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See on Scoop.itCardiovascular and vascular imaging

After a heart attack has occurred, inflammatory cells known as monocytes rush to the damaged tissue. This causes the heart to swell, further damaging the ti…

See on www.gizmag.com

Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 7/18/2021

ER

IMAGE SOURCE:

Claudio A. Hetz. Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

FIG. 3. Regulation of ER calcium homeostasis by the BCL-2 protein family. Different anti- and proapoptotic members of the BCL-2 family of proteins are located at the ER membrane, where they have an important role regulating ER calcium content. BCL-2 and BCL-XL interact with the IP3R calcium channel, modulating its activity. BCL-2 has been shown to increase ER calcium leak through the IP3R because of an increase on its phosphorylation levels.

BAX and BAK have the opposite effect on ER calcium content, a function that may be further modulated by BH3-only proteins (such as PUMA and BIK). In addition, the activity of BCL-2 at the ER membrane is regulated by phosphorylation. JNK phosphorylates BCL-2, decreasing its antiapoptotic activity and increasing ER calcium content, whereas the phosphatase PP2A decreases this phosphorylation through a direct interaction. Alternatively, ER stress activates the IRE1/JNK pathway that may alter the activity of BCL-2 at the ER membrane. BI-1 is also located at the ER membrane, where it regulates calcium homeostasis.

CONCLUSIONS AND THERAPEUTIC PERSPECTIVES

I have summarized different pieces of evidence suggesting that the BCL-2 family of proteins has evolved to regulate multiple processes involved in cell survival under stress conditions. The global view of the current state of the field indicates that the BCL-2–related proteins are not only the “death gateway” keeper (as upstream regulators of caspases), but they also have multiple functions in essential processes for the cell. BCL-2–related proteins are particularly important in the physiologic maintenance of the ER, where they operate as

(a) a calcium rheostat,

(b) modulators of the UPR,

(c) regulators of ER network structure, and

(d) regulators of autophagy.

In addition, examples of a role of the BCL-2 family of proteins in cell-cycle regulation (87, 113), DNA damage responses (37, 114), and glucose/energy metabolism (16) are available, strongly supporting the notion that the BCL-2 protein family is a multifunctional group of proteins that, under normal conditions, participate in essential cellular process. In doing so, the BCL-2 protein family may represent specialized stress sentinels that actively participate in essential processes, allowing a constant homeostatic “quality control.” In response to irreversible cellular damage, particular BCL-2 family members may turn into direct activators of apoptosis.

Mutations in specific genes are responsible for a variety of neurologic disorders due to the misfolding and accumulation of abnormal protein aggregates in the brain. In many of these diseases, it has been suggested that alteration in the homeostasis of the ER contributes significantly to neuronal dysfunction.

These diseases include Parkinson’s disease (32, 84), Alzheimer’s disease (22), prion diseases (27, 28, 31), amyotrophic lateral sclerosis (ALS) (97), Huntington’s disease (63, 90) and many others (see list of diseases in 86). Consequently, the first steps in the death pathways downstream of ER stress represent important therapeutic targets. In this line of thinking, pharmacologic manipulation of the activity of the BCL-2 protein family may have beneficial consequences to treat these fatal diseases. Different small molecules and synthetic peptides are currently available with proven therapeutic applications in mouse disease models, including BCL-2 inhibitors (71), BAX channel inhibitors (29), BAX/BAK activator peptides (100, 101) and many others (see reviews in 52, 79). These drugs may be used as pharmacologic tools to manipulate the activity of stress-signaling pathways regulated by the BCL-2 protein family (i.e., autophagy, calcium metabolism, or the UPR) and their possible role in pathologic conditions.

SOURCE

Claudio A. Hetz.Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

  • Published in Volume: 9 Issue 12: November 2, 2007
  • Online Ahead of Print: September 13, 2007

UPDATED on 7/1/2015

We add the following to this series:

Part XIII 

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

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, ArterialSmooth 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 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 – Part VIII

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 – Part IX

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 – Part X

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

Part XI

Sensors and Signaling in Oxidative Stress – Part XI

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)) – Part XII

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

 

Cambridge Healthtech Institute’s Inaugural
Biologics for Autoimmune Diseases
Emerging Targets, Therapeutic Strategies and Product Formats for a Growing Market
Part of the Tenth Annual PEGS: the essential protein engineering summit
May 5-6, 2014 | Seaport World Trade Center| Boston, MA

Reporter: Aviva Lev-Ari, PhD, RN

Day 1 | Day 2 | Download Brochure | Speaker Bios

The specificity, efficacy and safety profiles of biologics have traditionally made them good candidates for the treatment of autoimmune diseases. Emerging genetic understandings of the mechanisms of these complex disorders are now being combined with exciting new therapeutic formats and strategies in a renewed wave of attention for the use of biotherapeutics in this therapeutic area.  Bispecific and combination therapeutics will provide improved efficacy by impacting multiple targets and processes.  Development of biosimilars and biobetters in this space will build on the success of proven therapeutics, while new technologies will offer expanded options for the application of promising validated targets from the past that were not advanced to the market.

The inaugural Biologics for Autoimmune Diseases presents a focused meeting that will track current clinical progress in the major autoimmune diseases, and then offer an exciting exploration of ways in which the industry is applying new science and technology in the development of a next generation of effective and safe therapeutics.  Set in the context of the 10th annual PEGS, attendees of this meeting will join more than 1,500 colleagues working in the fields of protein engineering and biologics development, offering unprecedented opportunities for networking and scientific collaboration.

 

MONDAY, MAY 5

 

RECOMMENDED PRE-CONFERENCE SHORT COURSES*

Strategy for Entering the Biosimilars Market

*Separate registration required

 

7:00 am Registration and Morning Coffee

 

» Plenary Keynote Session

8:30 Chairperson’s Opening Plenary Remarks

Kristi Sarno, Chair, Greater Boston Chapter, Women in Bio; Director, Business Development, Pfenex, Inc.

8:40 Harnessing the Patient’s Immune System
to Combat Cancer

Bahija Jallal, Ph.D., Executive Vice President, MedImmune

With recent FDA approvals, modulation of the immune system is now a clinically validated approach in the treatment of some cancers. At MedImmune, the Oncology Department is developing assets and expertise in Immune Mediated Therapy of Cancer (IMT-C). The challenges from a drug development perspective are multi-fold. The talk will focus on the relevance of preclinical models and translational science to address key issues, including dose selection and rationale combinations.

9:25 Building Regeneron’s Pipeline: From Trap Technology to the VelocImmune Platform to Veloci-Next

George D. Yancopoulos, M.D., Ph.D., President, Regeneron Laboratories; CSO, Regeneron Pharmaceuticals, Inc.

George D. Yancopoulos, M.D., Ph.D., who is the Founding Scientist, President, Research Laboratories and Chief Scientific Officer of Regeneron Pharmaceuticals, one of the world’s top biotechnology companies, will discuss how he and his colleagues exploited a commitment to science and technology to start the company, withstand years of challenges and failures, and emerge with a pipeline of promising technologies and novel/biologics that are beginning to bring hope to countless patients and their families.

 

10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

11:05 Chairperson’s Remarks

RonaldHerbstRonald Herbst, Ph.D., Senior Director, Autoimmune Diseases, MedImmune

» 11:10 Keynote Presentation:

Biologics for Systemic Lupus Erythematosus

WilliamStohlWilliam Stohl, M.D., Ph.D., Professor, Medicine, Rheumatology, Keck School of Medicine, University of Southern California

With FDA approval of a biologic therapeutic for SLE, optimism abounds for approval of additional agents. Candidates include: biologics to effect B cell depletion/inactivation or generation of regulatory B cells; biologics to effect T cell tolerance, blockade of T cell activation/differentiation, or altered T cell trafficking; and biologics targeting individual cytokines. As understanding of SLE pathogenesis continues to expand, additional therapeutic targets will be identified.

12:10 pm Sponsored Presentation (Opportunity Available)

12:40 Luncheon Presentation I (Sponsorship Opportunity Available)

1:10 Luncheon Presentation II (Sponsorship Opportunity Available)

1:40 Session Break

 

CLINICAL AND PRECLINICAL UPDATES OF BIOLOGIC THERAPIES FOR AUTOIMMUNE DISEASES

2:00 Chairperson’s Remarks

LawrenWuLawren Wu, Ph.D., Senior Scientist, Immunology, Genentech, Inc.

2:05 Clinical Update of Secukinumab (Anti-IL-17A) for Psoriasis, Spondyloarthritis and Rheumatoid Arthritis

ChristianAntoniChristian Antoni, M.D., Ph.D., Vice President, Senior Global Program Head, Integrated Hospital Care Franchise, Novartis Pharmaceuticals Corporation

IL-17A has been implicated as the key cytokine in the pathogenesis of a number of inflammatory autoimmune diseases including psoriasis, spondyloarthritis and rheumatoid arthritis. Secukinumab, a fully human monoclonal antibody that selectively binds to and neutralizes IL-17A, has been shown to be effective in the treatment of plaque psoriasis in phase III studies. A clinical update and results of recent phase II/III studies will be presented.

2:35 Clinical Update of MEDI 551 (Anti-CD19 Antibody) for Autoimmune Disease

Ronald Herbst, Ph.D., Senior Director, Autoimmune Diseases, MedImmune

Human cluster of differentiation (CD) antigen 19 is a B cell-specific surface antigen and an attractive target for B cell depletion. MEDI-551 is an affinity-optimized and afucosylated CD19 mAb with enhanced antibody-dependent cellular cytotoxicity (ADCC). MEDI-551 is currently in several phase 1/2 clinical studies, including B cell malignancies, systemic sclerosis (SSc) and relapsing remitting multiple sclerosis (RRMS).

3:05 Cytokine Modulation by Protein Therapeutics in Anterior and Posterior Ocular Disorders

Christian Dombrowski Ph.D., Senior Scientist, Eleven Biotherapeutics, Inc.

Cytokines, chemokines, and growth factors mediate anterior and posterior eye diseases. A novel soluble receptor inhibitor of IL-17A and IL-17A with potential for treating uveitis and AMD was engineered, along with an IL-6 inhibitor with potential for treating diabetic macular edema. Our lead product, EBI-005 was designed and engineered for the topical treatment of dry eye disease and has evidence of biological activity in a clinical study.

3:35 IL-1a/b DVD-Ig™: From Design to Clinic for Autoimmune Indications

TariqGhayurTariq Ghayur, Ph.D., Senior Research Fellow, AbbVie

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:45 Problem Solving Breakout Discussions

5:45 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 End of Day

TUESDAY, MAY 6

7:45 am Morning Coffee

 

BISPECIFIC ANTIBODIES FOR AUTOIMMUNE DISEASES

8:25 Chairperson’s Remarks

TariqGhayurTariq Ghayur, Ph.D., Senior Research Fellow, AbbVie

8:30 Development of a Human IgG4 Bispecific Antibody for Dual Targeting of IL-4 and IL-13 Cytokines

LawrenWuLawren Wu, Ph.D., Senior Scientist, Immunology, Genentech, Inc.

Interleukins IL-4 and IL-13 have been implicated in the pathogenesis of asthma and allergy. We have extended a previously developed bispecific antibody technology to develop a human IgG4 bispecific antibody targeting both IL-4 and IL-13. Our work broadens the range of therapeutic bispecific antibody platforms to include both human IgG1 and IgG4 isotypes, resulting in the generation of an anti-IL-4/IL-13 bispecific suitable for clinical studies.

9:00 Proof-of-Concept Studies of B-Lymphocyte Targeted Bispecific DART® Molecules for Autoimmune Disorders

PaulMoorePaul Moore, Ph.D., Vice President, Cell Biology & Immunology, Macrogenics

To address limitations of existing B cell targeted therapies, we have developed MGD010, a bispecific Dual-Affinity ReTargeting (DART) molecule that coligates the inhibitory FcγRIIb (CD32B) receptor and the BCR component, CD79B, to inhibit B cell activation and dampen autoimmunity. Preclinical studies have demonstrated the ability of CD32BxCD79B DARTs to preferentially inhibit activated B cells through activation of the CD32B pathway.

9:30 XmAb5871: An FcgRIIb-Enhanced Anti-CD19 Antibody for Nondepleting B Cell Inhibition

JohnDesjarlaisJohn Desjarlais, Ph.D., Vice President, Research, Xencor

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

 

EMERGING BIOLOGIC FORMATS

10:45 mRNA-Engineered Mesenchymal Stem Cells as Targeted Drug Factories

OrenLevyOren Levy, Ph.D., Instructor in Medicine, Harvard Medical School

MSCs are promising candidates for cell-based therapy to treat inflammatory diseases and are compelling to consider as vehicles for delivery of biological agents. We harnessed mRNA transfection to rapidly target systemically administered MSCs to inflamed sites to which they delivered an immunosuppressive cytokine, significantly reducing local inflammation. This platform may be used for cell-based targeted delivery of therapeutics to disease sites.

11:15 AVX-470, An Oral Anti-TNF Antibody for Inflammatory Bowel Disease

BarbaraFoxBarbara S. Fox, Ph.D., CEO, Avaxia Biologics, Inc.

Avaxia is developing gut-targeted antibody therapeutics – antibodies designed to be taken orally and to act locally in the GI tract. AVX-470 is Avaxia’s lead product, an orally-delivered polyclonal anti-TNF antibody in clinical development for inflammatory bowel disease.

11:45 SOBI002, a Small Affibody-ABD Fusion Protein Targeting Complement Factor C5 as a Next-Generation Biologic for Autoimmune Disease

PatrickStrombergPatrik Strömberg, Ph.D., Principal Scientist, Drug Design and Development, Swedish Orphan Biovitrum (Sobi), Sweden

SOBI002 is composed of a C5 targeting Affibody molecule fused to an albumin binding domain. In vivo, this molecule displays long terminal half-life, high subcutaneous bioavailability and durable pharmacodynamic effects. No dose-limiting toxicity of SOBI002 was observed in repeat dose studies in monkey and rat. Based on these results, a study to evaluate safety, tolerability, PK and PD of SOBI002 in man is warranted.

12:15 pm Luncheon Presentation I (Sponsorship Opportunity Available)

12:45 Luncheon Presentation II (Sponsorship Opportunity Available)

1:15-1:45 Ice Cream Break in the Exhibit Hall

 

IMMUNE MODULATION AND TOLERANCE INDUCTION STRATEGIES

2:00 Chairperson’s Remarks

Paul Moore, Ph.D., Vice President, Cell Biology & Immunology, Macrogenics

2:05 Strategies Underlying Tolerance Induction with Antibodies as Combination Therapy

Herman Waldman, Ph.D., Emeritus Professor of Pathology, Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford, United Kingdom

Current immunosuppression is often long-term and it penalizes the whole immune system, as well as inflicting many unwanted side effects. If we could harness some of the key mechanisms of tolerance that the body uses, then we might be able to minimize the duration and quantity of drugs given. The talk will summarize approaches to using short-term exposure to anti-lymphocyte antibodies to achieve this end.

2:35 Inducing Antigenic-Specific B Cell Tolerance using Antigenic Liposomes Displaying CD22 Ligands

MatthewMacauleyMatthew Macauley, Ph.D., Researcher, Paulson Laboratory, Chemical Physiology, The Scripps Research Institute

New strategies are needed for antigen-specific suppression of undesired antibody responses. Liposomes displaying both antigen and glycan ligands of the inhibitory B cell co-receptor CD22, induce a tolerogenic program that selectively causes apoptosis in B cells. Since inhibitory antibodies to FVIII are problematic for hemophilia A patients, we used this approach to induce tolerance to FVIII in a hemophilia mouse model, allowing for effective administration of FVIII to prevent bleeding.

3:05 Sponsored Presentation (Opportunity Available)

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Antigen-Specific Immunotherapy for Autoimmune Diseases

DavidWraithDavid Wraith, Ph.D., Professor of Experimental Pathology, School of Cellular and Molecular Medicine, University of Bristol, United Kingdom

Antigen-specific immunotherapy is disease modifying and efficacious. The use of whole antigens for SIT is, however, associated with unacceptable side effects. Apitopes are T cell epitopes designed to modulate immune response to self-antigens or allergens while minimizing the side effects of SIT. This lecture reviews the design and MOA of tolerogenic epitopes and will discuss results of recent clinical trials in allergic and autoimmune diseases.

4:45 The MCAM/Laminin 411 Interaction Provides a TH17 Specific Mechanism for T Cell Entry into the CNS

KenFlanaganKen Flanagan, Ph.D., Senior Scientist, Cell Biology, Prothena Biosciences

Expression of MCAM/CD146 is enriched on TH17 cells. The ligand for MCAM is laminin 411, a molecule critical in T cell infiltration into tissues. Anti-MCAM antibodies inhibit the interaction with laminin 411. The specificity of MCAM expression on TH17 cells combined with the binding of MCAM exclusively to laminin 411 defines a targetable TH17/vascular interaction, to specifically inhibit a particularly pathogenic immune cell population.

5:15 End of Conference

Speaker Biographies | THERAPEUTICS STREAM

Christian Antoni, M.D., Ph.D., Vice President, Senior Global Program Head, Integrated Hospital Care Franchise, Novartis Pharmaceuticals Corporation

Dr. Christian Antoni MD, PhD is a rheumatologist by training who during his academic career has been involved in the development of multiple biologics in rheumatic diseases. He introduced the treatment of anti-TNF drugs into psoriatic arthritis and was co-founder of GRAPPA (group for research and assessment in psoriasis and psoriatic arthritis). He joined the pharmaceutical industry in 2004 and was involved in the development of the anti-TNF drugs infliximab and golimumab in multiple indications. He joined Novartis in 2008 and is currently VP and Senior Global Program Head for the development of secukinumab, a fully human anti-IL17A monoclonal antibody.

Ellen Border, D.Phil., Scientist, Protein Engineering, Adaptimmune Ltd.

Ellen Border received her DPhil in Structural Biology (supervised by Professor Yvonne Jones) from the University of Oxford before transferring to the Protein Engineering group at Adaptimmune Ltd.

Adrian Bot, M.D., Ph.D., Vice President, Scientific Affairs, Kite Pharma, Inc.

Adrian Bot brings over 13 years of experience in the biopharmaceutical industry and expertise in discovery, research and development of active immunotherapies in oncology. At Kite, Dr. Bot provides scientific and translational research leadership to the company’s technologies and growing product pipeline as well as management of its academic and corporate collaborations. He also supports Kite’s Chief Executive Officer in setting strategic directions as well as in other aspects of the company’s operations. Before joining Kite, Dr. Bot served as Vice President of Research at MannKind Corp, where he led the efforts to discover and advance through development a number of immunotherapies and targeted therapies for different cancer indications. Prior to joining MannKind, he served as Director of Immunology at Allecure Corp. and as Director of Immunology at Alliance Pharmaceutical Corp., where he led the research and development of novel vaccine adjuvants and immunotherapies. Dr. Bot received his M.D. degree from the University of Medicine and Pharmacy in Timisoara, Romania, and his Ph.D. in Biomedical Sciences from Mount Sinai School of Medicine in New York. He conducted his post-graduate training as a visiting scientist at the Scripps Research Institute in La Jolla, CA. He has authored more than 75 scientific publications in basic and applied immunology and is an inventor on more than 10 patents on immune therapeutic approaches and innovative drugs for autoimmune diseases and oncology.

Malcolm Brenner, M.D., Ph.D., Professor, Departments of Pediatrics and Medicine; Stem Cells and Regenerative Medicine (STaR) Center; Program in Translational Biology & Molecular Medicine; Director, Center for Cell and Gene Therapy, Baylor College of Medicine

Malcolm Brenner, M.D., Ph.D., is Director of the Center for Cell and Gene Therapy at Baylor College of Medicine (BCM), Texas Children’s Hospital and The Methodist Hospital. He serves as a professor, in the Departments of Pediatrics and of Medicine at BCM. Brenner received his medical degree and subsequent Ph.D. from Cambridge University, England. Brenner’s clinical research interests span many aspects of stem cell transplantation, using genetic manipulation of cultured cells to obtain therapeutic effects. Efforts in Brenner’s laboratory to analyze the cell of origin when relapse occurs in patients with acute myelogenous leukemia led Brenner’s team to be the first to label autologous bone marrow cells genetically after purging, prior to being reintroduced to the patient. He is studying the effects of gene transfer into autologous neuroblastoma cells and the use of gene-modified EBV-specific cytotoxic T lymphocyctes for prevention and treatment of lymphoproliferative disorders, Hodgkin’s disease, lung cancer and neuroblastoma. His group recently pioneered the first clinical use of a new safety switch for cellular therapy. Brenner is Editor in Chief of “Molecular Therapy” and a former President of the American Society for Gene and Cell Therapy (ASGCT) and the International Society for Cell Therapy. He has won many awards for his work and in 2011 these included the ASGCT Outstanding Achievement Award and the American Society of Hematology Mentor Award.

Cyrille Cohen, Ph.D., Senior Lecturer, Laboratory of Tumor Immunology, Bar-Ilan University Visiting Scientist, Surgery Branch, NCI, NIH

Cyrille Cohen trained as a research fellow at the National Cancer Institute (NIH), pioneering approaches to improve TCR-gene transfer clinically. In 2007, he established the Laboratory of Tumor Immunology and Immunotherapy at Bar-Ilan University (Ramat Gan, Israel), in which he and his group are devising novel strategies to enhance T-cell function to target tumor and viral-infected cells. He has received several research awards and published some 40 research peer-reviewed articles in the field of immunotherapy. Dr Cohen has served on the scientific board of several biotech companies and is also a member of the national committee for the approval of clinical trials based on cell and genetic engineering (Israel Ministry of Health). He is currently a visiting professor in the Surgery Branch collaborating with Dr Steven Rosenberg (NIH/National Cancer Institute, 2013-2014).

Laurence J.N. Cooper, M.D., Ph.D., Grant Taylor, W.W. Sutow and Margaret Sullivan Distinguished Professor in Pediatrics; MDACC Section Chief, Cell Therapy, Children’s Cancer Hospital, Division of Pediatrics (Unit 907); Associate Director, CCIR; Director, Immunology Laboratory of PhysicianScientists, Department of Immunology, MD Anderson Cancer Center

Laurence J.N. Cooper obtained his M.D. and Ph.D. degrees at Case Western Reserve University in Cleveland and then training in Pediatric Oncology and Bone Marrow Transplantation (BMT) at the Fred Hutchinson cancer Research Center in Seattle. He joined M.D. Anderson Cancer Center in 2006 and currently leads the Pediatric Cell Therapy service (formally named the BMT program). In addition to caring for children, adolescents and young adults undergoing autologous and allogeneic hematopoietic stem-cell transplantation (HSCT), he runs a laboratory translating immunology into clinical practice. His program has multiple investigator-initiated trials that infuse T cells and NK cells to target malignancies. The adoptive transfer of lymphocytes represents the future of HSCT as he and other investigators enhance the potency of the immune system to eliminate residual cancers.

John R. Desjarlais, Ph.D. Director of Protein Engineering at Xencor

Dr. Desjarlais is Director of Protein Engineering at Xencor, a drug discovery company dedicated to designing safer and more effective protein therapeutics. Xencor uses computational methods to rationally design protein drugs with features tuned for clinical use.  Before joining Xencor in 1997, Dr. Desjarlais was an Assistant Professor of Chemistry at Penn State University, where he continued the development of protein design methods that he initiated as a postdoctoral fellow at UC Berkeley. Ken Flanagan, Ph.D., Senior Scientist, Cell Biology, Prothena Biosciences He received his BS from Cornell University in 1998 in Nutrition. He completed his MS at Albert Einstein College of Medicine in 2001 in Immunology and his PhD at Columbia University in 2004 in Immunology.

Barbara S. Fox, Ph.D., Chief Executive Officer, Avaxia Biologics, Inc.

Barbara S. Fox, PhD, is founder and CEO of Avaxia Biologics, a leader in the growing field of gut-targeted therapeutics. Avaxia’s lead clinical candidate, AVX-470, is an oral anti-TNF antibody for inflammatory bowel disease. Dr. Fox’s previous positions have included Affiliated Entrepreneur at Oxford Bioscience Partners; founder, President and Chief Scientific Officer of Recovery Pharmaceuticals; Vice President, Discovery and Immunology at ImmuLogic Pharmaceutical Corp.; and Associate Professor of Rheumatology and Clinical Immunology at the U. Maryland School of Medicine. Dr. Fox received her PhD in Chemistry from MIT and trained as a post-doc in cellular immunology at the NIH.

Eric Furfine, Ph.D., Chief Scientific Officer, Eleven Biotherapeutics

With more than 20 years of experience in drug research and development, Eric Furfine has been involved in advancing numerous products into clinical development across multiple therapeutic areas. Prior to joining Eleven Biotherapeutics, Dr. Furfine was Senior Vice President of Research and Preclinical Development at Adnexus, a Bristol-Myers Squibb R&D Company. In this role, he directed and led all activities in the discovery, preclinical development and much of clinical pharmacology of Adnectins, which are novel targeted protein therapeutic agents. Previously, he was Vice President of Preclinical Development at Regeneron Pharmaceuticals, responsible for all aspects of preclinical development and a significant portion of clinical pharmacology. Dr. Furfine also spent more than a decade in senior level research positions at GlaxoSmithKline, where he was program leader and co-inventor of LEXIVA® (fosamprenavir calcium). Dr. Furfine conducted his postdoctoral research at University of California, San Francisco and holds a Ph.D. in Biochemistry from Brandeis University.

Ronald Herbst, Ph.D., Senior Director, Autoimmune Diseases, MedImmune

Dr. Ronald Herbst is senior director in the research organization of MedImmune, where he is leading a group dedicated to the development of novel antibody and protein therapeutics for the treatment of systemic autoimmune diseases. Dr. Herbst joined MedImmune in February of 2006 as Associate Director and lead of the Oncology/RIA B cell group. Prior to joining MedImmune, Dr. Herbst was senior principal investigator at Schering-Plough Biopharma (formerly DNAX), where he focused on signal transduction research and small and large molecule drug discovery in several disease areas. Dr. Herbst received his diploma (Masters) in microbiology and pharmacology/toxicology from the Ludwig-Maximilian University in Munich. Following his doctorate in molecular biology at the Max-Planck Institute of Biochemistry in Munich he conducted his postdoctoral research in the Department of Biology at Stanford University.

Michael C. Jensen, M.D., Professor, Pediatrics, University of Washington School of Medicine; Director, Ben Towne Center for Childhood Cancer Research/Seattle Children’s Research Institute; Joint Member, Program in Immunology, Fred Hutchinson Cancer Research Center

Michael Jensen graduated from the University of Pennsylvania School of Medicine then completed training in Pediatric Hematology and Oncology at the University of Washington/Fred Hutchinson Cancer Research Center.  His laboratory work began under the mentorship of Dr. Philip Greenberg, Program Head in Immunology, FHCRC and focused on the immunobiology of tumor-specific T-cells.   Following completion of his fellowship, Dr. Jensen joined the faculty at the City of Hope National Medical Center where he built a translational research program integrating gene therapy and cellular immunotherapy for cancer.  This program grew in to the Department of Cancer Immunotherapeutics & Tumor Immunology within the Beckman Research Institute and was incorporated into the institution’s NCI-Comprehensive Cancer Center as the Cancer Immunotherapeutics Program with Dr Jensen as its leader.  During his tenure at City of Hope, Dr Jensen’s research program placed a strong emphasis on bench-to-bedside translational research and resulted in five FDA-authorized Investigational New Drug Applications covering first-in-human applications of adoptive transfer of genetically engineered T-cells having re-directed tumor specificity for lymphoma, neuroblastoma, and malignant gliomas.  In 2010, Dr Jensen joined the University of Washington School of Medicine faculty as a Professor of Pediatrics and is the founding director of the Ben Towne Center for Childhood Cancer Research.

David Kranz, Ph.D., Phillip A. Sharp Professor, Biochemistry, University of Illinois

David Kranz received his PhD in 1982 from the University of Illinois in Urbana and conducted post-doctoral work at MIT for five years, examining the molecular basis of T cell recognition and function, in the laboratories of Professors Herman Eisen and Susumu Tonegawa. He joined the faculty of the Department of Biochemistry at the University of Illinois in 1987, where his research program has focused on the structure, function, and engineering of T cell receptors. He currently holds the Phillip A. Sharp Professorship in Biochemistry.

Oren Levy, Ph.D., Instructor in Medicine, Harvard Medical School

Dr. Oren Levy received his BSc degree in Biology from Ben Gurion University (BGU), Israel. He carried out his MSc and PhD research in BGU, focusing on the ERK1\2 and JAK\STAT pathways and their involvement in vascular smooth muscle cell (VSMC) hypertrophy as well as in human mesenchymal stromal cell (MSC) proliferation and osteogenic differentiation. In 2011, Dr. Levy joined the lab of Dr. Jeffrey Karp at Harvard Medical School/Brigham and Women’s hospital as a postdoctoral research fellow and in 2013 became an instructor of Medicine in Harvard Medical School. His research focuses on developing bio-engineering strategies to improve MSC therapeutic potential and to harness them for cell-based targeted delivery of therapeutics.

John Maher, Consultant and Senior Lecturer in Immunology, Department of Research Oncology, King’s College London

John Maher is a clinical immunologist and immunopathologist who leads the “CAR Mechanics” research group within King’s College London. He is also a consultant immunologist within King’s Health Partners and Barnet & Chase Farm NHS Trust.

Marcela V. Maus, M.D., Ph.D., Director, Translational Medicine and Early Clinical Development, Translational Research Program, Abramson Cancer Center, University of Pennsylvania

Marcela Maus completed undergraduate studies at MIT and her MD and PhD at Penn.  She has been in the field of gene and cell therapies since 1999. As a graduate student, she worked with Dr. Carl June on  the biology of human T cell activation; she developed artificial antigen presenting cells to optimally expand T cells for immunotherapy, and described the requirement for 4-1BB signaling to allow persistence and resistance to activation induced cell death in human T cells. After medical school, she spent one year in Dr. Kathy High’s laboratory, dissecting out the immune response to vector proteins that occurred in patients with hemophilia who had undergone liver-directed AAV-mediated gene transfer. She then completed residency training in internal medicine at the University of Pennsylvania Health System, and went to Memorial Sloan-Kettering to pursue fellowship training in Hematology and Medical Oncology, where she focused on melanoma and bone marrow transplantation, since these are the clinical modalities most relevant to gene and cell therapies.  She is board-certified in Internal Medicine, Medical Oncology and in Hematology. During the research portion of fellowship, she completed a post-doc in Michel Sadelain’s laboratory, where she engineered new antigen receptors to genetically modify T cells to target the cancer-testis antigen NY-ESO-1. Dr. Maus recently returned to Penn as Director of Translational Medicine and Early Clinical Development in the Translational Research Program headed by Dr. Carl June. Her laboratory effort focuses on pre-clinical development and correlative studies relevant to T cell immunotherapies, and acting as regulatory sponsor for new trials of T cell therapies. She is deeply involved in generating new forms of chimeric antigen receptors directed to new targets and bringing them to the clinical setting to treat patients with mesothelioma, ovary cancer, multiple myeloma, breast cancer, melanoma, and glioblastoma.

Jeffrey S. Miller, M.D., Deputy Director, Masonic Cancer Center; Deputy Director, Clinical and Translational Sciences Institute; Director, Cancer Experimental Therapeutics Initiative, University of Minnesota

Jeffrey S. Miller, MD, received a Bachelor of Science degree from Northwestern University in Evanston, Illinois and received his MD from Northwestern University School of Medicine.  He completed an internship and residency in Internal Medicine at the University of Iowa in Iowa City.  After completing a post-doctoral fellowship in Hematology, Oncology and Transplantation at the University of Minnesota, he joined the faculty in 1991.  Dr. Miller is currently a Professor of Medicine at the University of Minnesota.  He is the Deputy Director of the University of Minnesota Masonic Comprehensive Cancer Center and the Clinical and Translational Sciences Award (CTSA).  He has more than 20 years of experience studying the biology of NK cells and other immune effector cells and their use in clinical immunotherapy with over 150 peer-reviewed publications.  He is a member of numerous societies such as the American Society of Hematology, the American Association of Immunologists, a member of the American Society of Clinical Investigation since 1999.  He serves on the editorial board for Blood and is a reviewer for a number of journals and NIH grants.

Paul Moore, Ph.D., Vice President, Cell Biology & Immunology, Macrogenics

Dr. Moore has 20 years experience working in biotech, coordinating efforts focused on the discovery and development of novel biologic based therapies. He began his biotechnology career at Human Genome Sciences, where he directed genomic-based target discovery programs and the preclinical development of various protein and mAb based therapeutics for the treatment of cancer, metabolic, and autoimmune diseases. Notably these efforts led to the discovery of BLyS as a B-cell survival factor providing the basis for the development of Benlysta for the treatment for lupus. At MacroGenics, Dr Moore leads a group dedicated to the discovery, characterization and development of novel antibody based therapeutics including bispecific DARTs for the treatment of cancer or autoimmune disease. Dr Moore obtained his PhD from University of Glasgow, performed post-doctoral work at Hoffman La Roche and has (co)-authored 70 peer reviewed publications.

Matthew Porteus, M.D., Ph.D., Associate Professor, Pediatrics (Cancer Biology), Stanford School of Medicine

Matthew Porteus is an associate professor of Pediatrics whose research focuses on using homologous recombination based genome editing to develop novel cell based therapeutics.  He received his MD and PhD degrees from Stanford University and completed residency in Pediatrics at Boston Children’s Hospital and a fellowship in Pediatric Hematology/Oncology at Boston Children’s Hospital and the Dana Farber Cancer Institute. He did his postdoctoral work under the mentorship of Dr. David Baltimore and has been an associate professor at Stanford since 2010.

Laszlo Radvanyi, Ph.D., Professor, Melanoma Medical Oncology, University of Texas , MD Anderson Cancer Center

Since 2005 Laszlo Radvanyi has been a Professor in the Melanoma Medical Oncology Department at MD Anderson Cancer Center and co-leader of the TIL therapy program there. He also conducts translational research on TIL adoptive cell therapy and basic research on CD8+ T cell function in melanoma and breast cancer. Dr. Radvanyi has published over 85 papers. He was previously a Senior Scientist at Sanofi-Pasteur Canada helping lead a tumor antigen discovery program in breast cancer.

Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering & Gene Transfer and Gene Expression Laboratory; Stephen and Barbara Friedman Chair, Memorial Sloan-Kettering Cancer Center

Michel Sadelain, MD, PhD, is the director of the Center for Cell Engineering and the Stephen and Barbara Friedman Chair at Memorial Sloan-Kettering Cancer Center, as well as professor of medicine at Weill Cornell Medical College in New York. After earning his medical degree from the University of Paris, France, and his doctorate in Immunology from the University of Alberta, Canada, Dr. Sadelain trained as a fellow at the Massachusetts Institute of Technology in Cambridge, Massachusetts, before joining MSKCC in 1994. In October 2012, he was awarded the Cancer Research Institute’s prestigious Coley Award for Distinguished Research in Tumor Immunology. Dr. Sadelain investigates T lymphocytes, hematopoietic stem cells and induced pluripotent stem cells for their potential use in cell-based therapies to treat cancer and genetic disorders. His laboratory pioneered different strategies to target T lymphocytes to tumor cells and augment their anti-tumoral activity by reprogramming their antigen specificity and costimulatory support. His group was the first to demonstrate the feasibility of treating beta-thalassemia by transferring the human beta-globin gene in bone marrow stem cells of thalassemic mice, paving the way for clinical trials aiming to cure severe globin disorders with genetically engineered hematopoietic stem cells. His recent work explores the therapeutic potential of induced pluripotent stem cells, in particular the identification of genomic “safe harbors” for safe and effective genetic engineering.

William Stohl, M.D., Ph.D., Professor of Medicine, Division of Rheumatology, Keck School of Medicine, University of Southern California

William Stohl received his BS from the Massachusetts Institute of Technology, his MD and PhD from the University of Pennsylvania, his clinical training at Washington University of St. Louis, and his post-doctoral research training in the laboratory of the late Henry Kunkel at the Rockefeller University. Dr. Stohl is ABIM-certified in Internal Medicine and Rheumatology and is currently Professor of Medicine and Chief, Division of Rheumatology, at the University of Southern California Keck School of Medicine. Dr. Stohl’s research interests have largely focused on B cells and their dysregulation in systemic autoimmune disorders, especially SLE.

Patrik Strömberg, Ph.D., Principal Scientist, Drug Design and Development, Swedish Orphan Biovitrum (Sobi), Sweden

Patrik Strömberg defended his PhD thesis in medical biochemistry at the Karolinska Institutet in 2002. Since then he has spent more than ten years working with biopharmaceutical development, the first 5 years at the AstraZeneca Biotech Laboratory and the last 6 years at Swedish Orphan Biovitrum, where he is currently a principal scientist and project leader in the Drug Design and Development organization.

Herman Waldman, Ph.D., Emeritus Professor of Pathology, Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford, United Kingdom

Herman Waldmann, FRS is a Professor of Pathology and Head of the Sir William Dunn School of Pathology at the University of Oxford. An immunologist, he is best known for his work on therapeutic monoclonal antibodies, particularly Campath-1, now licensed as Lemtrada for the treatment of multiple sclerosis Dr. Walmann received his undergraduate and graduate degrees from the University of Cambridge and began his scientific career there in the Department of Pathology. He became Head of the Immunology Division and was named Kay Kendall Chair in Therapeutic Immunology. It was at Cambridge that he studied mechanisms by which cells of the immune system could interact to mount immune responses. This early work led him to become interested in immunological tolerance and achieving tolerance for therapeutic purposes. Since 1980 he has been funded by an Medical Research Council Programme Grant to study mechanisms of transplantation tolerance and strategies to achieve this both experimentally and clincially. In 1985 he published the first studies to show that short courses of CD4 antibody therapy could bring about long-term immunological tolerance to foreign proteins, and this work led to the first demonstrations of transplantation tolerance resulting from short-tem antibody blockade. His mechanistic studies of tolerance uncovered a role for regulatory T-cells in infectious tolerance which was published in a seminal paper in Science in 1993. The strategies emerging from his laboratory since that time have been based on the use of therapeutic antibodies to enhance regulation over conventional T-cell immunity. In order to apply antibodies clinically Waldmann developed the first academic antibody therapeutic manufacturing facility. He and his team were able to apply clinical-grade antibodies in a wide range of probing therapeutic studies that enabled them to develop a series of humanized antibodies (CD52, CD3, CD4 and others) which have since been transferred to the pharmceutical industry. His team’s work since 1971 has resulted in more than 500 publications, the majority directed to therapeutic antibodies and their mechanisms of action. These contributions have led to his election to the Royal Society in 1990. Professor Waldmann is the recipient of the Jose Carreras Medal of the European Hematology Society, the Juvenile Diabetes Research Foundation Excellence in Clinical Research Award (2005), University of Iowa Distinguished Professor Lecture, Thomas E Starzl Prize in Surgery and Immunology, Scrip Lifetime Achievement award (2007)and an Honorary Doctorate (DSc) University of Cambridge (2008).

David Wraith, Ph.D., Professor of Experimental Pathology, School of Cellular and Molecular Medicine, University of Bristol, United Kingdom

David Wraith trained as an immunologist: he has worked in the field of T cell biology and the role of T lymphocytes in protection from infection and in autoimmunity since 1981.  David worked with Dr Brigitte Askonas at the National Institute for Medical Research, Mill Hill to define the mechanism by which cytotoxic T cells respond to and kill influenza virus infected cells through recognition of peptide fragments of antigen.  Their work led to the development of a vaccine that would induce cytotoxic T cells capable of heterotypic immunity. In 1986 and 1987 David was awarded MRC and National MS Society fellowships to work in the laboratory of Hugh McDevitt in Stanford. Here he focused on MHC class II recognition and autoimmune disease.  Their work described how monoclonal antibodies and synthetic peptides could be developed for immunotherapy of autoimmune diseases.  In 1989 David was awarded the Wellcome Trust Senior Fellowship to establish a new laboratory in Cambridge where he worked on mechanisms of thymic selection and was among the first to demonstrate induction of peripheral tolerance by administration of soluble peptide antigens.  Since 1995 his laboratory in Bristol has focused on the mechanism of peptide therapy.  Their work provided the essential rules governing the design of therapeutic peptides and led to the establishment of a University of Bristol spinout company, Apitope NV (www.apitope.com).  The company has designed peptides for treatment of various autoimmune diseases and has successfully completed phase I trials in relapsing multiple sclerosis. David’s research laboratory is currently defining the differentiation pathway of antigen induced Treg cells, focusing on the role of specific genes including IL-10 and CTLA-4.  The aim of this approach is to improve the efficacy of peptide therapy for treating of allergic and autoimmune diseases in man.

Lawren Wu, Ph.D., Senior Scientist, Immunology, Genentech

Lawren Wu is a Senior Scientist in the Department of Immunology at Genentech, where his group is involved in the discovery of new targets and the development of new therapies for autoimmune and allergic diseases.  Lawren’s background and training is in immunology and protein biophysics/biochemistry.  At Genentech his group has a major focus on understanding the heterogeneity and pathogenesis of severe asthma and the biology of IgE production.  In addition, his group studies intracellular signaling pathways and mechanisms of T- and B-lymphocyte activation and differentiation.

PEPTIDE THERAPEUTICS

 

Jesper Lau, Ph.D., Vice President, Diabetes Protein & Peptide Chemistry, Novo Nordisk A/S Dr. Jesper Lau studied biology and chemistry at the University of Southern Denmark. After his Ph.D. in organic chemistry in 1990, and a research visitor stay in the group of Professor Barry Trost at Stanford University in California, he joined Health Care Discovery at Novo Nordisk.

Jesper Lau possesses long-term expertise within combinatorial chemistry, medicinal chemistry and drug discovery, but since 2002, has been engaged in protein and peptide engineering. The main focus has been establishing technologies to improve the therapeutic properties of endogenous peptides and proteins.  During +20 years in pharma, he has optimised numerous leads to clinical candidates within diseases in the central nervous system, growth hormone disorders, and especially within diabetes care with particular interest in glucagon like peptide 1 (GLP-1) where he was project responsible for once weekly GLP-1 and is first inventor of semaglutide.

Christophe Bonny, Ph.D., CSO, Bicycle Therapeutics, Ltd. 

Christophe Bonny, Ph.D., has over 20 years of experience in the field of molecular biology and signalling pathways, has authored over 70 scientific publications, and is an inventor on several patents. Dr. Bonny discovered D-JNKI, a cell permeable peptide inhibitor of the JNK protein, which formed the basis for the creation of the biotechnology company Xigen S.A. in 2003. In 2005, he received the Pfizer Research Prize for this discovery and the molecule is currently in Phase III clinical trials for hearing loss. Prior to joining Bicycle Therapeutics, Dr. Bonny was CSO of Xigen S.A. and also served as its President. He also held the position of Head of Research of the Medical Genetics unit at the University of Lausanne Hospital (CHUV). Following completion of a PhD at the University of Neuchâtel (CH), Dr. Bonny completed a Research Fellowship at Northwestern University Evanston IL (USA).

Yong S. Chang, Ph.D., Vice President, Biology and Translational Research, Aileron Therapeutics, Inc.

Yong Chang has served as Head of Biology since April 2011 and leads cell and molecular biology, translational pharmacology, DMPK, and in vivo pharmacology. Yong joined Aileron from MedImmune, Inc. where he was the head of translational pharmacology. As one of the senior members of the Global Oncology Leadership Team and research review committee, Dr. Chang played an instrumental role in formulating strategy and direction for the departments of Oncology and Translational Sciences. He also led multiple translational and product development teams. Prior to MedImmune, he worked with Bayer Pharmaceuticals, where he held positions with increasing responsibilities and contributed to the launch of Nexavar® (sorafenib). Prior to Bayer, Dr. Chang worked at Roche Pharmaceuticals.

William Bachovchin, Ph.D.,  Professor, Developmental, Molecular & Chemical Biology, Sackler School of Graduate and Biomedical Sciences, Tufts University

Dr Bachovchin received a BS degree in Biology from Wake Forest University a doctoral degree in Chemistry from The California Institute of Technology, and did postdoctoral work at Harvard Medical School before arriving at Tufts University School of Medicine, where he is a full Professor in the Department of Developmental, Molecular and Chemical Biology.  Dr. Bachovchin is an author on more than 100 peer reviewed journal articles, and an inventor on more than 15 issued patents as well as numerous pending applications.  Dr. Bachovchin is a leader in the areas of NMR spectroscopy, enzymes mechanisms and drug design and discovery, especially in areas pertaining to the post proline cleaving family of enzymes.  To date three drugs designed by Dr. Bachovchin have entered human clinical trials and several more are in late stage preclinical testing. Dr. Bachovchin also serves as Executive Vice President, Chief Scientist and member of the board of directors of Arisaph pharmaceuticals, a company he co-founded in 1999. He is also a co-founder of Point Therapeutics which was a publically traded biotechnology company prior to its merger with Dara BioSciences.

Ulrich Brinkmann, Ph.D., Scientific Director, Pharma Research and Early Development, Roche

Dr. Ulrich Brinkmann heads as Expert Scientist a New Technology / Protein Engineering unit within Roche Pharma Research in Penzberg, FRG. His Ph.D thesis covered development of expression systems to produce recombinant reteplase. Subsequently, he held positions as Postoc and Associate Scientist at the NIH/NCI (Ira Pastan Lab) focusing on antibody stabilization/engineering and recombinant immunotoxins for cancer therapy. Prior to joining Roche, he served as CSO in Functional Genetics and Pharmacogenetics companies, Xantos and Epidauros respectively.

Chris Herring, Ph.D., Head, Protein Sciences, GlaxoSmithKline

Dr Chris Herring has 15 years experience within the Biotech and Biopharmaceutical Industry. He is currently head of Protein Sciences in the Biopharm Innovation group in GSK’s Biopharm R&D unit. He leads a group of >20 scientists covering all aspects of protein engineering, antigen and antibody/antibody fragment expression, purification and biophysical characterisation. He has particular expertise with half-life extension technologies, particularly GSKs AlbudAb™ technology, and led the pre-clinical development of the most clinically advanced AlbudAb™ project.

Before their acquisition by GSK he was Associate Director at Domantis Limited, the domain antibody company. He was involved from shortly after the company’s founding, enjoying the opportunity to set up the first laboratories and Pichia and E. coli expression capabilities, as well as contributing to the early development work on domain antibodies and AlbudAbs™ and several therapeutic programs. From 1998-2001 he worked for Novartis Pharma AG focussing on retrovirology and retroviral safety. Prior to this he did a post-doc in the Department of Pathology at the University of Cambridge working on retroviral gene trapping.

He completed his PhD at the University of Manchester in 1996 studying DNA repair at the Cancer Research Campaign’s Paterson Institute for Cancer Research and his BSc (Hons) in Biochemistry from the University of Surrey in 1992.

Alan T. Remaley, M.D., Ph.D., Section Chief, Lipoprotein Metabolism Laboratory, National Institutes of Health (NIH)

Alan Remaley received his B.S. in biochemistry and chemistry from the University of Pittsburgh in 1981, and a M.D. and Ph.D. in biochemistry from the University of Pittsburgh in 1987. In 1990, he completed a residency in clinical pathology at the University of Pennsylvania and became board-certified in clinical pathology in 1992. He joined the NIH in 1990 as a medical staff fellow and did a postdoctoral fellowship on lipoprotein metabolism in the Molecular Disease Branch at the NHLBI. In 1995, Dr. Remaley became a senior staff member of the Department of Laboratory Medicine at the NIH, where he is currently the Director of the Immunoassay and Special Chemistry section. In 2007, he became the Section Chief of the Lipoprotein Metabolism laboratory in the Cardiovascular and Pulmonary Branch of the NHLBI. Dr. Remaley has received numerous honors and awards over his career and is a Captain in the United States Public Health Service. He has published more than 150 peer-reviewed articles and is on the editorial board of several journals, including Journal of Lipid Research, Journal of Pediatric Biochemistry, Atherosclerosis, and Clinical Chemistry. Dr. Remaley is a member of the American Association of Clinical Chemistry (AACC), College of American Pathologists, American Heart Association, and National Lipid Association.

ChiChi Huang, Ph.D., Scientific Director, Antibody Drug Discovery, Janssen R&D, LLC

Chichi Huang is a protein chemist with industrial experience in the design and engineering of protein therapeutics. He received his Ph.D. in Biochemistry from Tufts University Sackler School of Graduate Biomedical Sciences, Boston, MA. He completed his post-doctoral training in Dr. Timothy Springer’s Lab at Harvard Medical School, for studying the structure and function of beta2 integrins. Chichi Huang spent more than five years in the Pfizer Global Research Center at Groton, Connecticut, working on vaccine design and development. Since joined Centocor, Johnson and Johnson in 2002, he has been working on several antibody and peptide therapeutic projects and some of them are or will be in clinical trials.

Jan Johansson, Ph.D., CEO and President, Artery Therapeutics, Inc.

Jan O. Johansson,M.D., Ph.D., is CEO of Artery Therapeutics Inc. He is a serial Biotech entrepreneur and has as founder and/or corporate officer helped take 3 companies’ public and raised more than $400M in private and public markets.  He has published more than 60 peer-reviewed articles in the CVD area, more than 100 abstracts, and is the inventor of 30 patents.

Fredrik Frejd, Ph.D., CSO, Vice President R&D, Biopharma, Affibody AB

Prof. Fredrik Frejd is CSO and Vice President Research of Affibody AB. He is also professor at Uppsala University with special focus on development of targeting peptides for translational therapy in oncology. Dr. Frejd has over fifteen years of experience in life science research with particular expertise in tumor biology, phage display and therapeutic protein engineering of antibody fragments and alternative scaffolds. He joined Affibody AB in 2002 and received his PhD in 2001 in the group of professor Dario Neri at the Swiss Federal Institute of Technology, ETH, Zurich, where he worked on therapeutic targeting of tumoral angiogenesis.

Irwin Chaiken Ph.D., Professor, Department of Biochemistry and Molecular Biology Drexel University College of Medicine 

Dr. Chaiken received a Bachelor of Arts degree in 1964, with a major in Chemistry and minor in Biology, from Brown University, followed by a Ph.D. in 1968 in Biological Chemistry from University of California Los Angeles working with Dr. Emil L. Smith on the active site of papain.  After being a UCLA Postdoctoral Scholar 1968-9, he was awarded an NIH Postdoctoral Fellowship and carried out research on protein folding and interaction mechanisms 1969-70 at the National Institutes of Health in Bethesda with Dr. Christian B. Anfinsen.  He became an NIH Staff Fellow and from 1973-87 was Senior Investigator at the NIH. He was Director of Macromolecular Sciences and then a Research Fellow at SmithKline Beecham R&D from 1988-95.  After serving as a Research Professor at the University of Pennsylvania 1995-2003, he assumed his current position as Professor of Biochemistry and Molecular Biology at Drexel University College of Medicine.  Dr. Chaiken’s Research Group uses a combination of chemical and biological approaches to investigate the fundamental nature of protein interactions in solution and cells and their roles in disease pathogenesis. Their major current focus is on the envelope protein machine that controls HIV-1 cell entry into host cells.  They are using protein structure and mechanism as a basis to derive inactivators of HIV-1 and to determine their molecular and virological modes of action.  Env inhibitors being discovered in this work are being evaluated for use in the development of AIDS therapeutics, microbicides and vaccines.  In addition, they seek to stimulate cross-disciplinary research and education programs to reveal fundamental nanoscale mechanisms of protein machines at membrane surfaces and in cells.

Jean-Philippe Pellois, Ph.D., Associate Professor, Biochemistry and Biophysics, Texas A&M University

Jean-Philippe Pellois received a Master in Chemical Engineering from the Ecole Superieure de Chimie, Physique and Electronique, (Lyon, France) in 1999. He received a PhD in organic chemistry in 2002 from the University of Houston, Texas, in 2002. Under the guidance of Prof Xiaolian Gao, his thesis project consisted of the development of photogenerated reagents for the light-directed parallel synthesis of peptide microarrays. He joined the laboratory of Tom Muir at the Rockefeller University (NY, NY) as a postdoctoral associate in 2002. There, he developed semi-synthetic proteins that are activated with light and used these tools to study signal transduction pathways in live cells. Jean-Philippe Pellois joined the department of Biochemistry and Biophysics as an assistant professor in 2006.  He was promoted to associate professor in 2012.

Joyce A. Schroeder, Ph.D., Professor, Molecular and Cellular Biology, Program in Cancer Biology, BIO 5 Institute, Arizona Cancer Center, University of Arizona

Dr. Schroeder began studying breast cancer in 1993 as a graduate student at the University of North Carolina, Chapel Hill, where she earned her PhD in Microbiology and Immunology. After earning her PhD, she went to the Mayo Clinic in Scottsdale to perform her postdoc.  From the Mayo Clinic, she was hired as an Assistant Professor by the department of Molecular and Cellular Biology and the Arizona Cancer Center at the University of Arizona. Since coming to the UA in 2002, her lab has focused on understanding the molecular and cellular mechanisms of breast cancer, and that work has included the development of novel cancer therapeutics. She has published over 30 scientific articles on the mechanisms of breast cancer, including three describing novel peptide-based therapeutics.  She is the inventor of multiple patents, including national and international patents on peptide-based therapeutics.  Promoted to full Professor in 2013, she is also the Chief Scientific Officer of Arizona Cancer Therapeutics, a platform company designed to move peptide based cancer therapeutics to the clinic.

Hong Moulton, Ph.D., Associate Professor, Senior Researcher, Department of Biomedical Sciences, Oregon State University

Dr. Hong Moulton is a senior research Associate Professor at the Department of Biomedical Sciences of the College of Veterinary Medicine at Oregon State University.  After undergraduate education in chemistry and teaching chemistry in China, Dr. Moulton moved to the US and completed her Ph.D. studying biochemistry and biophysics at Portland State University.  After receiving her Ph.D, she started postdoctoral work with Dr. Jim Summerton, who invented Morpholino antisense oligos at AVI BioPharma Inc. (later renamed Sarepta Therapeutics, Inc.). Her postdoc focus was to improve systemic delivery of Morpholinos.  Dr. Moulton continued working on Morpholino delivery after Dr. Summerton left the company.  She invented the cell-penetrating peptide-Morpholino conjugate (known as PPMO) technology and has patented and published widely on optimization and applications of the conjugates as potential therapeutics for various infectious and genetic diseases.  Dr. Moulton left AVI BioPharma as Director of Discovery Research and joined Oregon State University in 2010.  She continues her work on delivery optimization of Morpholinos in her academic lab and collaborates broadly to develop the technology in various disease models.

Philippe Sarret, Ph.D., Professor, Physiology and Biophysics, University of Sherbrooke

Professor Sarret is Chair of Canadian Research in Neurophysiopharmacology of Chronic Pain, and is Director of the Center for Neurosciences Research at the University of Sherbrooke. He received his PhD at the Institute of Pharmacology in France and completed post-doctoral training at McGill University.

SOURCE

http://www.pegsummit.com/PEGS_Content.aspx?id=129521

Artificial Pancreas: A UK Biotech Invention – Potential for Replacement to Insulin Injections

Curator: Aviva Lev-Ari, PhD, RN

The diabetes disease has been researched in depth on this Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com/?s=Diabetes

The Pancreas gland and pathophysiologies of Panceas-Liver-Biliary System were thoroughly examined as the research findings emerged

http://pharmaceuticalintelligence.com/?s=Pancreas

http://pharmaceuticalintelligence.com/?s=Liver

OPINION Leadership

1. We view an Artificial Pancreas Invention, the UK Biotech Invention having the Potential for Replacement to Insulin Injections, to have potentially major benefit for the care of the Diabetic patient.

2. It will become a “Disruptive Technology” which will bring major changes and challenges in the

A. Medical Diagnostic field and the

B. Pharmaceutical Market for Antibiabetic drugs.

3. the technology will be commercialized as an Insulin PUMP worn or carried externally, which companies ranging from startups to giants like Johnson & Johnson ($JNJ) and Medtronic ($MDT) are marketing as alternatives to painful insulin injections.

Product Description

De Montfort’s artificial pancreas–Courtesy De Montfort U. The De Montfort insulin pump is about the size of a wristwatch and surgically implanted into the abdomen, unlike most rival technologies, which are worn externally and connected to insulin-delivery devices under the skin.

  • The pump contains gel that releases insulin in response to rising glucose levels, and it is attached by a small tube to a refill port just under the skin.
  • Patients will only need to refill the device by injection every two weeks, according to a story in the Daily Mail. “The device will not only remove the need to manually inject insulin, but will also ensure that perfect doses are administrated each and every time,” Taylor told the publication.

Regardless of whether such technologies are surgically implanted or worn outside the body, they are increasingly being referred to as “artificial pancreases” because they are designed to regulate blood-glucose levels automatically, eliminating the need for patients to inject insulin up to four times daily. The market has been heating up lately, led by Minnesota device maker Medtronic, which won FDA approval in September for its MiniMed 530G, a pump that automatically stops delivering insulin based on a preset minimum threshold, thereby lowering the risk of hypoglycemia–a potentially dangerous drop in blood glucose levels. 

Other companies that are perfecting artificial pancreas systems include

  • J&J’s Animas division, and
  • Becton Dickinson ($BDX), which teamed up with the Juvenile Diabetes Research Foundation last June to develop a new insulin-delivery device.

And in November, insulin pump developer Tandem Diabetes Care hauled in $120 million in an initial public offering, $20 million more than the San Diego company expected to raise. Tandem ($TNDM) plans to use the money to develop a high-capacity insulin pump called t:flex, which will include continuous glucose monitoring technology, according to regulatory filings.

Related articles:

Medtronic wins FDA nod to roll out auto-stop insulin device

Tandem banks $120M in topped-out IPO, stirring med tech market hopes

The race for the artificial pancreas

SOURCE

editors@fiercemedicaldevices.com

 

Potential diabetes ‘cure’ to end misery of insulin jabs: DIABETES sufferers will be spared the misery of daily jabs by a revolutionary implant.

Published: Fri, January 24, 2014
The British invention will transform the lives of millions who have to endure injections of insulin every day.

Health experts say that the artificial pancreas is as good as a cure because it means patients will no longer have to manage the condition themselves.

The wristwatch-size device is surgically implanted into the abdominal cavity and releases a precise amount of insulin into the bloodstream. Supplies are topped up via a short tube which passes through the skin.

Human trials are set to start in 2016 with the first implants taking place on the NHS within 10 years. Inventor Joan ­Taylor, 64, professor of pharmacy at De Montfort University, Leicester, said: “It works like a healthy pancreas should, regulating blood sugar by releasing just enough insulin into your bloodstream. You don’t need to fill it up every day, so avoid painful daily injections.

“We are extremely close to embarking on clinical trials. Could the procedure to fit it be available on the NHS? Definitely – hopefully within a decade. Diabetes is already an epidemic and it’s going to soon become a scourge on society.”

The implant contains a reservoir surrounded by a special gel which slowly releases the hormone insulin as blood sugar levels rise. As levels drop, the gel solidifies, ensuring the right amount of insulin is released.

It would cost £5,000 for the device and surgery to fit it.

The artificial pancreas will help all Type 1 insulin-dependant diabetics and some suffering Type 2 who need daily injections.

The prototype has taken 20 years and £1million to create with money from the NHS, the Lachesis Fund, which invests in research at the university, and the charitable Edith Murphy Foundation. The rest has come from private backers.

Related articles

It is not powered by batteries or electronics and has no moving parts, so the risk of rejection is very low

Polymer chemist Professor Taylor said her team needs a similar amount to refine the product, which is two and a half inches in diameter.The lives of almost four million Britons are already blighted by diabetes but that figure is expected to jump to 6.25 million by 2035, costing the economy £40billion a year.Unlike Type 1 diabetes, an auto-immune disease, Type 2 is largely driven by lifestyle and linked to obesity. It is thought there are almost a million who have this condition but do not realise it.The financial burden on the NHS for treating the illness is already £1million an hour or almost £9billion a year. But that figure does not take into account the millions of working days lost. The artificial pancreas maintains healthy blood sugar levels round the clock, minimising the risk of hypoglycaemia.It is not powered by batteries or electronics and has no moving parts, so the risk of rejection is very low.Professor Taylor said: “This device is cheap and simple to use.

“I believe it should be globally available, not just here but in some of the poorest countries.

“After 20 years of research we are hopeful we have found a solution which has the potential to bring an end to the misery of daily injections for diabetics across the world within the next 10 years.”

GP Dr Ian Campbell said: “Diabetes wreaks havoc on the health of millions of people across the UK, causing blindness, heart disease, stroke and kidney failure.

“Replacing the pancreas gland in this way would transform their lives. It’s been a long time coming but it will make a fantastic diff­erence.”

Dr Alasdair Rankin, director of research at Diabetes UK, said: “This is one of several research projects looking at potential ways to make it easier for people with diabetes who use insulin to manage their condition.

“We look forward to seeing the results of clinical trials.”

SOURCE

http://www.express.co.uk/news/health/455748/Potential-diabetes-cure-to-end-misery-of-insulin-jabs

Human trials in two years for artificial pancreas invention

DrTaylor-140910-MarkMakela4

DEVICE: The artificial pancreas

An artificial pancreas invented by a De Montfort University (DMU) professor could have its first human trials within two years.

Professor Joan Taylor’s creation ensures patients will no longer have to endure injections of insulin every day.

Instead, a device will be surgically implanted into the body and able to release a precise amount of insulin into the bloodstream. Supplies would be topped up every two weeks.

Human trials are due to begin in 2016 with the first implants taking place on the NHS within a decade – news which has featured prominently in the national press with articles in the Daily Express and the Daily Mail among others.

Professor of Pharmacy at DMU, Joan Taylor, said: “The device will not only remove the need to manually inject insulin, but will also ensure that perfect doses are administrated each and every time. By controlling blood glucose so effectively, we should be able to help reduce related health problems.

“We are extremely close to embarking on clinical trials. Diabetes is costing society more than £1million an hour in treatment, and much of that is spent on treating complications.”

The implant contains a reservoir of insulin kept in place by a special gel barrier. When glucose levels in the body rise, the gel liquefies and releases the insulin into the body, mimicking the normal pancreas.

As the insulin lowers the glucose levels, the gel reacts by hardening again and preserving the reservoir. It would eliminate the need for diabetics to inject insulin up to four times a day.

The artificial pancreas will help all Type 1 insulin-dependent diabetics and some suffering Type 2 who need daily injections.

Professor Taylor has spent 20 years developing the device, which requires no electronics. This means the risk of rejection by the body is minimised.

Until now, the project has had funding of £1 million from the NHS, the Lachesis Fund – which invests in research in the university – the charity Edith Murphy Foundation and private backers. Professor Taylor is now seeking a similar amount to refine the product.

“This device is cheap and simple to use,” added Professor Taylor. “It has the potential to bring an end to the misery of daily injections for diabetics.”

Posted on Friday 24th January 2014

– See more at: http://www.dmu.ac.uk/about-dmu/news/2014/january/human-trials-in-two-years-for-artificial-pancreas-invention.aspx#sthash.xZUttV4l.dpuf

SOURCE

http://www.dmu.ac.uk/about-dmu/news/2014/january/human-trials-in-two-years-for-artificial-pancreas-invention.aspx

End of the diabetes jab? New insulin implant controls blood glucose levels without injections

  • The wristwatch-size device can be surgically implanted into the abdomen
  • It contains a reservoir of insulin held in place by a gel barrier
  • When glucose levels in the body rise, the gel liquefies and releases insulin into the body – just like a normally functioning pancreas would do
  • As it lowers the glucose levels, the gel hardens again preserving the reservoir – the insulin reservoir has to be topped up every two weeks
  • Human trials are set to begin in 2016 and the first implants could take place on the NHS within a decade

By EMMA INNES

PUBLISHED: 05:23 EST, 24 January 2014 | UPDATED: 06:15 EST, 24 January 2014

Insulin injections for diabetics could soon be a thing of the past thanks to the creation of a revolutionary new implant.

The device, which has been created by British scientists, works like an artificial pancreas by releasing insulin into the bloodstream.

It can be implanted into the abdomen from where it releases a precise amount of insulin meaning injections are no longer needed.

A new abdominal implant could spell the end of insulin injections for people with diabetes

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A new abdominal implant could spell the end of insulin injections for people with diabetes

The supplies of insulin in the implant can be topped up every two weeks using a tube which passes out through the skin.

The wristwatch-size device was created by scientists at De Montfort University, in Leicester.

They say it is the next best thing to a cure for diabetes because it means the patient no longer has to manage the condition themselves.

Professor Joan Taylor, professor of pharmacy at De Montfort University in Leicester, said: ‘The device will not only remove the need to manually inject insulin, but will also ensure that perfect doses are administrated each and every time.

‘By controlling blood glucose so effectively, we should be able to help reduce related health problems.

‘We are extremely close to embarking on clinical trials. Diabetes is costing society more than £1 million an hour in treatment, and much of that is spent on treating complications.’

Human trials of the device are due to begin in 2016 and the researchers hope the first implants will take place on the NHS within a decade.

The implant, which has to be inserted surgically, contains a reservoir of insulin that is kept in place by a gel barrier.

Professor Joan Taylor

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Diabetes implant

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The implant was invented by Professor Joan Taylor (left) who says it is as good as a cure for diabetes as it means patients no longer need to monitor and control their condition themselves

The researchers hope their device could save millions of people from daily insulin injections (pictured) and that it could help to prevent the health problems associated with poor diabetes management

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The researchers hope their device could save millions of people from daily insulin injections (pictured) and that it could help to prevent the health problems associated with poor diabetes management

When glucose levels in the body rise, the gel liquefies and releases insulin into the body, mimicking the normal behaviour of a pancreas.

As the insulin lowers the glucose levels, the gel reacts by hardening again and preserving the reservoir.

It would eliminate the need for diabetics to inject insulin up to four times a day.

The artificial pancreas could help all type 1 insulin-dependent diabetics and some type 2 diabetics who need daily injections.

‘This device is cheap and simple to use,’ said Professor Taylor. ‘It has the potential to bring an end to the misery of daily injections for diabetics.’

Read more: http://www.dailymail.co.uk/health/article-2545180/The-end-diabetes-jabs-New-insulin-implant-controls-blood-glucose-levels-without-injections.html#ixzz2rdEVdHjz

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

Curator: Aviva Lev-Ari, PhD, RN

Article ID #108: Importance of Funding Replication Studies: NIH on Credibility of Basic Biomedical Studies. Published on 1/27/2014

WordCloud Image Produced by Adam Tubman

Policy: NIH plans to enhance reproducibility

27 January 2014

Francis S. Collins and Lawrence A. Tabak discuss initiatives that the US National Institutes of Health is exploring to restore the self-correcting nature of preclinical research.

A growing chorus of concern, from scientists and laypeople, contends that the complex system for ensuring the reproducibility of biomedical research is failing and is in need of restructuring12. As leaders of the US National Institutes of Health (NIH), we share this concern and here explore some of the significant interventions that we are planning.

Science has long been regarded as ‘self-correcting’, given that it is founded on the replication of earlier work. Over the long term, that principle remains true. In the shorter term, however, the checks and balances that once ensured scientific fidelity have been hobbled. This has compromised the ability of today’s researchers to reproduce others’ findings.

Let’s be clear: with rare exceptions, we have no evidence to suggest that irreproducibility is caused by scientific misconduct. In 2011, the Office of Research Integrity of the US Department of Health and Human Services pursued only 12 such cases3. Even if this represents only a fraction of the actual problem, fraudulent papers are vastly outnumbered by the hundreds of thousands published each year in good faith.

Instead, a complex array of other factors seems to have contributed to the lack of reproducibility. Factors include poor training of researchers in experimental design; increased emphasis on making provocative statements rather than presenting technical details; and publications that do not report basic elements of experimental design4. Crucial experimental design elements that are all too frequently ignored include blinding, randomization, replication, sample-size calculation and the effect of sex differences. And some scientists reputedly use a ‘secret sauce’ to make their experiments work — and withhold details from publication or describe them only vaguely to retain a competitive edge5. What hope is there that other scientists will be able to build on such work to further biomedical progress?

Exacerbating this situation are the policies and attitudes of funding agencies, academic centres and scientific publishers. Funding agencies often uncritically encourage the overvaluation of research published in high-profile journals. Some academic centres also provide incentives for publications in such journals, including promotion and tenure, and in extreme circumstances, cash rewards6.

Then there is the problem of what is not published. There are few venues for researchers to publish negative data or papers that point out scientific flaws in previously published work. Further compounding the problem is the difficulty of accessing unpublished data — and the failure of funding agencies to establish or enforce policies that insist on data access.

Preclinical problems

Reproducibility is potentially a problem in all scientific disciplines. However, human clinical trials seem to be less at risk because they are already governed by various regulations that stipulate rigorous design and independent oversight — including randomization, blinding, power estimates, pre-registration of outcome measures in standardized, public databases such as ClinicalTrials.gov and oversight by institutional review boards and data safety monitoring boards. Furthermore, the clinical trials community has taken important steps towards adopting standard reporting elements7.

Preclinical research, especially work that uses animal models1, seems to be the area that is currently most susceptible to reproducibility issues. Many of these failures have simple and practical explanations: different animal strains, different lab environments or subtle changes in protocol. Some irreproducible reports are probably the result of coincidental findings that happen to reach statistical significance, coupled with publication bias. Another pitfall is overinterpretation of creative ‘hypothesis-generating’ experiments, which are designed to uncover new avenues of inquiry rather than to provide definitive proof for any single question. Still, there remains a troubling frequency of published reports that claim a significant result, but fail to be reproducible.

Proposed NIH actions

As a funding agency, the NIH is deeply concerned about this problem. Because poor training is probably responsible for at least some of the challenges, the NIH is developing a training module on enhancing reproducibility and transparency of research findings, with an emphasis on good experimental design. This will be incorporated into the mandatory training on responsible conduct of research for NIH intramural postdoctoral fellows later this year. Informed by this pilot, final materials will be posted on the NIH website by the end of this year for broad dissemination, adoption or adaptation, on the basis of local institutional needs.

“Efforts by the NIH alone will not be sufficient to effect real change in this unhealthy environment.”

Several of the NIH’s institutes and centres are also testing the use of a checklist to ensure a more systematic evaluation of grant applications. Reviewers are reminded to check, for example, that appropriate experimental design features have been addressed, such as an analytical plan, plans for randomization, blinding and so on. A pilot was launched last year that we plan to complete by the end of this year to assess the value of assigning at least one reviewer on each panel the specific task of evaluating the ‘scientific premise’ of the application: the key publications on which the application is based (which may or may not come from the applicant’s own research efforts). This question will be particularly important when a potentially costly human clinical trial is proposed, based on animal-model results. If the antecedent work is questionable and the trial is particularly important, key preclinical studies may first need to be validated independently.

Informed by feedback from these pilots, the NIH leadership will decide by the fourth quarter of this year which approaches to adopt agency-wide, which should remain specific to institutes and centres, and which to abandon.

The NIH is also exploring ways to provide greater transparency of the data that are the basis of published manuscripts. As part of our Big Data initiative, the NIH has requested applications to develop a Data Discovery Index (DDI) to allow investigators to locate and access unpublished, primary data (see go.nature.com/rjjfoj). Should an investigator use these data in new work, the owner of the data set could be cited, thereby creating a new metric of scientific contribution unrelated to journal publication, such as downloads of the primary data set. If sufficiently meritorious applications to develop the DDI are received, a funding award of up to three years in duration will be made by September 2014. Finally, in mid-December, the NIH launched an online forum called PubMed Commons (see go.nature.com/8m4pfp) for open discourse about published articles. Authors can join and rate or contribute comments, and the system is being evaluated and refined in the coming months. More than 2,000 authors have joined to date, contributing more than 700 comments.

Community responsibility

Clearly, reproducibility is not a problem that the NIH can tackle alone. Consequently, we are reaching out broadly to the research community, scientific publishers, universities, industry, professional organizations, patient-advocacy groups and other stakeholders to take the steps necessary to reset the self-corrective process of scientific inquiry. Journals should be encouraged to devote more space to research conducted in an exemplary manner that reports negative findings, and should make room for papers that correct earlier work.

We are pleased to see that some of the leading journals have begun to change their review practices. For example, Nature Publishing Group, the publishers of this journal, announced8 in May 2013 the following: restrictions on the length of methods sections have been abolished to ensure the reporting of key methodological details; authors use a checklist to facilitate the verification by editors and reviewers that critical experimental design features have been incorporated into the report, and editors scrutinize the statistical treatment of the studies reported more thoroughly with the help of statisticians. Furthermore, authors are encouraged to provide more raw data to accompany their papers online.

Similar requirements have been implemented by the journals of the American Association for the Advancement of Science — Science Translational Medicine in 2013 and Science earlier this month9— on the basis of, in part, the efforts of the NIH’s National Institute of Neurological Disorders and Stroke to increase the transparency of how work is conducted10.

Perhaps the most vexed issue is the academic incentive system. It currently over-emphasizes publishing in high-profile journals. No doubt worsened by current budgetary woes, this encourages rapid submission of research findings to the detriment of careful replication. To address this, the NIH is contemplating modifying the format of its ‘biographical sketch’ form, which grant applicants are required to complete, to emphasize the significance of advances resulting from work in which the applicant participated, and to delineate the part played by the applicant. Other organizations such as the Howard Hughes Medical Institute have used this format and found it more revealing of actual contributions to science than the traditional list of unannotated publications. The NIH is also considering providing greater stability for investigators at certain, discrete career stages, utilizing grant mechanisms that allow more flexibility and a longer period than the current average of approximately four years of support per project.

In addition, the NIH is examining ways to anonymize the peer-review process to reduce the effect of unconscious bias (see go.nature.com/g5xr3c). Currently, the identifiers and accomplishments of all research participants are known to the reviewers. The committee will report its recommendations within 18 months.

Efforts by the NIH alone will not be sufficient to effect real change in this unhealthy environment. University promotion and tenure committees must resist the temptation to use arbitrary surrogates, such as the number of publications in journals with high impact factors, when evaluating an investigator’s scientific contributions and future potential.

The recent evidence showing the irreproducibility of significant numbers of biomedical-research publications demands immediate and substantive action. The NIH is firmly committed to making systematic changes that should reduce the frequency and severity of this problem — but success will come only with the full engagement of the entire biomedical-research enterprise.

http://www.nature.com/news/policy-nih-plans-to-enhance-reproducibility-1.14586

Rethinking Reproducibility Reporter in Genomeweb.com

August 02, 2013

Officials at the National Institutes of Health are contemplating changes to grant applications that would require researchers tovalidate some experimental procedures and results, “such as the foundational work that leads to costly clinical trials,” Nature News reports this week.

These measures are intended to combat the reproducibility problem that plagues many NIH-funded experiments and to help ensure that the agency’s tight research budget is spent on “verifiable science,” the article states.

Among other things, officials are considering “modifying peer review to bring greater scrutiny to the work a grant application is based on — perhaps just for applications that are likely to lead to clinical trials” as well as requiring that “independent labs validate the results of important preclinical studies as a condition of receiving grant funding,” Nature reports.

“There is certainly sufficient information now that the NIH feels it’s appropriate to look at this at a central-agency level,” Lawrence Tabak, the agency’s principal deputy director, tells Nature. He and other senior NIH officials are currently “assessing input gathered from the directors of the agency’s 27 institutes and centers” prior to meeting with NIH director Francis Collins, “who will decide what steps to take,” Nature adds.

Reactions to the possibility of a validation requirement are mixed. “It’s a disaster,” Peter Sorger, a systems biologist at Harvard Medical School, tells Nature arguing that “frontier science often relies on ideas, tools, and protocols that do not exist in run-of-the-mill labs, let alone in companies that have been contracted to perform verification.”

Others, such as, Elizabeth Iorns, chief executive of Science Exchange, a company in Palo Alto, California, say that requiring validation “either through random audits or selecting the highest-profile papers” would be a good idea. In fact, her company has launched a program with a German reagent vendor to independently validate research antibodies.

NIH to Researchers: Credibility Counts

Published: Jan 27, 2014

By Michael Smith, North American Correspondent, MedPage Today

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The NIH is planning “significant interventions” to ensure that basic biomedical studies stand the test of time, its two top officials say.

In the long term, science remains self-correcting, according to NIH Director Francis Collins, MD, PhD, and Principal Deputy Director Lawrence Tabak, DDS, PhD.

But in the short term — and especially in preclinical research using animal models — “the checks and balances that once ensured scientific fidelity have been hobbled,” they argue in a Comment article in Nature.

One report has suggested that “as many as two-thirds of studies related to preclinical animal trials were not able to be reproduced,” Tabak told MedPage Today.

“Anecdotally, of course, we hear of other such circumstances,” he said, adding: “The truth is we don’t really know what the full scope of the problem is.”

Collins and Tabak said the problem is not scientific fraud, which is rare, but a combination of factors — including the pressure to publish rapidly and poor training in experimental design — that lead to lack of reproducibility.

The issue is significant because more advanced research is therefore often based on an insubstantial foundation, wasting effort and resources, Collins and Tabak argued.

The NIH is planning to investigate several approaches to try to improve matters, Collins and Tabak wrote, including:

  • Mandatory training on responsible conduct of research for its intramural postdoctoral fellows.
  • Checklists for its reviewers to make evaluation of grant applications more systematic.
  • Ways to “anonymize” the peer-review process to reduce the effect of unconscious bias.
  • Rejigging the biographical sketch that grant applicants are required to fill in so that it emphasizes advances resulting from previous work.
  • At some career stages, offering flexible or longer funding to provide “greater stability” for investigators.

 

However, Tabak told MedPage Today, “NIH alone can’t solve this — this is something that requires the efforts of all our stakeholders, the academic community, those that publish scientific journals, and, of course, the scientists themselves.”

The NIH position met with a mixed reaction from investigators who have tackled the issue of reproducibility.

The article by Collins and Tabak is “really very welcome,” commented John Ioannidis, MD, PhD, of Stanford University School of Medicine in Stanford, Calif.

“Everything I read in the NIH comment seems very reasonable,” Ioannidis told MedPage Today. But he cautioned that it’s not clear which interventions will work and which will not.

The Nature piece comes just a few days after Ioannidis and colleagues published a series of articles in The Lancet outlining the issue of reproducibility and suggesting solutions, some of which are similar to those proposed by the NIH.

Ioannidis has long been known as a provocative and skeptical critic of much of the published biomedical research and a famous 2005 article — Why Most Published Research Findings Are False — cemented that reputation.

The field of “meta-research” — research into research — remains observational, he noted. But because it is large and varied, the NIH is actually in a position to conduct experiments and randomized trials to test what interventions work to improve reproducibility, he said.

“I feel a little bit uneasy about having experts — like myself — say what needs to be done and really not have the best evidence for that,” he said.

Another critic of the research enterprise, however, said the NIH doesn’t go far enough and because of that won’t know if any of its interventions succeeds.

“All of the suggestions are steps in the right direction,” said Elizabeth Iorns, PhD, CEO of Science Exchange in Palo Alto, Calif., which calls itself an “online marketplace for science experiments.”

But, she told MedPage Today, “What really needs to happen is for replication studies to be funded.”

In the absence of an NIH attempt to replicate a large number of studies, Iorns said, “There isn’t any baseline … so we won’t know if any of those changes actually made any difference.”

Her organization, she said, has just been given private funding to replicate 50 cancer biology studies, all from high-impact journals — a project she hopes to have completed within a year. That will help clarify the landscape, she said.

Tabak told MedPage Today that the reason the issue is at the forefront today is because of concern from the scientific community and “feedback” from scientists will show the NIH whether it’s on the right track.

But he added that if one of the NIH institutes is planning to invest in a major clinical trial based on preclinical animal studies, it might first replicate that basic research.

“That investment would not be small,” he said, but “it is much smaller than the actual cost to do a trial.”

REFERENCES in Nature 505, 612–613 (30 January 2014) doi:10.1038/505612a

http://www.nature.com/news/policy-nih-plans-to-enhance-reproducibility-1.14586

References

  1. Prinz, F., Schlange, T. & Asadullah, K. Nature Rev. Drug Disc. 10, 712–713 (2011).

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  2. The Economist ‘Trouble at the Lab’ (19 October 2013); available at http://go.nature.com/dstij3Show context
  3. US Department of Health and Human Services, 2011 Office of Research Integrity Annual Report 2011 (US HHS, 2011); available at http://go.nature.com/t7ykcvShow context
  4. Carp, J. NeuroImage 63, 289–300 (2012).

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  5. Vasilevsky, N. A. et al. PeerJ 1, e148 (2013).

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  6. Franzoni, C., Scellato, G. & Stephan, P. Science 333, 702–703 (2011).

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  7. Moher, D., Jones, A. & Lepage, L. for the CONSORT Group J. Am. Med. Assoc. 285,1992–1995 (2001).

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  8. Nature 496, 398 (2013).

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  9. McNutt, M. Science 343, 229 (2014).

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  10. Landis, S. C. et al. Nature 490, 187–191 (2012).

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SOURCES

Francis S. Collins, Lawrence A. Tabak “NIH plans to enhance reproducibility” Nature 2014; 505: 612-613.

NIH mulls rules for validating key results by Meredith Wadman US biomedical agency could enlist independent labs for verification

http://www.nature.com/news/nih-mulls-rules-for-validating-key-results-1.13469


e-Books: Perspectives by American Library Association (ALA) is the oldest and largest library association in the World

Reporter: Aviva Lev-Ari, PhD, RN

Last year was a year of progress for libraries on the e-book issue. But at an engaging ALA Midwinter 2014 session hosted by the Digital Content Working Group, librarians were urged not to be satisfied by recent developments, or complacent, but rather to look more deeply at their digital future.

The session kicked off with remarks from Sari Feldman, co-chair, ALA Digital Content Working Group, and executive director of the Cuyahoga County (Ohio) Public Library. Feldman ran down the advances of the last year.

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“We now have all of the big five working with libraries,” she said, noting that the progress was in part due to “the excellent year-round outreach” of ALA leaders and working group members. “There is still a lot of work to be done , but we’re very excited about the ground we’ve covered.”

The most striking change, she said, has been the “change in the temperature” of the talks between libraries and publishers. “Questions previously were whether publishers should have library e-book lending,” she said. “The question now is how to do it. And there is much more openness and dialogue.”

Indeed, after a slow start that had some librarians concerned about the e-book future, the working group has proven to be very productive, and increasingly important. Now in its third year, DCWG has been out front and visible, and in 2014, members have been invited to present at the Paris Book Fair in March, in addition to a slated talk at the Public Library Association meeting in Indianapolis. In addition, the group is working with state officials in Connecticut as the state legislature studies e-books, and is working on digital copyright issues.

Not content with its progress, the question on tap at ALA Midwinter was where to go from here.

Monopolies?

In his brief talk, Alan Inouye, director, ALA Office for Information Technology Policy, laid out some of the broader issues and challenges for libraries to consider.

For example, he pointed out that “the value proposition” for libraries had changed. With print book lending, libraries had for decades enjoyed a monopoly. But in the digital world, there is competition from commercial vendors. And, with digital lending, libraries are now competing for user attention with other kinds of digital content.

“It’s a very different kind of world,” Inouye said. “We have to think about what is the value added for libraries, and we keep coming back to the discoverability and exposure issues.”

Inouye also touched on other issues, from self-publishing, to pricing, to consortial buying. “Now we have basic access,” Inouye said. “But what is a fair price? What is the right price?” He urged libraries to offer their input to the working group.

It was clear, however, that ALA DCWG has a direction: As panel moderator Robert Wolven, co-chair, ALA Digital Content Working Group, and associate university librarian, Columbia University, noted in his talk, the library strategy will increasingly focus on authors.

“So far we have focused a good deal of work on different points in the supply chain,” Wolven said. “We have talked to many publishers, engaged them on their points of view, and lots of discussions with digital sellers, OverDrive and so forth. So now its time to turn to authors.”

To that end, Wolven noted that the universe of authors—and author desires—was broad, as different authors want different things. As an example, he went through a slide of two authors—J.K. Rowling, mega-bestselling author of the Harry Potter series; and Wolven himself, who publishes generally for academic reasons.

“Authors have different interests,” he said. “But they all want readers, recognition, and royalites.”

What Authors Want

Wolven then turned the program over to the day’s featured speakers: Ginger Clark, literary agent, Curtis Brown LTD, New York City, and a board member of the Association of Authors’ Representatives; and Peter Brantley, director, Scholarly Communications, hypothes.is and contributing editor at Publishers Weekly.

In their talks, Clark and Brantley offered a good look at where the ALA DCWG is: one foot in the present, and one foot on stepping toward the future.

Clark began her talk by by explaining her role as an agent—basically functioning as an author’s business manager, with services ranging from editorial advice to negotiation, contract drafting, tax planning, and other things.

Clark, clearly well-versed in the long and winding road of the e-book, suggested that authors are indeed amenable to libraries offering e-books—but the digital age is just beginning to unfold, with many lessons to be learned and battles to be fought, they were cautious.

The biggest battle: digital royalties. Clark spoke at length on the developments that have now more or less left digital royalties at 25% of net revenues—a split that she says has left authors with a smaller cut of the profits.

“This is what authors are concerned about,” Clark said. “We have to balance connecting with readers with also making money. And I hope you can understand that.” Clark stressed that authors really do want to connect more with readers via libraries, but too often, the e-book decisions are out of their hands. But authors are paying attention, she said, and “authors do want to know about these issues.”

Clark also said she believed the security was not a concern, and that libraries have demonstrated that they can lend e-books safely. She also suggested that libraries can help fight piracy, by getting content out in a “cheap and legal manner.”

In sum, authors are “fine with libraries,” Clark said. “They just want a fair share of the money.”

In his talk, Brantley offered a longer view of the digital issues libraries now face, a talk he conceded was a little more “edgy” and “a little less relevant to daily life today,” but nonetheless vital for libraries to consider as they think about how to position themselves for the future.

Brantley spoke of the way authorship is changing with the advent of digital, web-based tools, and of the clash between tech culture and traditional publishing culture that has marked the early history of the e-book.

But, there is “a growing sense of comfort,” he said, as a leading edge of publishers are thinking more boldly about the reach of Internet tools and “what it means to publish an author’s material.”

Brantley also spoke about a growing sense of “digital craft” that will expand and enrich the storytelling and information environments. With the advent of web-based tools, storytelling is moving into a new space where creators can do things beyond simple replication of text, or additional media. But he was quick to add that not every e-book needs to offer gaming or a rich interactive experience.

“Text will still be a primary mode of storytelling, because of its low barrier to entry,” he said. “But text online is inherently addressable by machines, and is linkable,” he said, which is creating an exciting, powerful new environment, and is giving authors the ability to “gain more control back” over the production and exploitation of their work.

With digital tools, “Authors can now see themselves as the locus of production,” Brantley said. “They can think more about publishing for themselves [as businesses].” And, he said, it can liberate them in terms of offerings, from e-books, to short stories, and other fragements that previously might never have been brought to market.

He cautioned, however against the current state of the market, with companies like Amazon and its Kindle Direct Publishing platform snapping up self-published works, and making huge inroads in certain genres.

“There is a growing gap between what is really on the market and what libraries can provide through e-book lending channels,” Brantley said. “This is more a political point. A market in which authors only have Amazon KDP to handle their books is not a healthy market. There is a real role for libraries to start thinking about how to reach authors directly…It is okay for Amazon to be a discovery agent, but personally, I don’t think it is okay for Amazon to be a primary source for a big chunk of literature in the coming years.”

In response to a question from NYPL’s Josh Hadro about libraries hosting original community content, Brantley reiterated his point with emphasis, invoking a recent series of posts from author Hugh Howey.

“I almost wanna pound my hands on table and say this is really important stuff and nobody is addressing it,” he said. “There is so much energy focused on getting books from the Big 5, and under what terms and what prices and how many copies, but the fact of the matter is that there is whole new world of publishing exploding right before our eyes and we’re not doing anything about in any kind of concerted way. I think we need to do that.”

SOURCE

http://www.publishersweekly.com/pw/by-topic/digital/content-and-e-books/article/60809-ala-midwinter-2014-on-e-books-librarians-urged-to-think-bigger-and-smaller.html?utm_source=Publishers+Weekly&utm_campaign=8b85f51fe9-UA-15906914-1&utm_medium=email&utm_term=0_0bb2959cbb-8b85f51fe9-304629057

Transcatheter Valve Competition in the United States: Medtronic CoreValve infringes on Edwards Lifesciences Corp. Transcatheter Device Patents

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 4/22/2014

Appeals court stays ban on Medtronic’s CoreValve device

April 21, 2014 by Brad Perriello

A federal appeals court stays a ban on U.S. sales of Medtronic’s CoreValve replacement heart valve “pending further notice” in a patent infringement battle with Edwards Lifesciences and its Sapien transcatheter aortic valve implant.

Appeals court stays ban on Medtronic's CoreValve device

A federal appeals court today put a hold on the impending ban on U.S. sales of Medtronic‘s (NYSE:MDT) CoreValve replacement heart valve “pending further notice,” as Medtronic’s patent infringement war with rival Edwards Lifesciences (NYSE:EW) and its competing Sapien valve grinds on.

Earlier this month Judge Gregory Sleet of the U.S. District Court for Delaware granted a preliminary injunction to Edwards, limiting U.S. sales of the CoreValve transcatheter aortic heart implant to patients deemed unsuitable for Edwards’ rival Sapien device.

Medtronic promptly appealed the ban, slated to begin April 23, to the U.S. Court of Appeals for the Federal Circuit, drawing a rebuke from Sleet.

But the appeals court today granted Medtronic’s bid to stay the injunction indefinitely, with 2 of the Federal Circuit’s 3 judges agreeing to hold the sales ban on CoreValve, according to court documents.

“The district court’s injunction is stayed pending further notice by this court,” according to the documents.

But Federal Circuit Judge Pauline Newman dissented, citing a deal between Medtronic and Edwards that would have allowed limited CoreValve sales to patients deemed unsuitable to receive the Sapien device.

“I would deny the motion to stay subject to the terms of the recent agreement between Edwards and Medtronic that Medtronic may provide its devices pending this appeal,” Newman wrote.

“We believe this ruling is good news for patients who need the CoreValve device, and our primary objective has been to work closely with physicians to ensure that their patients are able to get the therapy they need,” Medtronic structural heart president Dr. John Liddicoat said in a statement.

“We have always made every effort to ensure patients receive the treatment they need and will continue to seek a durable solution that benefits physicians and their patients. We’re proud of the track record and large amount of clinical data supporting the performance of the Sapien family of valves, making them the preferred choice for doctors treating their patients around the world,” Edwards chairman & CEO Mike Mussallem said in prepared remarks.

Edwards initially filed the infringement claim in 2008 against CoreValve, then an independent entity (Medtronic acquired CoreValve in 2009). A federal jury ruled in 2010 that the CoreValve device willfully infringes Edwards’ “Andersen” patent, also known as the ‘552 patent. The U.S. Court of Appeals affirmed that decision in 2012 and the Supreme Court last year refused to hear Medtronic’s appeal. Earlier this year the FDA approved the CoreValve system for sale in the U.S.

The legal battle is also happening overseas, where the European Patent Office in October 2013 issued a preliminary, non-binding ruling that an Edwards’ patent was invalid, allowing CoreValve back on the German market after a temporary ban. The EPO last month finalized that ruling, entirely invalidating and revoking the so-called “Spenser patent” at the heart of the overseas dispute.

Edwards earlier this year won a $393 million decision after a Delaware jury ruled that CoreValve infringes on Edwards’ “Cribier” patent.

SOURCE

 

 

Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment

June 4, 2012 by 2012pharmaceutical

ar04118transapical

ar04118transapical

The Edwards SAPIEN transcatheter heart valve is an investigational device which is placed either through a transfemoral (RetroFlex 3 Transfemoral Delivery System) or transapical (Ascendra Transapical Delivery System) approach. The Edwards SAPIEN valve is being evaluated in the treatment of patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-heartvalve replacement surgery.Cohort A of the PARTNER (Placement of AoRTic traNscatheterER valves) Trial is designed for patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-chest valve replacement due to the risk surgery might pose to them. These patients may be eligible to participate in a new, investigational transcatheter valve replacement procedure that is performed without

Investigational Devices: Edwards Sapien Transcatheter Aortic Heart Valve Replacement Transfemoral Deployment

June 10, 2012 by 2012pharmaceutical

ar04322transfemoral

ar04322transfemoral

The Edwards SAPIEN transcatheter heart valve is an investigational device which is placed either through a transfemoral (RetroFlex 3 Transfemoral Delivery System) or transapical (Ascendra Transapical Delivery System) approach. The Edwards SAPIEN valve is being evaluated in the treatment of patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-heartvalve replacement surgery.

Cohort A of the PARTNER (Placement of AoRTic traNscatheterER valves) Trial is designed for patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-chest valve replacement due to the risk surgery might pose to them. These patients may be eligible to participate in a new, investigational transcatheter valve replacement procedure that is performed without

 http://www.edwards.com/products/investigationaldevices/Pages/SapienTHV.aspx

 

U.S. Jury Finds Medtronic CoreValve Infringes on Edwards’ Transcatheter Valve Patent

Medtronic plans to appeal federal district court verdict
By:

Dave Fornell

January 15, 2014
Medtronic, corevalve, edwards, litigation, TAVR, TAVI
In a move that calls into question the future of transcatheter valve competition in the United States, a jury in the Federal District Court of Delaware decided Jan. 15 the Medtronic CoreValve infringes on transcatheter device patents held by Edwards Lifesciences Corp. Medtronic said it intends to appeal the decision.
Medtronic anticipates U.S. regulatory approval of the CoreValve transcatheter aortic valve replacement (TAVR) system for extreme risk patients by the end of 2014 to enter the U.S. market.
The jury found that Edwards’ United States Cribier transcatheter heart valve patent (U.S. Pat. No. 8,002,825) is valid and that Medtronic CoreValve LLC willfully infringes it. Edwards said it plans to move to enforce this verdict and intends to seek a permanent injunction. The jury also awarded Edwards $394 million in damages. Edwards may seek increased damages of up to three times that amount, in addition to attorneys’ fees.
“While we are disappointed in the jury’s verdict, we continue to believe that this decision will be overturned on appeal,” said Neil Ayotte, vice president and acting general counsel at Medtronic. “Medtronic has prevailed against Edwards in several legal actions related to a European counterpart to this patent and others, and believes the Federal Circuit Court of Appeals will find no merit to Edward’s infringement claim. Today’s jury verdict does not impose an injunction, and Medtronic will oppose any requests for an injunction by Edwards. “
The patent involved in this suit is part of the Cribier family of patents and expires in December 2017. This case was tried in the U.S. District Court for the District of Delaware and is directed at the manufacture and sale of the CoreValve ReValving System in the United States, as well as the worldwide sales of valves assembled in Medtronic’s Tijuana, Mexico, facility using U.S. made components.
“Edwards invests in promising early technologies. As a result, Edwards holds a number of important patents in transcatheter valve technology, and we intend to continue to defend this intellectual property when it is used by others without permission,” said Larry L. Wood, Edwards’ corporate vice president, transcatheter heart valves.
The Rocky Road Ahead
As with the “stent wars” in the late 1990s through the past decade where key stent vendors were involved in extensive patent litigation and counter suits to block competition, a similar pattern has developed with TAVR devices.
Edwards Lifesciences currently has the only U.S. Food and Drug Administration (FDA)-cleared TAVR device on the U.S. market, the balloon-expandable Sapien Valve. The FDA approved the Sapien in November 2011. It has indications for the treatment of inoperable patients and high-risk surgical patients. The CoreValve is expected to become the second FDA-cleared TAVR system, but litigation may hinder its U.S. market launch. 
In 2010, a federal jury found that Medtronic CoreValve LLC willfully infringed on another Edwards patent, the U.S. Andersen transcatheter heart valve patent, and awarded damages to Edwards. The Anderson patent was set to expire in 2011. That finding was upheld on appeal and an initial payment of $84 million was made by Medtronic to Edwards in 2013. A decision on Edwards’ request to enjoin Medtronic’s entrance into the U.S. market and additional damages is still pending. Because some of the sales have been found to infringe both the Andersen and Cribier patents, a portion of the damages awarded in the Cribier case could be reduced, Edwards said in a statement. 
Edwards challanged CorValve in German courts and succeeded in getting an injunction against the sale of the device. However, in November 2013, a German court ordered the discontinuation of a prior court ruling that prohibited Medtronic from commercially marketing or selling the CoreValve system in Germany since Aug. 26, 2013. The Higher Regional Court of Karlsruhe explained that, due to the European Patent Office (EPO) preliminary opinion, the Edwards Lifesciences’ EP2055266 Spenser patent claims are not valid, and it could not assume “with sufficient likelihood” that the Spenser patent is valid. Metronic has since resumed sales in Germany.
CoreValve’s Positive Clinical Results 
The first results from the CoreValve U.S. pivotal trial were very positive. The data on the self-expanding TAVR device was presented as a late-breaking clinical trial session of the 25th annual Transcatheter Cardiovascular Therapeutics (TCT) conference last October. The trial met its primary endpoint in patients who were considered too ill or frail to have their aortic valves replaced through traditional open-heart surgery, with a rate of death or major stroke at one year of 25.5 percent. This result is highly significant (p < 0.0001) as it was 40.7 percent lower in patients treated with the CoreValve system than was expected with standard therapy.

MORE LIKE THIS

Clinical Trials on Transcatheter Aortic Valve Replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/24/2013

Second Generation Transcatheter Aortic Valve Shown to Successfully Address TAVR Complications

Results of the REPRISE II trial reported at TCT 2013
November 4, 2013 — In a clinical trial of the Boston Scientific Lotus valve, a second-generationtranscatheter aortic valve, the device demonstrated low rates of complications that are sometimes seen in transcatheter aortic valve replacement (TAVR), including challenges with positioning, post-procedure paravalvular aortic regurgitation, vascular complications and stroke.
The findings were presented at the 25th annual Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2013).
The valve studied in REPRISE II is fully retrievable and repositionable with an adaptive seal intended to minimize paravalvular regurgitation, a complication that has been associated with higher mortality among patients undergoing TAVR. In this prospective, single-arm, multicenter study, symptomatic patients at high risk for surgery received the Lotus valve to treat calcific aortic stenosis.
The trial enrolled 120 patients; mean age was 84.4±5.3 years, 56.7 percent were female and 75.8 percent were considered New York Heart Association (NYHA) Class III or IV. The mean Society of Thoracic Surgeons score was 7.1±4.6 percent and all patients were confirmed by their site heart team to be at high risk for surgery due to frailty or associated comorbidities.
The valve was successfully implanted in all 120 patients with valve repositioning and retrieval performed as needed. There was no embolization, ectopic valve deployment or need for implantation of a second prosthetic valve.
The primary device performance endpoint was the mean aortic valve pressure gradient at 30 days compared to a performance goal of 18 mmHg; the primary safety endpoint was 30-day mortality. The primary device performance endpoint was met with a 30 day mean aortic valve pressure gradient of 11.5±5.2 mmHg; mean effective orifice area was 1.7±0.4 cm2.
All cause mortality and disabling stroke were low at 30 days (4.2 percent and 1.7 percent, respectively). Additional clinical event rates were consistent with those reported for other valves. Aortic regurgitation at 30 days was negligible in 99 percent of patients (78.3 percent none, 5.2 percent trace and 15.5 percent mild). The total stroke rate, disabling and non-disabling, was 5.9 percent, which is the same as the rate as the Edward’s Sapien valve’s performance in the PARTNER trial.
“These findings suggest this valve, which is a differentiated, second generation TAVR device, will be a valuable addition for the treatment of severe aortic stenosis,” said Ian Meredith, MBBS, Ph.D., director, Monash HEART, executive director, Monash Cardiovascular Research Centre, professor of medicine, Monash University in Melbourne, Australia, and lead investigator of the study.

 Related articles were published on this Open Access Online Scientific Journal, including the following:

Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

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

http://pharmaceuticalintelligence.com/2013/06/17/postdilatation-to-reduce-paravalvular-regurgitation-during-transcatheter-aortic-valve-replacement/

Lev-Ari, A. 2/12/2013 Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

http://pharmaceuticalintelligence.com/2013/02/12/american-college-of-cardiologys-and-the-society-of-thoracic-surgeons-entrance-into-clinical-trials-is-noteworthy-read-more-two-medical-societies-jump-into-clinical-trial-effort-for-tavr-tech-f/

  

Lev-Ari, A. 8/13/2012 Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents http://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

 

Lev-Ari, A. 7/18/2012 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

http://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

 

Lev-Ari, A. 6/22/2012 Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

http://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Lev-Ari, A. 6/19/2012 Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market

http://pharmaceuticalintelligence.com/2012/06/19/executive-compensation-and-comparator-group-definition-in-the-cardiac-and-vascular-medical-devices-sector-a-bright-future-for-edwards-lifesciences-corporation-in-the-transcatheter-heart-valve-replace/

 

Lev-Ari, A. 6/22/2012 Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

http://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/

 We reported on the following Medical Devices News:

Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity”    http://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI    http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology
http://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
http://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX
http://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
http://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Ablation Devices Market to 2016 – Global Market Forecast and Trends Analysis by Technology, Devices & Applications
http://pharmaceuticalintelligence.com/2012/12/23/ablation-devices-market-to-2016-global-market-forecast-and-trends-analysis-by-technology-devices-applications/

Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered
http://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

To Stent or Not? A Critical Decision
http://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

http://pharmaceuticalintelligence.com/2012/09/03/transcatheter-aortic-valve-replacement-for-inoperable-severe-aortic-stenosis/

New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

http://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

New Drug-Eluting Stent Works Well in STEMI
http://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

Expected New Trends in Cardiology and Cardiovascular Medical Devices
http://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

Developments on the Frontier of Transcatheter Aortic Valve Replacement (TAVR) Devices

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 4/28/2016

Recent TAVR approvals prompt changes to Direct Flow’s Salus trial

http://www.massdevice.com/recent-tavr-approvals-prompt-changes-direct-flow-trial/?utm_source=newsletter-160428&utm_medium=email&utm_campaign=newsletter-160428&spMailingID=8852051&spUserID=MTI2MTQxNTczMjM5S0&spJobID=902900938&spReportId=OTAyOTAwOTM4S0

 

acWire for Precise Transcatheter Aortic Valve Replacement Gets FDA Green Light (VIDEO)

by EDITORS on Jan 14, 2014 • 1:58 pm

acwire acWire for Precise Transcatheter Aortic Valve Replacement Gets FDA Green Light (VIDEO)MediValve, a company based in Kibbutz HaMa’apil, Israel, just received 510(k) clearance from the FDA to bring to the U.S. its acWire guidewire. The device is primarily designed to position transcatheter prosthetic heart valves with greater precision than many current delivery systems allow.

The advantage of the acWire is that once its active components are moved past the diseased valve, it’s opened up like a flower and drawn back to the valve, aligning itself snugly just past the valve opening. Three radiopaque markers on the petals help the physician visualize how the device is positioned before placing the valve.

Here’s a quick animation that demonstrates the functionality of acWire:

VIEW VIDEO

http://www.medgadget.com/2014/01/acwire-for-precise-transcatheter-aortic-valve-replacement-gets-fda-green-light.html?utm_content=buffer0c685&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer#!

Product page: acWire…

Press release: MediValve, Ltd., Announces Clearance of a 510(k) Pre-Marketing Notification with the US Food and Drug Administration for the acWire™ Guidewire…

SOURCE

http://www.medgadget.com/2014/01/acwire-for-precise-transcatheter-aortic-valve-replacement-gets-fda-green-light.html?utm_content=buffer0c685&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer#!

FORTY articles on TAVR, TAVI were published on this Open Access Online Scientific Journal, including the following:

http://pharmaceuticalintelligence.com/category/cardiac-and-cardiovascular-surgical-procedures/aortic-valve-tavr-tavi-vs-open-heart-surgery/

inVentiv Clinical Trial Recruitment Solutions (iCTRS) in Partnership with ViS Research: Efficiencies Gains in Clinical Trial Feasibility Studies

Reporter: Aviva Lev-Ari, PhD, RN

For Immediate Release

ViS Research Contact:

James Rosenstein

+1 917 715 2820

james.rosenstein@visresearch.com

 

 

 

 

 

inVentiv Contact:

Danielle DeForge

Office: +1 781 425 4624

Mobile: +1 202 210 5992

danielle.deforge@inventivhealth.com

 

 

 

INVENTIV HEALTH LEVERAGES ADVANCED DIGITAL TECHNOLOGY TO SLASH THE TIME REQUIRED TO CONDUCT FEASIBILITY STUDIES

 

Partnership with ViS Research Has the Potential to Cut in Half the Time Needed to Conduct Clinical Trial Feasibility Studies Through Process Innovation

 

BURLINGTON, Mass. (January 23, 2014) – inVentiv Clinical Trial Recruitment Solutions (iCTRS), an inVentiv Health company leading the biopharmaceutical sector in reducing the time to the start of  clinical trials, announced today that the process innovations offered by its partnership with ViS could cut in half the time required to conduct feasibility studies.

 

The most recent report issued this month by the Tufts Center for the Study of Drug Development noted that the drug development model had not fundamentally changed in years, and that the future success of pharmaceutical companies will depend in part on their ability to adopt greater efficiencies and best practices.

 

One area ripe for improvement is clinical site feasibility in the planning for a trial. Even though the selection of sites capable of enrolling patients is a critical step to ensuring the smooth operation of a clinical trial, site selection is fraught with inefficiencies. An estimated $10 billion a year is wasted because of poor site selection.

 

The use of technology is critical to process improvement in feasibility. To demonstrate the potential for savings, iCTRS took data from 100 feasibility studies conducted by inVentiv, and analyzed the time required to perform each of the individual tasks involved in such studies. The company then looked at how much time the application of ViS technology could save for each task. Cumulatively, the efficiencies offered by ViS cut the total feasibility study hours by 54% — while delivering better quality.  Additional time savings potentially could be realized by applying other technologies in the iCTRS portfolio.

 

ViS Research, creator of the world’s first comprehensive online feasibility platform, gives trial planners better, real-time data for the efficient evaluations of locations, sites, investigators, and networks for possible inclusion in clinical trials. The ViS global map of clinical research infrastructure, assembled over a decade of research, includes detailed and vetted information on more than 400,000 disease-specific centers.

 

Research centers and investigators can efficiently share their capabilities by uploading a profile on the digital platform where the information can be stored and updated regularly, eliminating redundant paper questionnaires. Up until now, many investigators chose to not participate in feasibility because it was so difficult.  Instead of answering the same questions multiple times, investigators can now build upon the existing profile and focus on answering protocol-specific questions that will help differentiate their site from other sites being considered.

 

For trial sponsors, the ViS profile provides answers to 85% of the routine questions they normally ask.  Sponsors can review the profiles, use the platform to contact investigators and gather additional information. High-quality analytics and visualization tools allow sponsors to quickly and easily compare sites and feasibility data for accelerated selection of sites that are properly equipped, staffed, and ready to be activated for study participation.

 

“At the end of the day, this is all about doing feasibility studies better, faster and getting drugs and devices into quality clinical trials at an accelerated rate,” said Ramita Tandon, senior vice president and general manager for iCTRS. “In the next phase of development on the ViS platform we’ll accelerate processes even more.”

iCTRS this month launched its own proprietary network on the ViS platform, using the social media functions that enable far easier networking.  iCTRS is the only service provider with rights to use the ViS database for building its own social network. Investigators will have access to information on new trial opportunities posted by iCTRS, while sponsors can share information on upcoming trials and more closely interact and collaborate with investigators.

iCTRS and ViS are developing additional, exclusive functionality, including automating the workflow process for confidential disclosure agreements (CDA) and the onboarding of clinical trial investigators. Streamlining and simplifying processes will help attract and retain more high-quality investigators who can enroll patients, conduct efficient trials and move the start-up phases of the drug development process into the 21st century.

 

iCTRS was specifically created to integrate a game-changing set of global capabilities specifically to accelerate trials in a predictable and cost-efficient way.  “It’s all about hitting timelines, and it starts with feasibility.  This is the first place we challenge assumptions about old ways of doing trials and find efficiencies through technology to do things better,” Tandon said.

 

 

About inVentiv Health

Our broad range of services and our global scale, represented by approximately 12,000 employees supporting clients in more than 70 countries, allow us to serve as a critical strategic partner for pharmaceutical, biotechnology, medical device and diagnostics, and healthcare companies in their dynamic and rapidly changing regulatory and commercial environments. We serve more than 550 client organizations, including all 20 of the largest global pharmaceutical companies. For more information, visit http://www.inVentivHealth.com.

 

About ViS Research (ViS)

The ViS online feasibility platform is the first to integrate analytics about investigators, sites, networks, and trial locations, while enabling engagement between trial planners and sites.  Trial planners use interactive visualizations to navigate the intricate, disease-specific decision matrix to immediately gather feasibility information from 400,000+ disease-specific research sites and 360,000+ investigators. ViS helps these investigative sites by decreasing their administrative burden related to feasibility questionnaires, while enabling them to efficiently display their disease-specific capabilities, at no cost. The end result is that optimal decisions can be reached using a small fraction of the time and cost incurred through conventional methods. ViS Research was created as a global enterprise in 2010, with trial planning experts in four continents. More information at http://www.visresearch.com.

 

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve known and unknown risks that may cause our performance to differ materially. These forward-looking statements reflect our current views about future events and are subject to risks, uncertainties and assumptions. We wish to caution readers that certain important factors may have affected and could in the future affect our actual results and could cause actual results to differ significantly from those expressed in any forward-looking statement. Such factors include, without limitation: the impact of our substantial level of indebtedness on our ability to generate sufficient cash to fulfill our obligations under our existing debt instruments or our ability to incur additional indebtedness; the impact of customer project delays and cancellations and our ability to sufficiently increase our revenues and manage expenses and capital expenditures to permit us to fund our operations; the impact of the consummation of our acquisition of Catalina Health Resource, LLC and any future acquisitions; the impact of any change in our current credit ratings and the ratings of our debt securities on our relationships with customers, vendors and other third parties;  the impact of any additional leverage we may incur on our ratings and the ratings of our debt securities; our ability to continue to comply with the covenants and terms of our senior secured credit facilities and to access sufficient capital under our credit agreement or from other sources of debt or equity financing to fund our operations; the impact of any default by any of our credit providers; our ability to accurately forecast costs to be incurred in providing services under fixed price contracts; our ability to accurately forecast insurance claims within our self- insured programs; the potential impact on pharmaceutical manufacturers, including pricing pressures, from healthcare reform initiatives or from changes in the reimbursement policies of third-party payers; our ability to grow our existing client relationships, obtain new clients and cross-sell our services; the potential impact of financial, economic, political and other risks, including interest rate and exchange rate risks, related to conducting business internationally; our ability to successfully operate new lines of business; our ability to manage our infrastructure and resources to support our growth, including through outsourced service providers; our ability to successfully identify new businesses to acquire, conclude acquisition negotiations and integrate the acquired businesses into our operation, and achieve the resulting synergies; any disruptions, impairments, or malfunctions affecting software as well as excessive costs or delays that may adversely impact our continued investment in and development of software; the potential impact of government regulation on us and on our client base, including the impact of the final HIPAA Privacy Rule on the willingness of pharmaceutical manufacturers to sponsor patient adherence programs; our ability to comply with all applicable laws as well as our ability to successfully adapt to any changes in applicable laws on a timely and cost effective basis; our ability to recruit, motivate and retain qualified personnel; any potential impairment of goodwill or intangible assets; consolidation in the pharmaceutical industry; changes in trends in the healthcare and pharmaceutical industries or in pharmaceutical outsourcing, including

initiatives by our clients to perform services we offer internally; our ability to convert backlog into revenue; the potential liability associated with injury to clinical trial participants; the actual impact of the adoption of certain accounting standards; and our ability to maintain technological advantages in a variety of functional areas, including sales force automation, electronic claims surveillance and patient compliance. Holders of our debt instruments are referred to reports provided to investors from time to time and the offering memoranda provided in connection with the issuance of our notes for further discussion of these risks and other factors. 

# # # #

SOURCE

From: James Rosenstein <james.rosenstein@visresearch.com>
Date: Thu, 23 Jan 2014 15:44:58 +0000
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Conversation: press release

Loss of Gene Islands May Promote a Cancer Cell’s Survival, Proliferation and Evolution: A new Hypothesis (and second paper validating model) on Oncogenesis from the Elledge Laboratory

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

It is well established that a critical event in the transformation of a cell to the malignant state involves the mutation of hosts of oncogenes and tumor suppressor genes, which in turn, confer on a cell the inability to properly control its proliferation.    On a genomic scale, these mutations can result in gene amplifications, loss of heterozygosity (LOH), and epigenetic changes resulting in tumorigenesis.  The “two hit hypothesis”, proposed by Dr. Al Knudson of Fox Chase Cancer Center[1], proposes that two mutations in the same gene are required for tumorigenesis, initially proposed to explain the progression of retinoblastoma in children, indicating a recessive disease.

(Excerpts from a great article explaining the two-hit-hypothesis is given at the end of this post).

And, although many tumor genomes display haploinsufficeint tumor suppressor genes, and fit the two hit model quite nicely, recent data show that most tumors display hemizygous recurrent deletions within their genomes.  Tumors display numerous recurrent hemizygous focal deletions that seem to contain no known tumor suppressor genes. For instance a recent analysis of over three thousand tumors including breast, bladder, pancreatic, ovarian and gastric cancers averaged greater than 10 deletions/tumor and 82 regions of recurrent focal deletions,

It has been proposed these great number of hemizygous deletions may be a result of:

  • a recessive tumor suppressor gene requiring mutation or silencing of second allele
  • the mutation may recur as they are located in fragile sites (unstable genomic regions)
  • single-copy loss may provide selective advantage regardless of the other allele

Note: some definitions of hemizygosity are given below.  In general at any locus, each parental chromosome can have 3 deletion states:

  1. wild type
  2. large deletion
  3. small deletion

Hemizygous deletions only involve one allele, not both alleles which is unlike the classic tumor suppressor like TP53

To see if it is possible that only one mutated allele of a tumor suppressor gene may be a casual event for tumorigenesis, Dr. Nicole Solimini and colleagues, from Dr. Stephen Elledge’s lab at Harvard, proposed a hypothesis they termed the cancer gene island model, after analyzing the regions of these hemizygous deletions for cancer related genes[2].  Dr. Soliin and colleagues analyzed whole-genome sequence data for 526 tumors in the COSMIC database comparing to a list generated from the Cancer Gene Census for homozygous loss-of-function mutations (mutations which result in a termination codon or frame-shift mutation: {this produces a premature stop in the protein or an altered sequence leading to a nonfunctional protein}.

Results of this analysis revealed:

  1. although tumors have a wide range of deletions per tumor (most epithelial high grade like ovarian, bladder, pancreatic, and esophageal adenocarcinomas had 10-14 deletions per tumor
  2. and although tumors exhibited a wide range (2- 16 ) loss of function mutations
  3. ONLY 14 of 82 recurrent deletions contained a known tumor suppressor gene and was a low frequency event
  4. Most recurrent cancer deletions do not contain putative tumor suppressor genes.

Therefore, as the authors suggest, an alternate method to the two-hit hypothesis may account for a selective growth advantage for these types of deletions, defining these low frequency hemizygous mutations in two general classes

  1. STOP genes: suppressors of tumor growth and proliferation
  2. GO genes: growth enhancers and oncogenes

Identifying potential STOP genes

To identify the STOP and GO genes the authors performed a primary screen of an shRNA library in telomerase (hTERT) immortalized human mammary epithelial cells using increased PROLIFERATION as a screening endpoint to determine STOP genes and decreased proliferation and lethality (essential genes) to determine possible GO genes. An initial screen identified 3582 possible STOP genes.  Using further screens and higher stringency criteria which focused on:

  • Only genes which increased proliferation in independent triplicate screens
  • Validated by competition assays
  • Were enriched more than four fold in three independent shRNA screens

the authors were able to focus on and validate 878 genes to determine the molecular pathways involved in proliferation.

These genes were involved in cell cycle regulation, apoptosis, and autophagy (which will be discussed in further posts).

To further validate that these putative STOP genes are relevant in human cancer, the list of validated STOP genes found in the screen was compared to the list of loss-of-function mutations in the 526 tumors in the COSMIC databaseSurprisingly, the validated STOP gene list were significantly enriched for known and possibly NOVEL tumor suppressor genes and especially loss of function and deletion mutations but also clustered in gene deletions in cancer.  This not only validated the authors’ model system and method but suggests that hemizygous deletions in multiple STOP genes may contribute to tumorigenesis

as the function of the majority of STOP genes is to restrain tumorigenesis

A few key conclusions from this study offer strength to an alternative view of oncogenesis NAMELY:

  • Loss of multiple STOP genes per deletion optimize a cancer cell’s proliferative capacity
  • Cancer cells display an insignificant loss of GO genes, minimizing negative impacts on cellular fitness
  • Haploinsufficiency in multiple STOP genes can result in similar alteration of function similar to complete loss of both alleles of
  • Cancer evolution may result from selection of hemizygous loss of high number of STOP and low number of GO genes
  • Leads to a CANCER GENE ISLAND model where there is a clonal evolution of transformed cells due to selective pressures

A link to the supplemental data containing STOP and GO genes found in validation screens and KEGG analysis can be found at the following link:

http://www.sciencemag.org/content/337/6090/104/suppl/DC1#

A link to an interview with the authors, originally posted on Harvard’s site can be found here.

Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome; a new paper from the Elledge group in the journal Cell

http://www.cell.com/retrieve/pii/S0092867413012877

A concern of the authors was the extent to which gene silencing could have on their model in tumors.  The validation of the model was performed in cancer cell lines and compared to tumor genome sequence in publicly available databases however a followup paper by the same group shows that haploinsufficiency contributes a greater impact on the cancer genome than these studies have suggested.

In a follow-up paper by the Elledge group in the journal Cell[3], Theresa Davoli and colleagues, after analyzing 8,200 tumor-normal pairs, show there are many more cancer driver genes than once had been predicted.  In addition, the distribution and potency of STOP genes, oncogenes, and essential genes (GO) contribute to the complex picture of aneuploidy seen in many sporadic tumors.  The authors proposed that, together with these and their previous findings, that haploinsufficiency plays a crucial role in shaping the cancer genome.

Hemizygosity and Haploinsufficiency

Below are a few definitions from Wikipedia:

Zygosity is the degree of similarity of the alleles for a trait in an organism.

Most eukaryotes have two matching sets of chromosomes; that is, they are diploid. Diploid organisms have the same loci on each of their two sets of homologous chromosomes, except that the sequences at these loci may differ between the two chromosomes in a matching pair and that a few chromosomes may be mismatched as part of a chromosomal sex-determination system. If both alleles of a diploid organism are the same, the organism is homozygous at that locus. If they are different, the organism is heterozygous at that locus. If one allele is missing, it is hemizygous, and, if both alleles are missing, it is nullizygous.

Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.

Al Knudsen and The “Two-Hit Hypothesis” of Cancer

Excerpt from a Scientist article by Eugene Russo about Dr. Knudson’s Two hit Hypothesis;

for full article please follow the link http://www.the-scientist.com/?articles.view/articleNo/19649/title/-Two-Hit–Hypothesis/

The “two-hit” hypothesis was, according to many, among the more significant milestones in that rapid evolution of biomedical science. The theory explains the relationship between the hereditary and nonhereditary, or sporadic, forms of retinoblastoma, a rare cancer affecting one in 20,000 children. Years prior to the age of gene cloning, Knudson’s 1971 paper proposed that individuals will develop cancer of the retina if they either inherit one mutated retinoblastoma (Rb) gene and incur a second mutation (possibly environmentally induced) after conception, or if they incur two mutations or hits after conception.3 If only one Rb gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogenes; other scientists renamed them tumor suppressors.

When first introduced, the “two-hit” hypothesis garnered more interest from geneticists than from cancer researchers. Cancer researchers thought “even if it’s right, it may not have much significance for the world of cancer,” Knudson recalls. “But I had been taught from the early days that very often we learn fundamental things from unusual cases.” Knudson’s initial motivation for the model: a desire to understand the relationship between nonhereditary forms of cancer and the much rarer hereditary forms. He also hoped to elucidate the mechanism by which common cancers, such as those of the breast, stomach, and colon, become more prevalent with age.

According to the then-accepted somatic mutation theory, the more mutations, the greater the risk of cancer. But this didn’t jibe with Knudson’s own studies on childhood cancers, which suggested that, in the case of cancers such as retinoblastoma, disease onset peaks in early childhood. Knudson set out to determine the smallest number of cancer-inducing events necessary to cause cancer and the role of these events in hereditary vs. nonhereditary cancers. Based on existing data on cancer cases and some mathematical deduction, Knudson came up with the “two-hit” hypothesis.

Not until 1986, when researchers at the Whitehead Institute for Biomedical Research in Cambridge, Mass., cloned the Rb gene, would there be solid evidence to back up Knudson’s pathogenesis paradigm.4 “Even with the cloning of the gene, it wasn’t clear how general it would be,” says Knudson. There are, it turns out, several two-hit lesions, including polyposis, neurofibromitosis, and basal cell carcinoma syndrome. Other cancers show only some correspondence with the two-hit model. In the case of Wilm’s tumor, for example, the model accounts for about 15 percent of the cancer incidence; the remaining cases seem to be more complicated.

knudsonTwoHit1600

His seminal paper on the two-hit hypothesis[1]

A.G. Knudson, “Mutation and cancer: statistical study of retinoblastoma,” Proceedings of the National Academy of Sciences, 68:820-3, 1971.

The two hit hypothesis proposed by A.G. Knudson.  A description with video of Dr. Knudson talk at AACR can be found at the following link (photo creditied to A.G. Knudson and Fox Chase Cancer Center at the following link:http://www.fccc.edu/research/research-awards/knudson/index.html

Sources

1.            Knudson AG, Jr.: Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 1971, 68(4):820-823.

2.            Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR, Luo J, Burrows AE, Anselmo AN, Bredemeyer AL, Li MZ et al: Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 2012, 337(6090):104-109.

3.            Davoli T, Xu Andrew W, Mengwasser Kristen E, Sack Laura M, Yoon John C, Park Peter J, Elledge Stephen J: Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome. Cell 2013, 155(4):948-962.

Other papers on this site on CANCER and MUTATION include:

Cancer Mutations Across the Landscape

Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Breast Cancer and Mitochondrial Mutations

Winning Over Cancer Progression: New Oncology Drugs to Suppress Passengers Mutations vs. Driver Mutations

Hold on. Mutations in Cancer do good.

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

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