility and similarity to human embryogenesis. Finally, to monitor alterations in gene expression in normal and mutant embryos, we will develop new techniques for in situ hybridization that permit simultaneous analysis of multiple marker genes in a sensitive and potentially quantitative manner. Our goal is to combine real time analysis of gene expression on a genome-wide scale coupled with the ability to mutate genes of interest and examine global alterations in gene expression as a result of gene loss. Much of the value will come from the development of new and broadly applicable technologies. In contrast to a typical technology development grant, however, there will be experimental fruit emerging from at least two vertebrate systems (zebrafish and avian). The following aims will be pursued: Specific Aim 1: Real-time “in toto” image analysis of reporter gene expression; Specific Aim 2: Comprehensive spatiotemporal analysis of gene function of the developing vertebrate embryo using the FlipTrap approach for gene trapping; Specific Aim 3: Design of quantitative, multiplexed ‘hybridization chain reaction’ (HCR) amplifiers for in vivo imaging with active background suppression; Specific Aim 4: Data analysis and integration of data sets to produce a “digital” fish and a “digital” bird. The technologies and the resulting atlases will be made broadly available via electronic publication.

Center Web Site: California Institute of Technology Center of Excellence in Genomic Science

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Causal Transcriptional Consequences of Human Genetic Variation

P50 HG005550
George M. Church
Harvard University, Cambridge, Mass.

The Center for Transcriptional Consequences of Human Genetic Variation (CTCHGV) will develop innovative and powerful genetic engineering methods and use them to identify genetic variations that causally control gene transcription levels. Genome Wide Association Studies (GWAS) find many variations associated with disease and other phenotypes, but the variations that may actually cause these conditions are hard to identify because nearby variations in the same haplotype blocks consistently co-occur with them in human populations, so that specifically causative ones cannot be distinguished. About 95% of GWAS variations are not in gene coding regions, and many of these presumably associate with altered gene expression levels. CTCHGV will identify the variations that directly control gene expression by engineering precise combinations of changes to gene regulatory regions that break down the haplotype blocks, allowing each variations’ effect on gene expression to be discerned independently of the others. To perform this analysis, CTCHGV will extract ~100kbps gene regulatory regions from human cell samples, create precise variations in them in E. coli, and re-introduce the altered regions back into human cells, using zinc finger nucleases (ZFNs) to efficiently induce recombination. CTCHGV will target 1000 genes for this analysis (Aim 1), and will use human induced Pluripotent Stem cells (iPS) to study the effects of variations in diverse human cell types (Aim 2). To explore the effects of variations in complex human tissues, CTCHGV will develop methods of measuring gene expression at transcriptome-wide levels in many single cells, including in situ in structured tissues (Aim 3). Finally, CTCHGV will develop novel advanced technologies that integrate DNA sequencing and synthesis to construct thousands of large DNA constructs from oligonucleotides, that enable very precise targeting and highly efficient performance of ZFNs, and that enable cells to be sorted on the basis of morphology as well as fluorescence and labeling (Aim 4). CTCHGV will also develop direct oligo-mediated engineering of human cells, and create “marked allele” iPS that will enable easy ascertainment of complete exon distributions for many pairs of gene alleles in many cell types.

Center Web Site: Center for Causal Transcriptional Consequences of Human Genetic Variation (CTCHGV)

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Center for the Epigenetics of Common Human Disease

P50 HG003233
Andrew P. Feinberg
Johns Hopkins University, Baltimore
(co-funded by National Institute of Mental Health)

Epigenetics, the study of non-DNA sequence-related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual’s genetic background, the environment, aging, and disease. The Center for the Epigenetics of Common Human Disease was created in 2004 to begin to develop the interface between epigenetics and epidemiologic-based phenotype studies, recognizing that epigenetics requires new ways of thinking about disease. We created a highly interdisciplinary group of faculty and trainees, including molecular biologists, biostatisticians, epidemiologists, and clinical investigators. We developed novel approaches to genome-wide DNA methylation (DNAm) analysis, allele-specific expression, and new statistical epigenetic tools. Using these tools, we discovered that most variable DNAm is in neither CpG islands nor promoters, but in what we term “CpG island shores,” regions of lower CpG density up to several kb from islands, and we have found altered DNAm in these regions in cancer, depression and autism. In the renewal period, we will develop the novel field of epigenetic epidemiology, the relationship between epigenetic variation, genetic variation, environment and phenotype. We will continue to pioneer genome-wide epigenetic technology that is cost effective for large scale analysis of population-based samples, applying our knowledge from the current period to second-generation sequencing for epigenetic measurement, including DNAm and allele-specific methylation. We will continue to pioneer new statistical approaches for quantitative and binary DNAm assessment in populations, including an Epigenetic Barcode. We will develop Foundational Epigenetic Epidemiology, examining: time-dependence, heritability and environmental relationship of epigenetic marks; heritability in MZ and DZ twins; and develop an epigenetic transmission disequilibrium test. We will then pioneer Etiologic Epigenetic Epidemiology, by integrating novel genome-wide methylation scans (GWMs) with existing Genome-Wide Association Study (GWAS) and epidemiologic phenotype data, a design we term Genome-Wide Integrated Susceptibility (GWIS), focusing on bipolar disorder, aging, and autism as paradigms for epigenetic studies of family-based samples, longitudinal analyses, and parent-of-origin effects, respectively. This work will be critical to realizing the full value of previous genetic and phenotypic studies, by developing and applying molecular and statistical tools necessary to integrate DNA sequence with epigenetic and environmental causes of disease.

Center Web Site: Center of Excellence in Genomic Science at Johns Hopkins

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Genomic Basis of Vertebrate Diversity

P50 HG002568
David M. Kingsley
Stanford University, Stanford, Calif.

The long-term goal of this project is to understand the genomic mechanisms that generate phenotypic diversity in vertebrates. Rapid progress in genomics has provided nearly complete sequences for several organisms. Comparative analysis suggests many fundamental pathways and gene networks are conserved between organisms. And yet, the morphology, physiology, and behavior of different species are obviously and profoundly different. What are the mechanisms that generate these key differences? Are unique traits controlled by few or many genetic changes? What kinds of changes? Are there particular genes and mechanisms that are used repeatedly when organisms adapt to new environments? Can better understanding of these mechanisms help explain dramatic differences in disease susceptibility that also exist between groups? The Stanford CEGS will use an innovative combination of approaches in fish, mice, and humans to identify the molecular basis of major phenotypic change in natural populations of vertebrates. Specific aims include: 1) cross stickleback fish and develop a genome wide map of the chromosomes, genes, and mutations that control a broad range of new morphological, physiological, and behavioral traits in natural environments; 2) test which population genetic measures provide the most reliable “signatures of selection” surrounding genes that are known to have served as the basis of parallel adaptive change in many different natural populations around the world; 3) assemble the stickleback proto Y chromosome and test whether either sex or autosomal rearrangements play an important role in generating phenotypic diversity, or are enriched in genomic regions that control phenotypic change; 4) test whether particular genes and mechanisms are used repeatedly to control phenotypic change in many different vertebrates. Preliminary data suggests that mechanisms identified as the basis of adaptive change in natural fish populations may be broadly predictive of adaptive mechanisms across a surprisingly large range of animals, including humans. Genetic regions hypothesized to be under selection in humans will be compared to genetic regions under selection in fish. Regions predicted to play an important role in natural human variation and disease susceptibility will be modeled in mice, generating new model systems for confirming functional variants predicted from human population genetics and comparative genomics.

Center Web Site: Stanford Genome Evolution Center

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Microscale Life Sciences Center

P50 HG002360
Deirdre R. Meldrum
Arizona State University, Tempe

Increasingly, it is becoming apparent that understanding, predicting, and diagnosing disease states is confounded by the inherent heterogeneity of in situ cell populations. This variation in cell fate can be dramatic, for instance, one cell living while an adjacent cell dies. Thus, in order to understand fundamental pathways involved in disease states, it is necessary to link preexisting cell state to cell fate in the disease process at the individual cell level.

The Microscale Life Sciences Center (MLSC) at the University of Washington is focused on solving this problem, by developing cutting-edge microscale technology for high throughput genomic-level and multi-parameter single-cell analysis, and applying that technology to fundamental problems of biology and health. Our vision is to address pathways to disease states directly at the individual cell level, at increasing levels of complexity that progressively move to an in vivo understanding of disease. We propose to apply MLSC technological innovations to questions that focus on the balance between cell proliferation and cell death. The top three killers in the United States, cancer, heart disease and stroke, all involve an imbalance in this cellular decision-making process. Because of intrinsic cellular heterogeneity in the live/die decision, this fundamental cellular biology problem is an example of one for which analysis of individual cells is essential for developing the link between genomics, cell function, and disease. The specific systems to be studied are proinflammatory cell death (pyroptosis) in a mouse macrophage model, and neoplastic progression in the Barrett’s Esophagus (BE) precancerous model. In each case, diagnostic signatures for specific cell states will be determined by measuring both physiological (cell cycle, ploidy, respiration rate, membrane potential) and genomic (gene expression profiles by single-cell proteomics, qRT-PCR and transcriptomics; LOH by LATE-PCR) parameters. These will then be correlated with cell fate via the same sets of measurements after a challenge is administered, for instance, a cell death stimulus for pyroptosis or a predisposing risk factor challenge (acid reflux) for BE. Ultimately, time series will be taken to map out the pathways that underlie the live/die decision.

Finally, this information will be used as a platform to define cell-cell interactions at the single-cell level, to move information on disease pathways towards greater in vivo relevance. New technology will be developed and integrated into the existing MLSC Living Cell Analysis cassette system to support these ambitious biological goals including 1) automated systems for cell placement, off-chip device interconnects, and high throughput data analysis with user friendly interfaces; 2) new optical and electronic sensors based on a new detection platform, new dyes and nanowires; and 3) new micromodules for single-cell qRT-PCR, LATE-PCR for LOH including single-cell pyrosequencing, on-chip single-cell proteomics, and single-cell transcriptomics using barcoded nanobeads.

Collaborating InstitutionsFred Hutchison Cancer Research Center, Brandeis University, University of Washington.

Center Web Site: Microscale Life Sciences Center

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Wisconsin Center of Excellence in Genomics Science

P50 HG004952
Michael Olivier
Medical College of Wisconsin, Milwaukee

The successful completion of the human genome and model organism sequences has ushered in a new era in biological research, with attention now focused on understanding the way in which genome sequence information is expressed and controlled. The focus of this proposed Wisconsin Center of Excellence in Genomics Science is to facilitate understanding of the complex and integrated regulatory mechanisms affecting gene transcription by developing novel technology for the comprehensive characterization and quantitative analysis of proteins interacting with DNA. This new technology will help provide for a genome-wide functional interpretation of the underlying mechanisms by which gene transcriptional regulation is altered during biological processes, development, disease, and in response to physiological, pharmacological, or environmental stressors. The development of chromatin immunoprecipitation approaches has allowed identification of the specific DNA sequences bound by proteins of interest. We propose to reverse this strategy and develop an entirely novel technology that will use oligonucleotide capture to pull down DNA sequences of interest, and mass spectrometry to identify and characterize the proteins and protein complexes bound and associated with particular DNA regions. This new approach will create an invaluable tool for deciphering the critical control processes regulating an essential biological function. The proposed interdisciplinary and multi-institutional Center of Excellence in Genomics Science combines specific expertise at the Medical College of Wisconsin, the University of Wisconsin Madison, and Marquette University. Technological developments in four specific areas will be pursued to develop this new approach: (1) cross-linking of proteins to DNA and fragmentation of chromatin; (2) capture of the protein-DNA complexes in a DNA sequence-specific manner; (3) mass spectrometry analysis to identify and quantify bound proteins; and (4) informatics to develop tools enabling the global analysis of the relationship between changes in protein-DNA interactions and gene expression. The Center will use carefully selected biological systems to develop and test the technology in an integrated genome-wide analysis platform that includes efficient data management and analysis tools. As part of the Center mission, we will combine our technology development efforts with an interdisciplinary training program for students and fellows designed to train qualified scientists experienced in cutting-edge genomics technology. Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities.

Collaborating InstitutionsUniversity of Wisconsin-Madison, Marquette University

Center Web Site: Wisconsin Center of Excellence in Genomic Science

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P50 MH090338
Fernando Pardo-Manuel de Villena
University of North Carolina, Chapel Hill

p>In this application, we propose a highly ambitious yet realistically attainable goal: to align existing expertise at UNC-Chapel Hill into a CEGS called CISGen. The overarching purpose of CISGen is to develop as a resource and to exploit the utility of the murine Collaborative Cross (CC) mouse model of the heterogeneous human population to delineate genetic and environmental determinants of complex phenotypes drawn from psychiatry, which are among the most intractable set of problems in all of biomedicine. Psychiatric disorders present a paradox – the associated morbidity, mortality, and costs are enormous and yet, despite over a century of scientific study, there are few hard facts about the etiology of the core diseases. Although our GWAS meta- analyses are in progress, early results suggest that strong and replicable findings may be elusive. Therefore, our proposal provides a complementary approach to the study of fundamental psychiatric phenotypes.

We propose a particularly challenging definition of success – we will identify high probability etiological models (which can be realistically complex) and then prove the predictive capacity of these models by generating novel strains of mice predicted to be at very high risk for the phenotype. Once validated, these high confidence models can then be tested in subsequent human studies – we do not propose human extension studies in CISGen but this is achievable for the investigators and their colleagues. Data collected in CISGen would be a valuable resource to the wider scientific community and could be applied to a large set of biological problems and these data can rapidly add to the knowledge base for any new genomewide association study (GWAS) finding. Delivery of sophisticated and user-friendly databases are a key component of CISGen.

Accomplishing this overarching goal requires an exceptional diversity of scientific expertise – psychiatry, human genetics, mouse behavior, mouse genetics, statistical genetics, computational biology, and systems biology. Experts in these disciplines are deeply involved in CISGen and are committed to the projects described herein. Successful integration of these diverse fields is non-trivial; however, all scientists on this application have had extensive interactions over the past five years, already know how to work together, and have a working knowledge of their colleagues’ expertise. UNC-Chapel Hill has an intense commitment to inter- disciplinary genomics research and provides a fertile backdrop for 21st century projects like CISGen.

Collaborating InstitutionsThe Jackson Laboratory, North Carolina State University, University of Texas at Arlington

Center Web Site: Center for Integrated Systems Genomics at UNC (CISGen)

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Center for Cell Circuits

P50 HG006193
Aviv Regev
The Broad Institute, Inc., Cambridge, Mass.

Systematic reconstruction of genetic and molecular circuits in mammalian cells remains a significant, largescale and unsolved challenge in genomics. The urgency to address it is underscored by the sizeable number of GWAS-derived disease genes whose functions remain largely obscure, limiting our progress towards biological understanding and therapeutic intervention. Recent advances in probing and manipulating cellular circuits on a genomic scale open the way for the development of a systematic method for circuit reconstruction. Here, we propose a Center for Cell Circuits to develop the reagents, technologies, algorithms, protocols and strategies needed to reconstruct molecular circuits. Our preliminary studies chart an initial path towards a universal strategy, which we will fully implement by developing a broad and integrated experimental and computational toolkit. We will develop methods for comprehensive profiling, genetic perturbations and mesoscale monitoring of diverse circuit layers (Aim 1). In parallel, we will develop a computational framework to analyze profiles, derive provisional models, use them to determine targets for perturbation and monitoring, and evaluate, refine and validate circuits based on those experiments (Aim 2). We will develop, test and refine this strategy in the context of two distinct and complementary mammalian circuits. First, we will produce an integrated, multi-layer circuit of the transcriptional response to pathogens in dendritic cells (Aim 3) as an example of an acute environmental response. Second, we will reconstruct the circuit of chromatin factors and non-coding RNAs that control chromatin organization and gene expression in mouse embryonic stem cells (Aim 4) as an example of the circuitry underlying stable cell states. These detailed datasets and models will reveal general principles of circuit organization, provide a resource for scientists in these two important fields, and allow computational biologists to test and develop algorithms. We will broadly disseminate our tools and methods to the community, enabling researchers to dissect any cell circuit of interest at unprecedented detail. Our work will open the way for reconstructing cellular circuits in human disease and individuals, to improve the accuracy of both diagnosis and treatment.

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Analysis of Human Genome Using Integrated Technologies

P50 HG002357
Michael P. Snyder
Yale University, New Haven, Conn.

We propose to establish a center to build genomic DNA arrays and develop novel technologies that will use these arrays for the large-scale functional analysis of the human genome. 0.3-1.4 kb fragments of nonrepetitive DNA from each of chromosomes 22, 21, 20, 19,7, 17, and perhaps the X chromosome will be prepared by PCR and attached to microscope slides. The arrays will be used to develop technologies for the large-scale mapping of 1) Transcribed sequences. 2) Binding sites of chromosomal proteins. 3) Origins of replication. 4) Genetic mutation and variation. A web-accessible database will be constructed to house the information generated in this study; data from other studies will also be integrated into the database. The arrays and technologies will be made available throughout both the Yale University and the larger scientific community. They will be integrated into our training programs for postdoctoral fellows, graduate students and undergraduates at Yale. We expect these procedures to be applicable to the analysis of the entire human genome and the genomes of many other organisms.

Center Web Site: Yale University Center for Excellence in Genomic Science

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Genomic Analysis of the Genotype-Phenotype Map

P50 HG002790
Simon Tavaré
University of Southern California, Los Angeles

Our Center, which started in 2003, focused on implications of haplotype structure in the human genome. Since that time, there have been extraordinary advances in genomics: Genome-wide association studies using single nucleotide polymorphisms and copy number variants are now commonplace, and we are rapidly moving towards whole-genome sequence data for large samples of individuals. Our Center has undergone similar dramatic changes. While the underlying theme remains the same — making sense of genetic variation — our focus is now explicitly on how we can use the heterogeneous data produced by modern genomics technologies to achieve such an understanding. The overall goal of our proposal is to develop an intellectual framework, together with computational and statistical analysis tools, for illuminating the path from genotype to phenotype, and for predicting the latter from the former. We will address three broad questions related to this problem: 1) How do we infer mechanisms by which genetic variation leads to changes in phenotype? 2) How do we improve the design, understanding and interpretation of association studies by exploiting prior information? 3) How do we identify general principles about the genotype-phenotype map? We will approach these questions through a series of interrelated projects that combine computational and experimental methods, explored in Arabidopsis, Drosophila and human, and involve a wide range of researchers including molecular biologists, population geneticists, genetic epidemiologists, statisticians, computer scientists, and mathematicians.

Collaborating InstitutionsUniversity of Utah

Center Web Site: The USC Center of Excellence in Genomic Science

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Genomic Analysis of Network Perturbations in Human Disease

P50 HG004233
Marc Vidal
Dana-Farber Cancer Institute, Boston

Genetic differences between individuals can greatly influence their susceptibility to disease. The information originating from the Human Genome Project (HGP), including the genome sequence and its annotation, together with projects such as the HapMap and the Human Cancer Genome Project (HCGP) have greatly accelerated our ability to find genetic variants and associate genes with a wide range of human diseases. Despite these advances, linking individual genes and their variations to disease remains a daunting challenge. Even where a causal variant has been identified, the biological insight that must precede a strategy for therapeutic intervention has generally been slow in coming. The primary reason for this is that the phenotypic effects of functional sequence variants are mediated by a dynamic network of gene products and metabolites, which exhibit emergent properties that cannot be understood one gene at a time. Our central hypothesis is that both human genetic variations and pathogens such as viruses influence local and global properties of networks to induce “disease states.” Therefore, we propose a general approach to understanding cellular networks based on environmental and genetic perturbations of network structure and readout of the effects using interactome mapping, proteomic analysis, and transcriptional profiling. We have chosen a defined model system with a variety of disease outcomes: viral infection. We will explore the concept that one must understand changes in complex cellular networks to fully understand the link between genotype, environment, and phenotype. We will integrate observations from network-level perturbations caused by particular viruses together with genome-wide human variation datasets for related human diseases with the goal of developing general principles for data integration and network prediction, instantiation of these in open-source software tools, and development of testable hypotheses that can be used to assess the value of our methods. Our plans to achieve these goals are summarized in the following specific aims: 1. Profile all viral-host protein-protein interactions for a group of viruses with related biological properties. 2. Profile the perturbations that viral proteins induce on the transcriptome of their host cells. 3. Combine the resulting interaction and perturbation data to derive cellular network-based models. 4. Use the developed models to interpret genome-wide genetic variations observed in human disease, 5. Integrate the bioinformatics resources developed by the various CCSG members within a Bioinformatics Core for data management and dissemination. 6. Building on existing education and outreach programs, we plan to develop a genomic and network centered educational program, with particular emphasis on providing access for underrepresented minorities to internships, workshop and scientific meetings.

Center Web SiteCenter for Cancer Systems Biology (CCSB) Center of Excellence in Genomic Science

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