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We celebrated 5,700 Scientific Articles in @PharmaceuticalIntelligence.com on November 20, 2019

Editor-in-Chief: Aviva Lev-Ari, PhD, RN

 

5,700 Articles

691 Categories

10,128 Tags

 

1,688,036 e-Readers

7,369 comments

 

The Digital Age Gave Rise to New Definitions – New Benchmarks were born on the World Wide Web for the Intangible Asset of Firm’s Reputation: Pay a Premium for buying e-Reputation

 

For the Journal Access:

https://wordpress.com/view/pharmaceuticalintelligence.com

For the BioMed e-Series Access:

https://wordpress.com/view/pharmaceuticalintelligence.com

For 70 Conference e-Proceedings Access:

https://pharmaceuticalintelligence.com/press-coverage/part-three-conference-eproceedings-deliverables-social-media-analytics/

 

Other links may be of interest:

  1. Executive Summary
  2. Opportunities Map in the Acquisition Arena
  3. Dynamic Contents for LPBI Group’s PowerPoint Presentation
  4. Detailed Technology Description
  5. Curation Methodology – Digital Communication Technology to mitigate Published Information Explosion and Obsolescence in Medicine and Life Sciences
  6. Top Authors by Number of eReaders Views
  7. Top Articles by Number of e-Readers for All Days ending 2019-02-17
  8. LPBI Group’s Social Media Presence
  9. Financial Valuation of Three Health Care Intellectual Property (IP) Content Asset Classes
  10. Global Market Penetration Forecast for each Volume in the 16 Volume BioMed e-Series
  11. Potential Use of LPBI IP as Value Price Driver by Potential Acquirer: Assumptions per Asset Class 
  12. Financial Advisory & Legal Advisory Providers: US & Israel
  13. Founder’s Role in the Development of Venture’s Factors of Content Production – Biographical Notes by Aviva Lev-Ari, PhD, RN, LPBI Group
  14. FIT Members Contribute to Opportunities Map
  15. FINAL IMPROVEMENT TEAM (FIT): Definition of Active, Lapsing of Active Status, COMPs Formulas
  16. Mostly HONORED to be followed by [from an Excerpt of 117 Followers of the Twitter Account @AVIVA1950 from the List of 359 Followers] by the Number of their Followers on 2/24/2019
  17. LPBI Group is mostly HONORED to be followed by [from an Excerpt of 136 Followers of the Twitter Account @pharma_BI from the List of 505 Followers] by the Number of their Followers on 3/20/2019
  18. FIT members – Who works on WHAT?
  19. Comparative Analysis of the Level of Engagement for Four Twitter Accounts: @KDNuggets (Big Data) @GilPress @Forbes @pharma_BI @AVIVA1950
  20. MEDIA organizations as Followers of @pharma_BI the Official Twitter Account of LPBI Group (136 out of 505 Followers): Number of Followers’ Followers, Institutions (I) and Individuals (Persons(P)), RED = Mostly Honored to be followed by
  21. JOURNAL Statistics on 2/24/2019
  22. Excerpt of 136 Followers of @pharma_BI (from the List of 505 Followers) by the Number of their Followers on 3/20/2019
  23. Excerpt of 117 Followers of @AVIVA1950 (from the List of 359 Followers) by the Number of their Followers
  24. REACH – Two Handles on Twitter.com @AVIVA1950 @pharma_BI
  25. 2013-2019, On the Medical & Scientific Bookshelf in Kindle Store: eReader Behaviors: Browsing, Page Downloads and Buying e-Books – LPBI Group’s BioMed e-Series, Royalties Payment Analysis 
  26. Connections First Level on LinkedIn: 500 CEOs, 200 Big Pharma Professionals, 7,000 in Total: LPBI Group Founder – Aviva Lev-Ari, PhD, RN
  27. Summer 2019 Plan – Research Associates Tasks
  28. LPBI’s Pipeline Map: A Positioning Perspectives – An Outlook to the Future from the Present
  29. WHAT ARE LPBI Group’s NEEDS in June 2019: Aviva’s BOLD VISION on June 11, 2019
  30. For @AVIVA1950, Founder, LPBI Group @pharma_BI: Twitter Analytics [Engagement Rate, Link Clicks, Retweets, Likes, Replies] & Tweet Highlights [Tweets, Impressions, Profile Visits, Mentions, New Followers] https://analytics.twitter.com/user/AVIVA1950/tweets

Risks from Dual Antiplatelet Therapy (DAPT) may be reduced by Genotyping Guidance of Cardiac Patients

Reporter: Aviva Lev-Ari, PhD, RN

 

Genotyping Cardiac Patients May Reduce Risks From DAPT

-STEMI patient study reaches noninferiority mark for adverse cardiac events

In the investigational arm, all 1,242 patients were tested for CYP2C19 loss-of-function alleles *2 or *3. Carriers received ticagrelor or prasugrel, while noncarriers received clopidogrel, considered to be less powerful.

No genetic testing was performed in the standard treatment arm (n=1,246), in which patients largely went on to receive ticagrelor or prasugrel. Nearly all patients in both cohorts received dual antiplatelet therapy (DAPT) with aspirin.

Following primary PCI, patients went on to the P2Y12 inhibitor for at least 12 months, with drug adherence similar between the genotype-guided (84.5%) and standard groups (82.0%).

For patients with CYP2C19 loss-of-function alleles in the genotype-guided arm, 38% received ticagrelor and 1% received prasugrel. The remaining 61% of patients — the noncarriers — received clopidogrel. In the control arm, 91% were treated with ticagrelor, 2% with prasugrel, and 7% with clopidogrel, according to local protocol.

Ten Berg said that prasugrel is not typically used in the Netherlands, where eight of the centers in the trial were located, but that this might change given that the drug lowered rates of ischemic events versus ticagrelor in the head-to-head ISAR REACT 5 trial, which was also presented at ESC.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent

 

Reporter: Aviva Lev-Ari, PhD, RN

Next stop, filing for approval. The Medicines Company has said it plans to submit inclisiran for FDA review by the end of 2019 and EMA review in the first quarter of 2020. If the drug’s approved it’ll be the third anti-PCSK9 behind mAbs Repatha and Praluent, and could try to compete on price to gain market share.

The company’s been very careful not to disclose its pricing plans for inclisiran, said ORION-10 principal investigator Dr. Scott Wright, professor and cardiologist at the Mayo Clinic. But, Wright said, The Medicines Co. and other companies he advises on clinical trial design “have learned the lesson from the sponsors of the monoclonal antibodies [against PCSK9], they’re not going to come in and price a drug that’s out of proportion to what the market will bear.” 

Because the anti-PCSK9 mAbs were initially priced beyond what patients and insurers were willing to pay, “now most of the physicians that I meet have a resistance to using them just because they’re fearful about the pre-approval process” with insurers, said Wright. “They’re much easier to get approved and paid for today than they’ve ever been, but that message is not out in the medical community yet.”

SOURCE

From: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Reply-To: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Date: Monday, November 18, 2019 at 2:59 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Interim look at Amarin data, an inclisiran update, & Philly’s giant heart


Tweets and Retweets by @AVIVA1950 and by @pharma_BI for 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

see also,

eProceedings 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA

https://pharmaceuticalintelligence.com/2019/07/19/15th-annual-personalized-medicine-conference-at-harvard-medical-school-the-paradigm-evolves-november-13-14-2019-%e2%80%a2-harvard-medical-school-boston-ma/

 

 

Tweets by @AVIVA1950 and by @pharma_BI

Aviva Lev-Ari
@AVIVA1950

#PMConf

Donald L. Siegel, Ph.D., M.D., Director, Division of Transfusion Medicine & Therapeutic Biology, Director, Clinical Cell and Vaccine Production Facility, UPenn’s Perelman School of Medicine no relations explored between Immune T cells and microbiome

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Paul Stoffels, M.D., Vice Chairman, Executive Committee, Chief Scientific Officer, Johnson & Johnson Impact of Mirobiome it plays a key role in many diseases difficult to develop therapeutics derived from microbiome data

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Harpreet Singh, Ph.D., CEO, Immatics T Cell peptide started 15 years ago Peptonomics,  tumors of solid cancer – cell therapies selected from libraries  off the shelf cells from health donors Biologics bridges tumor cells and solid cells

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Donald L. Siegel, Ph.D., M.D., Director, Division of Transfusion Medicine & Therapeutic Biology, Director, Clinical Cell and Vaccine Production Facility, UPenn’s Medicine CAR-T therapy started the Transfusion Medicine & Therapeutic Biology industry

Aviva Lev-Ari
@AVIVA1950

#PMConf

Paul Stoffels, M.D., Vice Chairman, Executive Committee, Chief Scientific Officer, Johnson & Johnson Combination therapy emerges, MOA partnerships: cell therapy can transform cancer treatment INFECTIOUS disease had Global impact need stop the virus

Aviva Lev-Ari
@AVIVA1950

#PMConf

Paul Stoffels, M.D., #CSO

Platforms are established, every 20-30 another one emergences access to data – critical platform AI for diagnostics and decision making biomarkers J&J try to learn on every disease: Lungs and GI Diagnosis HIV Vaccine

Aviva Lev-Ari
@AVIVA1950

#PMConf

Paul Stoffels, M.D., Vice Chairman, Executive Committee, Chief Scientific Officer, Johnson & Johnson Goals of medicine in 2019 early detection Vaccines in disease prevention Longevity

Aviva Lev-Ari
@AVIVA1950

#PMConf

Joseph B. Martin, M.D., Ph.D., Dean Emeritus

fascinating personal history story on development of interest in genetic analysis

Aviva Lev-Ari
@AVIVA1950

#PMConf

Michael J. Pellini, MD Diagnostics Pain management  Patients can fight more broadly F for sharing data and data exchange 80% patients do not access Academic Centers for treatment

Aviva Lev-Ari
@AVIVA1950

#PMConf

Michael J. Pellini, MD surgery, chemo, radiation – cost, harmful, INEFFECTIVE, Dr. Reza Columbia Medical School Oncologist 35 years How are we doing with technology? Very remarkable Clinical Utility to the Payer Regulatory – a super star in ten years

Aviva Lev-Ari
@AVIVA1950

#PMConf

Stephen L. Eck, Carl June, UPenn Beyond Cancer: Chronic diseases have systemic of specific immune or autoimmune components: CNS, neurodegenerative and Diabetes, Sickle cell anemia – treatment by cell therapy microphages

Aviva Lev-Ari
@AVIVA1950

#PMConf

Stephen L. Eck, Carl June, UPenn Cost of cell transfection therapy: Cost of Goods, Cost of Labor – pay for performance,  Manufacture in NJ shipped to Europe – not effective

Aviva Lev-Ari
@AVIVA1950

#PMConf

Stephen L. Eck, Carl June, UPenn Similarity between Transfusion Medicine industry and Cell therapy – Transfection of cells therapy  Manufacturing of Cells for transfection: Over regulation like in small molecules vs too little regulation

Aviva Lev-Ari
@AVIVA1950

#PMConf

Stephen L. Eck, Carl June, UPenn engineering T cells life farming – innovation is the driver, FDA is evolving in handling patents involved in Cell engineering Regulatory science needs to evolve in light of gene therapy in Human cell line in China

Aviva Lev-Ari
@AVIVA1950

#PMConf

Stephen L. Eck, Carl June, UPenn Children vs Adults 2011 reported better results in Adults, children’s immune system is evolving  In 2019 – 13 biotech companies in CAR-T cell therapies, Gene therapy is growing FDA, drug cycle T cells vs stem cells

Aviva Lev-Ari
@AVIVA1950

#PMConf

15th Annual meeting is at a historic moment in Boston where Prof. Church launched the Human Genome Project and Eric Launder at MIT and the Cancer Genome Project. Genzyme conceived gene therapy sold to Sanofi for $ Billion  Foundation Medicine

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Edward Abrahams, Ph.D., President, PMC 170 drugs with biomarkers, up 15% from 2000 in Biomarker strategy Gene therapy started in 2005, today personalized medicine is becoming standard of care. Science & Technology need additional friendly environment

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Kenna R. Mills Shaw, Ph.D., MD Anderson Institute does not sequence genome of each patient unlike Dana Farber clinicians need to access information for decision making when disease progresses – what new test to order data sharing inside the institute

Aviva Lev-Ari
@AVIVA1950

#PMConf

Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, PMC Genomic sequencing for a single test that covers many biomarkers Improve treatment efficiency Growing recognition of the need to demonstrate value, evidence for Payers to pay

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Ammar Qadan, Vice President, Global Head of Market Access, Illumina Illumina is building evidence for Harvard Pilgrim on theirs patient data on risk pregnancies Illumina is expanding  building evidence for ALL rare diseases for all Test diagnostics

Aviva Lev-Ari
@AVIVA1950

#PMConf

Roy J. Gandolfi, M.D., Medical Director, SelectHealth, UT is the Payer of Intermountain Healthcare, UT Regional approach vs National perspective medical policies requires experts for Payer to approve a treatment Consumer in the health plan

Aviva Lev-Ari
@AVIVA1950

#PMConf

Lincoln Nadauld, M.D., Ph.D., Chief, Precision Health, Intermountain Healthcare, UT Precision Oncology Program: Need, study, analysis outcome, publish dataPharmacogenetics testing will be covered for all employees & Neonatal

Aviva Lev-Ari
@AVIVA1950

#PMConf

Peter J. Neumann, Sc.D., Tufts Medical Center clinical utility evidence of value: saving by diagnostics cost for quality cost of diagnostics cost effectiveness – characterize utility cost effectiveness – study Value to families value of knowledge

Aviva Lev-Ari
@AVIVA1950

#PMConf

Ammar Qadan, Vice President, Global Head of Market Access, Illumina Illumina is partnering with providers and Payer Illumina & Blue Cross Blue Shield 150 Million are covered for genomics 2500 genomics test done Under utilization educate physician

Aviva Lev-Ari
@AVIVA1950

#PMConf

Mark P. Stevenson, COO Thermo Fisher Scientific Context: Therapy selection in personalized medicine navigate diagnostics in use and policies when implementations is considered Physicians need precise testing now Payers evidence of utility is needed

1

Aviva Lev-Ari
@AVIVA1950

#PMConf

Mark P. Stevenson, Executive Vice President, Chief Operating Officer, Thermo Fisher Scientific Patient Outcome – Data analytics, ML, AI for genomics, proteomics, metabolomics, Tests must be precise and inform the diagnosis by diagnostics Solutions

Aviva Lev-Ari
@AVIVA1950

#PMConf

Paul Stoffels, M.D., Vice Chairman, Executive Committee, Chief Scientific Officer, Johnson & Johnson Passion of Scientists pharmaceutics development is based on insights looking into the future – important goal to solve

Aviva Lev-Ari
@AVIVA1950

#PMConf

best conference on Personalized Medicine in 15 years eProceedings 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA

eProceedings 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM…
eProceedings 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA   The 15th Annual …
pharmaceuticalintelligence.com

Aviva Lev-Ari
@AVIVA1950

Your synopsis of the best Personalized Medicine Conference organized to date #PMConf

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Aviva Lev-Ari
@AVIVA1950
·
#PMConf @pharma_BI @AVIVA1950 best conference on Personalized Medicine in 15 years eProceedings 15th Annual Personalized Medicine Conference at Harvard Medical School – THE PARADIGM EVOLVES, November 13 – 14, 2019 • Harvard Medical School, Boston, MA pharmaceuticalintelligence.com/2019/07/19/15t

 Retweet by @AVIVA1950

Aviva Lev-Ari
@AVIVA1950

A true leader in Pharmaceutical domain, also Member of the National Academy of Art and Sciences #PMConf

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Cynthia Bens
@bens_cynthia
·
Introducing the amazing @ScottGottliebMD was a highlight of #pmconf. His vision for balanced regulatory and coverage policies is desperately needed now to support the future of #personalizedmedicine @permedcoalition

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Best Case study

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PMC
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·
This year’s #PMConf case study on the @TheDDFund puts a spotlight on what one can do to combine modern entrepreneurial finance approaches to tackle a very complex problem such as Alzheimer’s Disease. @RHamermesh @HarvardHBS #PMConf

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Aviva Lev-Ari
@AVIVA1950

#PMConf

Edward Abrahams, Ph.D., President, PMC 170 drugs with biomarkers, up 15% from 2000 in Biomarker strategy Gene therapy started in 2005, today personalized medicine is becoming standard of care. Science & Technology need additional friendly environment

1

Genomic Health®
@GenomicHealth

We’re proud to announce Steve Shak is the recipient of the Leadership in Personalized Medicine Award at the 15th Annual Personalized Medicine Conference: The Paradigm Evolves. Please come and see him speak at the conference. bit.ly/2lMAteZ #PMConf

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CRISPR companies calling for article retraction from Nature Methods – If the same or similar sequence of letters appears elsewhere in the genome, that can result in an unintentional or off-target edit – Concerns of Harm caused by Gene Editing using CRISPR-Cas9

 

Reporter: Aviva Lev-Ari, PhD, RN

Storm around the call for “Nature Methods editorial board to retract this paper.”

A spokesperson at Springer Nature, which publishes Nature Methods, said the organization had received “a number of communications” already about the paper. “We are carefully considering all concerns that have been raised with us and are discussing them with the authors,” the journal said. Vinit Mahajan of Stanford University, who was the paper’s senior author, did not immediately respond to a request for comment. Another author, Alexander Bassuck of the University of Iowa, said he was traveling and unable to respond immediately.

 

The paper, titled

Unexpected mutations after CRISPR–Cas9 editing in vivo, triggered a rash of negative headlines after claiming the gene-editing tool caused widespread and unpredictable havoc in the genomes of edited mice, introducing hundreds of unintended errors.

The stock market value of Editas Medicine, Intellia Therapeutics, and CRISPR Therapeutics, which together have raised more than $1 billion to pursue CRISPR treatments, all fell sharply on the news.

CRISPR technology is widely touted as a revolutionary new means of easily altering DNA. But its promise is being exaggerated in media reports, including some that claim it will cure all genetic disease and solve the world’s food problems with superplants.

CRISPR can be programmed to cut specific sequences of DNA letters, thereby correcting or changing genes. While this versatility is what makes it powerful, if the same or similar sequence of letters appears elsewhere in the genome, that can result in an unintentional or off-target edit. Concern over the technique’s potential side effects is widely shared, even by some of its inventors.

The fear is that planned medical treatments using CRISPR could prove dangerous. A single erroneous cut could be disastrous for patients if it lands in a vital gene. Fifteen years ago, pioneering experiments in gene therapy were set back when unintentional genetic changes caused cancer in some children. Many scientists believe careful programming can eliminate most of the risk.

The ease of use of CRISPR means nearly any lab can try it. In China, some human experiments have already begun. The rush to use the method is part of what’s creating anxiety, since it makes mistakes more likely. Editas recently postponed its own planned study of CRISPR to correct an eye disease until next year.

According to Intellia, however, the authors showed “disregard” for what’s already known about CRISPR. “It is clear the authors are not experts on the CRISPR Cas9, whole genome sequencing, nor basic genetics. Their claim of ‘unexpected mutations’ clearly demonstrates their lack of scientific acumen around this topic,” the company said.

SOURCE

Gene-Editing Companies Hit Back at Paper That Criticized CRISPR

Report that suggested CRISPR is too dangerous to use as a drug was wrong, say biotech companies.

Jun 9, 2017

EmTech: Risks of Gene-Editing Drugs Need Study, Pioneer Warns

One of the inventors of gene editing says scientists should proceed cautiously before testing it in people.


Contributions to Neuronal Systems by University Professors Eve Marder and Irv Epstein at Brandeis University

Reporter: Aviva Lev-Ari, PhD, RN

Oscillators: Chemicals, Neurons and People: A Celebration of Eve Marder, Irving Epstein and the Volen Center for Complex Systems
Sunday, Nov. 17, 2019, 1 – 5:30 p.m.
Location Schwartz
Room Auditorium
Event Sponsor(S) Office of the Provost
Website www.brandeis.edu…

A celebration for new university professors Eve Marder and Irving Epstein, and the 25th anniversary of the Volen Center!

Schedule of Events

  • 1p.m. – Opening remarks: Leslie Griffith, Nancy Lurie Marks Professor of Neuroscience and Director of the Volen National Center for Complex Systems
  • 1:30 p.m. – Panel Discussion: “Oscillators: Chemicals, Neurons and People”
    • Moderator: Gina Turrigiano, Joseph Levitan Professor of Vision Science
    • Panelist: Jorge Golowasch, Professor, Department of Biological Sciences, New Jersey Institute of Technology
    • Panelist: Nancy Kopell, Professor of Mathematics, Boston University
    • Panelist: Horacio Rotstein, Professor of Mathematical Biology & Computational Neuroscience, Department of Biological Sciences, New Jersey Institute of Technology
    • Panelist: Frances Skinner, Senior Scientist, Krembil Research Institute and Professor, Division of Neurology, Department of Medicine and Department of Physiology, University of Toront
  • 2:30 p.m. – Coffee
  • 3 p.m. – Irving Epstein: “How I Wandered into an Oscillatory State”
  • 4 p.m. – Eve Marder: “The Challenges Posed by Neuronal Oscillators that are both Stable and Plastic”
  • 5 p.m. – Closing remarks: Leslie Griffith

 

Eve Marder and Irv Epstein recall the collaborations that started it all

The University Professors will lead a public symposium on Nov. 17

headshots of University Professors Eve Marder, left, and Irv EpsteinPhoto/Mike LovettUniversity professors Eve Marder ’69, Left, and Irving R. Epstein

University Professors Eve Marder ’69 and Irv Epstein will help celebrate the 25th anniversary of the Volen National Center for Complex Systems in a public symposium November 17.

Marder, the Victor and Gwendolyn Beinfield Professor of Neuroscience, and Epstein, the Henry F. Fischbach Professor of Chemistry, were named University Professors last spring in recognition of their pioneering interdisciplinary achievements. At the symposium, they will each deliver a lecture drawing on their collaborative research on oscillators. In the case of Epstein, these are oscillating chemical reactions. In Marder’s case, it is rhythmically active neurons and/or circuits.   

But some 35 years ago, before they were leaders in their fields, Epstein and Marder saw the benefit of sharing ideas. A mutual colleague noticed that the chemical reactions recorded on the chart recorder Epstein was using looked intriguingly similar to the neuronal signals Marder was recording in her research.

“It’s relatively unusual behavior for chemistry, but it’s sort of the essence of what goes on in neuronal systems,” said Epstein, who soon learned some rudiments of neuroscience from Marder and began mathematically modeling groups of neurons. For her part, Marder “got an appreciation for what interacting with theorists could bring, to help her answer the kind of questions she wanted to answer,” said Epstein.

These days, Marder’s research on small neural circuits found in lobsters and crabs is credited with revolutionizing understanding of the fundamental nature of neuronal circuit operation, including how neuromodulators control behavioral outputs and how the stability of circuits is maintained over time. She has won many top prizes in neuroscience, including the Gruber Award in Neuroscience, the Kavli Prize in Neuroscience, and the National Academy of Sciences Neuroscience Prize. In March, she will receive the Carnegie Prize in Mind and Brain Science from Carnegie Mellon University.

Epstein, a Howard Hughes Medical Institute professor, pioneered the field of chemical oscillators. “When we got into the field of oscillating reactions, there were just three that were known, and they were all discovered accidentally,” said Epstein. “We decided that if we really understood these systems, we should be able to design them.”

Although it took him several years and three unsuccessful grant applications to secure funding for his ideas, Epstein and his lab ultimately won funding, and within a few months succeeded in developing their first novel chemical oscillating reaction.

Writ large, Marder and Epstein collaboratively demonstrate that the kinds of phenomena seen in neurons are also found in chemical and physical systems. “What you learn from modeling chemical reactions can help you understand how neurons work, and vice versa,” said Epstein.

“Volen is a place where you get all kinds of collaborations,” said Marder. “One of Brandeis’ strengths is its interactivity; those early days were quite catalytic.”

 

Categories: ResearchScience and Technology

SOURCE

https://www.brandeis.edu/now/2019/november/eve-irv-volen.html


New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target

Curator: Stephen J. Williams, Ph.D.

The November 1st issue of Science highlights a series of findings which give cancer researchers some hope in finally winning a thirty year war with the discovery of drugs that target KRAS, one of the most commonly mutated oncogenes  (25% of cancers), and thought to be a major driver of tumorigenesis. Once considered an undruggable target, mainly because of the smooth surface with no obvious pockets to fit a drug in, as well as the plethora of failed attempts to develop such an inhibitor, new findings with recently developed candidates, highlighted in this article and other curated within, are finally giving hope to researchers and oncologists who have been hoping for a clinically successful inhibitor of this once considered elusive target.

 

For a great review on development of G12C KRas inhibitors please see Dr. Hobb’s and Channing Der’s review in Cell Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down

Figure 1Mechanism of Action of ARS853 showing that the inhibitors may not need bind to the active conformation of KRAS for efficacy

Abstract: Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

 

Although the development of the KRASG12C-specific inhibitor, compound 12 (Ostrem et al., 2013), was groundbreaking, subsequent studies found that the potency of compound 12 in cellular assays was limited (Lito et al., 2016, Patricelli et al., 2016). A search for more-effective analogs led to the development of ARS853 (Patricelli et al., 2016), which exhibited a 600-fold increase of its reaction rate in vitro over compound 12 and cellular activities in the low micromolar range.

 

A Summary and more in-depth curation of the Science article is given below:

After decades, progress against an ‘undruggable’ cancer target

Summary

Cancer researchers are making progress toward a goal that has eluded them for more than 30 years: shrinking tumors by shutting off a protein called KRAS that drives growth in many cancer types. A new type of drug aimed at KRAS made tumors disappear in mice and shrank tumors in lung cancer patients, two companies report in papers published this week. It’s not yet clear whether the drugs will extend patients’ lives, but the results are generating a wave of excitement. And one company, Amgen, reports an unexpected bonus: Its drug also appears to stimulate the immune system to attack tumors, suggesting it could be even more powerful if paired with widely available immunotherapy treatments.

Jocelyn Kaiser. After decades, progress against an ‘undruggable’ cancer target. Science  01 Nov 2019: Vol. 366, Issue 6465, pp. 561 DOI: 10.1126/science.366.6465.561

The article highlights the development of three inhibitors: by Wellspring Biosciences, Amgen, and Mirati Therapeutics.

Wellspring BioSciences

 

In 2013, Dr. Kevan Shokat’s lab at UCSF discovered a small molecule that could fit in the groove of the KRAS mutant G12C.  The G12C as well as the G12D is a common mutation found in KRAS in cancers. KRAS p.G12C mutations predominate in NSCLC comprising 11%–16% of lung adenocarcinomas (45%–50% of mutant KRAS is p.G12C) (Campbell et al., 2016; Jordan et al., 2017), as well as 1%–4% of pancreatic and colorectal adenocarcinomas, respectively (Bailey et al., 2016; Giannakis et al., 2016).  This inhibitor was effective in shrinking, in mouse studies conducted by Wellspring Biosciences,  implanted tumors containing this mutant KRAS.

 

See Wellspring’s news releases below:

March, 2016 – Publication – Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

February, 2016 – Publication – Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Amgen

 

Amgen press release on AMG510 Clinical Trial at ASCO 2019

 

THOUSAND OAKS, Calif., June 3, 2019 /PRNewswire/ — Amgen (NASDAQ: AMGN) today announced the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage. In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies.”

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. 

Canon, J., Rex, K., Saiki, A.Y. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019) doi:10.1038/s41586-019-1694-1

Besides blocking tumor growth, AMG510 appears to stimulate T cells to attack the tumor, thus potentially supplying a two pronged attack to the tumor, inhibiting oncogenic RAS and stimulating anti-tumor immunity.

 

Mirati Therapeutics

 

Mirati’s G12C KRAS inhibitor (MRTX849) is being investigated in a variety of solid malignancies containing the KRAS mutation.

 

For recent publication on results in lung cancer see Patricelli M.P., et al. Cancer Discov. 2016; (Published online January 6, 2016)

For more information on Mirati’s KRAS G12C inhibitor see https://www.mirati.com/pipeline/kras-g12c/

 

KRAS G12C Inhibitor (MRTX849)

Study 849-001 – Phase 1b/2 of single agent MRTX849 for solid tumors with KRAS G12C mutation

Phase 1b/2 clinical trial of single agent MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation.

See details for this study at clinicaltrials.gov

 

Additional References:

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

Lito P et al. Science. (2016)

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes MR et al. Cell. (2018)

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.

Zeng M et al. Cell Chem Biol. (2017)

Campbell, J.D., Alexandrov, A., Kim, J., Wala, J., Berger, A.H., Pedamallu, C.S., Shukla, S.A., Guo, G., Brooks, A.N., Murray, B.A., et al.; Cancer Genome Atlas Research Network (2016). Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616

Jordan, E.J., Kim, H.R., Arcila, M.E., Barron, D., Chakravarty, D., Gao, J., Chang, M.T., Ni, A., Kundra, R., Jonsson, P., et al. (2017). Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609.

Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C., et al.; Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52.

Giannakis, M., Mu, X.J., Shukla, S.A., Qian, Z.R., Cohen, O., Nishihara, R., Bahl, S., Cao, Y., Amin-Mansour, A., Yamauchi, M., et al. (2016). Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865.