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Posts Tagged ‘Harvard Medical School’


Use of 3D Bioprinting for Development of Toxicity Prediction Models

Curator: Stephen J. Williams, PhD

SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019

The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”

Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.

A synopsis of the schedule and related works from the speakers is given below:

 

8:40 AM–9:20 AM Overview and Challenges of Bioprinting
Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM Putting 3D Bioprinting to the Use of Tissue Model Fabrication
Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM Break
10:20 AM–11:00 AM Uses of Bioprinted Liver Tissue in Drug Development
Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening
Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD

Sharon Presnell, Ph.D. President, Amnion Foundation

Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.

A few of her relevant publications:

Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis

Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner.  This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:

Please click here for Web based and PDF version of interview

Some highlights of the interview include

  • Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
  • Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
  • Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems”  however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
  • Additional challenges include the scalability of such systems and making such system accessible in a larger way
  1. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology

Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of BioprintingHeliyonBMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.

Some relevant references from Dr. Zhang

Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.

Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.

 

Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies.

Wu H, Lei P, Liu G, Shrike Zhang Y, Yang J, Zhang L, Xie J, Niu W, Liu H, Ruan J, Hu Y, Zhang C.

Sci Rep. 2017 Mar 23;7(1):359. doi: 10.1038/s41598-017-00506-z.

 

 

A liver-on-a-chip platform with bioprinted hepatic spheroids.

Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.

Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.

 

Marc Ferrer, National Center for Advancing Translational Sciences, NIH

Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.

At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.

Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.

 

Some relevant references for Dr. Ferrer

Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function.

Derr K, Zou J, Luo K, Song MJ, Sittampalam GS, Zhou C, Michael S, Ferrer M, Derr P.

Tissue Eng Part C Methods. 2019 Apr 22. doi: 10.1089/ten.TEC.2018.0318. [Epub ahead of print]

 

Determination of the Elasticity Modulus of 3D-Printed Octet-Truss Structures for Use in Porous Prosthesis Implants.

Bagheri A, Buj-Corral I, Ferrer M, Pastor MM, Roure F.

Materials (Basel). 2018 Nov 29;11(12). pii: E2420. doi: 10.3390/ma11122420.

 

Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.

Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.

SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.

 

A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models.

Boutin ME, Voss TC, Titus SA, Cruz-Gutierrez K, Michael S, Ferrer M.

Sci Rep. 2018 Jul 24;8(1):11135. doi: 10.1038/s41598-018-29169-0.

A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.

SLAS Discov. 2017 Jun;22(5):494-506. doi: 10.1177/2472555216687082. Epub 2017 Jan 31.

 

Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

Lal-Nag M, McGee L, Titus SA, Brimacombe K, Michael S, Sittampalam G, Ferrer M.

SLAS Discov. 2017 Jun;22(5):537-546. doi: 10.1177/2472555217698818. Epub 2017 Mar 15.

 

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions.

Fu J, Fernandez D, Ferrer M, Titus SA, Buehler E, Lal-Nag MA.

SLAS Discov. 2017 Jun;22(5):525-536. doi: 10.1177/2472555217696796. Epub 2017 Mar 9.

 

Other Articles on 3D Bioprinting on this Open Access Journal include:

Global Technology Conferences on 3D BioPrinting 2015 – 2016

3D Medical BioPrinting Technology Reporting by Irina Robu, PhD – a forthcoming Article in “Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices”

Bio-Inks and 3D BioPrinting

New Scaffold-Free 3D Bioprinting Method Available to Researchers

Gene Editing for Gene Therapies with 3D BioPrinting

 

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Atul Gawande: Physician, Surgeon and Writer

Curator: Aviva Lev Ari, PhD, RN

Atul Gawande: Surgeon, Writer, Epidemiologist, Health Outcomes Researcher

Eric J. Topol, MD: Editor’s Note on The Young Surgeon

Atul Gawande, MD, MPH, wears many hats, including that of a surgeon, researcher, journalist, and author. In this segment of Medscape One-on-One, Dr. Gawande talks with Eric J. Topol, MD, about what inspires him, his plans for the future, and why he’s secretly a frustrated rock singer.

WATCH the INTERVIEW of December 06, 2013 on VIDEO

Eric Topol on Medscape > Medscape One-on-One

Atul Gawande on the Secrets of a Puzzle-Filled Career

, Atul Gawande, MD, MPH

http://www.medscape.com/viewarticle/815241?nlid=41903_2105&src=wnl_edit_medp_card&uac=93761AJ&spon=2

Atul Gawande is a surgeon, writer, and public health researcher. He practices general and endocrine surgery at Brigham and Women’s Hospital in Boston, and is Director of Ariadne Labs, a joint center for health systems innovation. He is Professor in the Department of Health Policy and Management at the Harvard School of Public Health and Professor of Surgery at Harvard Medical School. And he is also co-founder and chairman of Lifebox, an international not-for-profit implementing systems and technologies to reduce surgical deaths globally.

Soon after he began his residency, his friend Jacob Weisberg, editor of Slate, asked him to contribute to the online magazine. His pieces on the life of a surgical resident caught the eye of The New Yorker which published several pieces by him before making him a staff writer in 1998.

A June 2009 New Yorker essay by Gawande[12] compared the health care of two towns in Texas to show why health care was more expensive in one town compared to the other. Using the town of McAllen, Texas, as an example, it argued that a revenue-maximizing businessman-like culture (which can provide substantial amounts of unnecessary care) was an important factor in driving up costs, unlike a culture of low-cost high-quality care as provided by the Mayo Clinic and other efficient health systems.

Ezra Klein of The Washington Post called it “the best article you’ll see this year on American health care—why it’s so expensive, why it’s so poor, [and] what can be done.”[13] The article was cited by Pres. Barack Obama during Obama’s attempt to get health care reform legislation passed by the United States Congress. The article “made waves”[14] and according to Senator Ron Wyden, the article “affected [Obama’s] thinking dramatically”, and was shown to a group of senators by Obama, who said, “This is what we’ve got to fix.”[15] After reading the New Yorkerarticle, Warren Buffett‘s long-time business partner Charlie Mungermailed a check to Gawande in the amount of $20,000 as a thank you to Dr. Gawande for providing something so socially useful.[16] Gawande donated the $20,000 to the Brigham and Women’s Hospital Center for Surgery and Public Health.[17]

In addition to his popular writing, Gawande has published studies on topics including military surgery techniques and error in medicine, included in the New England Journal of Medicine. He is also the director of theWorld Health Organization‘s Global Patient Safety Challenge. His essays have appeared in The Best American Essays 2003, The Best American Science Writing 2002, The Best American Science Writing 2009 andBest American Science and Nature Writing 2011.

He has been a staff writer for the New Yorker magazine since 1998. He has written three bestselling books: Complications, which was a finalist for the National Book Award in 2002; Better, which was selected as one of the ten best books of 2007 by Amazon.com; and The Checklist Manifesto. He has won two National Magazine Awards, AcademyHealth’s Impact Award for highest research impact on health care, a MacArthur Fellowship, and he has been named one of the world’s hundred most influential thinkers by Foreign Policy and TIME.

ADDITIONAL LINKS

http://gawande.com/about

RESEARCH by Dr. Atul Gawande

Tsai TC, Joynt KE, Orav EJ, Gawande AA, Jha AK. Variation in Surgical-Readmission Rates and Quality of Hospital CareNew England Journal of Medicine Published online September, 2013.

Funk LM, Conley DM, Berry WR, Gawande AA. Hospital Management Practices and Availability of Surgery in Sub-Saharan Africa: A Pilot Study of Three HospitalsWorld Journal of Surgery Published online August, 2013.

Nehs MA, Ruan DT, Gawande AA, Moore FD Jr, Cho NL.Bilateral neck exploration decreases operative time compared to minimally invasive parathyroidectomy in patients with discordant imagingWorld Journal of SurgeryPublished online July, 2013.

Joynt KE, Gawande AA, Orav EJ, Jha AK.Contribution of Preventable Acute Care Spending to Total Spending for High-Cost Medicare PatientsJAMA Published online June 24, 2013.

McCrum ML, Joynt KE, Orav EJ, Gawande AA, Jha AK.Mortality for Publicly Reported Conditions and Overall Hospital Mortality RatesJAMA Published online June 24, 2013.

Spector JM, Lashoher A, Agrawal P, Lemer C, Dziekan G, Bahl R, Mathai M, Merialdi M, Berry W, and Gawande AA.Designing the WHO Safe Childbirth Checklist Program to Improve Quality of Care at ChildbirthInternational Journal of Gynecology & Obstetrics Published online June 5, 2013.

Barnet CS, Arriaga AF, Hepner DL, Correll DJ, Gawande AA, Bader AM. Surgery at the End of LifeThe Journal of the American Society of Anathesiologists Published online June, 2013.

Bowman KG, Jovic G, Rangel S, Berry WR, Gawande AA.Pediatric emergency and essential surgical care in Zambian hospitals: A nationwide studyJournal of Pediatric Surgery Published online June, 2013.

Rice-Townsend S, Gawande A, Lipsitz S, Rangel SJ.Relationship between unplanned readmission and total treatment-related hospital days following management of complicated appendicitis at 31 children’s hospitalsJournal of Pediatric Surgery Published online June, 2013.

Eappen S, Lane BH, Rosenberg B, Lipsitz SA, Sadoff D, Matheson D, Berry WR, Lester M, Gawande AA. Relationship Between Occurrence of Surgical Complications and Hospital FinancesJAMA April 17, 2013;309:1599-1606.

Kwok AC, Funk LM, Baltaga R, Lipsitz SR, Merry AF, Dziekan G, Ciobanu G, Berry WR, Gawande AA. Implementation of the World Health Organization Surgical Safety Checklist, Including Introduction of Pulse Oximetry, in a Resource-Limited SettingAnnals of Surgery April 4, 2013.

Molina G, Funk LM, Rodriguez V, Lipsitz SR, Gawande A.Evaluation of Surgical Care in El Salvador Using the WHO Surgical Vital StatisticsWorld Journal of Surgery Published online, March 2013.

Arriaga AF, Bader AM, Wong JM, Lipsitz SR, Berry WR, Ziewacz JE, Hepner DL, Boorman DJ, Pozner CN, Smink DS, Gawande AA. Simulation-Based Trial of Surgical-Crisis ChecklistsNew England Journal Of Medicine 2013;368:246-53.

Spector JM, Reisman J, Lipsitz S, Desai P, and Gawande AA.Access to Essential Technologies for Safe Childbirth: A Survey of Health Workers in Africa and AsiaBMC Pregnancy and Childbirth February 20, 2013;13:43-49.

Wong JM, Panchmatia JR, Ziewacz JE, Bader AM, Dunn IF, Laws ER, Gawande AA. Patterns in neurosurgical adverse events: intracranial neoplasm surgeryJournal of Neurosurgery 2012;33(5):E16.

Wong JM, Ziewacz JE, Ho AL, Panchmatia JR, Kim AH, Bader AM, Thompson BG, Du R, Gawande AA. Patterns in neurosurgical adverse events: open cerebrovascular neurosurgeryJournal of Neurosurgery 2012;33(5):E15.

GO TO the First article

http://gawande.com/articles

FIRST ARTICLE

Nanevicz TM, Prince MR, Gawande AA, Puliafito CA. Excimer laser ablation of the lens.Archives of Ophthalmology. 1986;104(12):1825-9.

Selected References

  1. Dr Atul Gawande – 2014 Reith Lectures. BBC Radio 4. Retrieved October 18, 2014.
  2. Atul Gawande on Twitter
  3.  Atul Gawande: ‘If I haven’t succeeded in making you itchy, disgusted or cry I haven’t done my job’, The Guardian
  4.  Former Policymaker Opts for Hands-On Health Care – International Herald Tribune
  5. MacArthur Fellows 2006. Atul Gawand
  6. “Atul Gawande Named MacArthur Fellow”. Press release by Brigham and Women’s Hospital. September 19, 2006. Retrieved February 25, 2010
  7. “Q&A with Atul Gawande, Part 2” H&HN. June 30, 2011. Retrieved July 7, 2011.
  8. Why Do Doctors Fail?The Reith Lectures, Dr Atul Gawande: The Future of Medicine Episode 1 of 4, BBC
  9. “Atul Gawande: surgeon, health policy scholar, and writer”.Harvard Magazine. Sep–Oct 2009
  10. Bates, D. W.; Gawande, A. A. (2003). “Improving Safety with Information Technology”. New England Journal of Medicine 348(25): 2526. doi:10.1056/NEJMsa020847.
  11. Weiser, T. G.; Regenbogen, S. E.; Thompson, K. D.; Haynes, A. B.; Lipsitz, S. R.; Berry, W. R.; Gawande, A. A. (2008). “An estimation of the global volume of surgery: A modelling strategy based on available data”. The Lancet 372 (9633): 139.doi:10.1016/S0140-6736(08)60878-8.
  12. Gawande, A. A.; Studdert, D. M.; Orav, E. J.; Brennan, T. A.; Zinner, M. J. (2003). “Risk factors for retained instruments and sponges after surgery”. New England Journal of Medicine 348 (3): 229–35. doi:10.1056/NEJMsa021721. PMID 12529464.
  13. Gawande, A. A.; Thomas, E. J.; Zinner, M. J.; Brennan, T. A. (1999). “The incidence and nature of surgical adverse events in Colorado and Utah in 1992”. Surgery 126 (1): 66–75.doi:10.1067/msy.1999.98664. PMID 10418594.

Dr. Atul Gawande’s Articles in the New Yorker

States of Health
New Yorker
October 7, 2013

Slow Ideas
New Yorker
July 29, 2013

Why Boston’s Hospitals Were Ready
New Yorker
April 17, 2013

Big Med
New Yorker
August 6, 2012

Something Wicked This Way Comes
New Yorker
June 28, 2012

Failure and Rescue
New Yorker
June 4, 2012

200 Years of Surgery
New England Journal of Medicine
May 2, 2012
Documentary

Personal Best
The New Yorker
September 26, 2011

A Townie Speaks
Ohio University Commencement Address
June 11, 2011

Cowboys and Pit Crews
2011 Harvard Medical School Commencement Address
May 26, 2011

The Hot Spotters
The New Yorker
January 17, 2011

Seeing Spots
The New Yorker News Desk
January 27, 2011

Letting Go
The New Yorker
July 26, 2010
(citations)

Now What?
The New Yorker
Apr 5, 2010

Testing, Testing 
The New Yorker
Dec 14, 2009

The Cost Conundrum Redux
The New Yorker
News Desk Blog
Jun 23, 2009

The Cost Conundrum 
The New Yorker
Jun 1, 2009

Hellhole
The New Yorker
Mar 30, 2009

Getting There from Here 
The New Yorker
Jan 26, 2009

The Itch 
The New Yorker
Jun 30, 2008

A Lifesaving Checklist 
The New York Times
Dec 30, 2007

The Checklist 
The New Yorker
Dec 10, 2007

Sick and Twisted
The New Yorker
Jul 23, 2007

The Obama Health Plan
The New York Times
May 31, 2007

A Katrina Health Care System 
The New York Times
May 26, 2007

Rethinking Old Age
The New York Times
May 24, 2007

Let’s Talk About Sex 
The New York Times
May 19, 2007

Doctors, Drugs, and the Poor 
The New York Times
May 17, 2007

Bad Medicine, Sneaking In 
The New York Times
May 12, 2007

Curing the System
The New York Times
May 10, 2007

Can This Patient Be Saved? 
The New York Times
May 5, 2007

The Power of Negative Thinking
The New York Times
May 1, 2007

The Way We Age Now 
The New Yorker
Apr 30, 2007

The Score
The New Yorker
Oct 9, 2006

The Malpractice Mess
The New Yorker
Nov 14, 2005

Piecework
The New Yorker
Apr 4, 2005

The Bell Curve
The New Yorker
Dec 6, 2004

The Mop-Up
The New Yorker
Jan 12, 2004

Desperate Measures
The New Yorker
May 5, 2003

Cold comfort
The New Yorker
Mar 11, 2002

The learning curve
The New Yorker
Jan 28, 2002

The man who couldn’t stop eating
The New Yorker
Jul 9, 2001

Final cut
The New Yorker
Mar 19, 2001

Crimson tide

The New Yorker

Feb 12, 2001

Under suspicion
The New Yorker
Jan 8, 2001

When good doctors go bad
The New Yorker
Aug 7, 2000

GO TO the First article

FIRST ARTICLE
The Gist: Persian Gulf War Syndrome
The Gist
Slate
Oct 25, 1996
BOOKS

THE CHECKLIST MANIFESTO

A New York Times Bestseller and an Amazon Best Book of the Month: December 2009

http://gawande.com/the-checklist-manifesto

BETTER
One of Amazon.com’s 10 Best Books of 2007
Complications
“Essential Reading For Anyone Involved In Medicine”–Amazon.com –  2002

Overkill
An avalanche of unnecessary medical care is harming patients physically and financially. What can we do about it?
Annals of Health Care MAY 11, 2015
http://www.newyorker.com/magazine/2015/05/11/overkill-atul-gawande

It was lunchtime before my afternoon surgery clinic, which meant that I was at my desk, eating a ham-and-cheese sandwich and clicking through medical articles. Among those which caught my eye: a British case report on the first 3-D-printed hip implanted in a human being, a Canadian analysis of the rising volume of emergency-room visits by children who have ingested magnets, and a Colorado study finding that the percentage of fatal motor-vehicle accidents involving marijuana had doubled since its commercial distribution became legal. The one that got me thinking, however, was a study of more than a million Medicare patients. It suggested that a huge proportion had received care that was simply a waste.

tests, drugs, and operations

Millions of Americans get tests, drugs, and operations that won’t make them better, may cause harm, and cost billions.
Our medical systems are broken. Doctors are capable of extraordinary (and expensive) treatments, but they are losing their core focus: actually treating people. Doctor and writer Atul Gawande suggests we take a step back and look at new ways to do medicine — with fewer cowboys and more pit crews.

Being Mortal: Medicine and What Matters in the End – Deckle Edge, Oct 7, 2014

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Why Does Cytotoxic Chemotherapy Still Remain a Mainstay in Many Chemotherapeutic Regimens? [6.1.1]

 

Reporter: Stephen J. Williams, Ph.D.

At the 2015 AACR National Meeting, Drs. Anthony Letai, Dr. Michael Hermann, Dr. Rene Bernards, and Dr. Guido Kroemer gave The 2015 Stanley J. Korsmeyer Memorial Symposium: Cell Death and Cancer Therapy: Why Has Conventional Chemotherapy Been So Successful?

Cytotoxic chemotherapy, for which the mechanism of action is centered on the ability of the drug to kill a cell by either necrosis, genotoxic, apoptosis, or autophagy mechanisms rather than just halting cell growth, is still, in this era of personalized and cytostatic therapies, is still a mainstay in many treatment regimens for a majority of cancers. Treatment regimens such as MOPP (mechlorethamine, Oncovin, procarbazine, prednisone), CMF (cyclophosphamide, methotrexate, 5-fluorouracil) , carboplatin with taxol, and even with personalized therapies, which usually are given in combination with a cytotoxic agent. However treatment regimens containing these cytotoxic chemotherapeutics show some of the best survival rates. The abstract for the Symposium is given below:

In this current era of precisely targeted therapies and –omics technologies, it is often forgotten that no medical therapy has cured, and continues to cure, more people of cancer than conventional chemotherapy. Notwithstanding its superior performance across many cancer types, the mechanism of the therapeutic index of conventional agents, largely targeting ubiquitous elements like DNA and microtubules, is poorly understood. The textbook explanation of conventional chemotherapy’s working by killing supposedly rapidly dividing cancer cells lacks clinical evidence and flies in the face of many obvious clinical counter-examples. In the session,m the speakers will describe how conventional cytotoxic chemotherapy preferentially kills cancer cells. Moreover, they will describe how clinical response to chemotherapy might be better predicted.

This post is presented as the speakers titles and a brief curation of their papers related to the subject matter.

Anthony G. Letai, Dana-Farber Cancer Institute, Boston, MA. Conventional chemotherapy cures people by exploiting apoptotic priming.

Conventional chemotherapy has an amazing track record that is often under-appreciated in today’s world of genomics and targeted pathway inhibitors. Conventional chemotherapy is responsible for curing millions of cancer patients over the past 5 decades. That is, millions of patients have presented to their doctors with an otherwise fatal malignancy, were given a finite course of chemotherapy (largely DNA and microtubule perturbing agents) and had their cancer eradicated, never to return. Perhaps as remarkable as the magnitude of the achievement of conventional chemotherapy is the magnitude of our ignorance of why it should ever work, and why it works far better in some tumors than in others. Textbook explanations rely on concepts of differential proliferation rates in cancers that are incompletely supported in the clinical literature. Successful chemotherapy treatments usually kill via the mitochondrial pathway of apoptosis. We have found that simple functional measurements of the pre-treatment state of the tumor cell can be rapidly made with BH3 profiling. These measurements demonstrate that a major, if not the major, reason for a therapeutic index for cancer chemotherapy is that chemo-sensitive cancer cells are simply more primed for apoptosis than normal cells. Moreover, apoptotic priming can be measured to make clinical predictions regarding quality of response on an individualized basis. Enhancing pretreatment priming of cancer cells with selectively acting targeted agents is a promising strategy to extend the demonstrated curative power of conventional chemotherapy.

Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher, Anthony Letai

Cancer Discov. Author manuscript; available in PMC 2015 March 1.

Published in final edited form as: Cancer Discov. 2014 September; 4(9): 1074–1087. Published online 2014 July 3. doi: 10.1158/2159-8290.CD-14-0353

 

High Mitochondrial Priming Sensitizes hESCs to DNA-Damage-Induced Apoptosis

Julia C. Liu, Xiao Guan, Jeremy A. Ryan, Ana G. Rivera, Caroline Mock, Vishesh Agrawal, Anthony Letai, Paul H. Lerou, Galit Lahav

Cell Stem Cell. Author manuscript; available in PMC 2014 October 3.

Published in final edited form as: Cell Stem Cell. 2013 October 3; 13(4): 483–491. Published online 2013 August 15. doi: 10.1016/j.stem.2013.07.018

Correction in: volume 13 on page 634

 

Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction

James D. Orth, Alexander Loewer, Galit Lahav, Timothy J. Mitchison

Mol Biol Cell. 2012 February 15; 23(4): 567–576. doi: 10.1091/mbc.E11-09-0781

 

Stem cells: Balancing resistance and sensitivity to DNA damage

Julia C. Liu, Paul H. Lerou, Galit Lahav

Trends Cell Biol. Author manuscript; available in PMC 2015 May 1.

Published in final edited form as: Trends Cell Biol. 2014 May; 24(5): 268–274. Published online 2014 April 7. doi: 10.1016/j.tcb.2014.03.002

 

Michael T. Hermann, MIT Koch Institute for Integrated Cancer Research, Cambridge MA. Using convential chemotherapy as targeted agents.

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas

Harsh Vardhan Jain, Alan Richardson, Michael Meyer-Hermann, Helen M. Byrne

PLoS One. 2014; 9(1): e81582. Published online 2014 January 6.

 

Rene Bernards, Netherlands Cancer Institute, Amsterdam, The Netherlands. Identifying responders to chemotherapies through functional genomics

MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling

Sidong Huang, Michael Hölzel, Theo Knijnenburg, Andreas Schlicker, Paul Roepman, Ultan McDermott, Mathew Garnett, Wipawadee Grernrum, Chong Sun, Anirudh Prahallad, Floris H. Groenendijk, Lorenza Mittempergher, Wouter Nijkamp, Jacques Neefjes, Ramon Salazar, Peter ten Dijke, Hidetaka Uramoto, Fumihiro Tanaka, Roderick L. Beijersbergen, Lodewyk F.A. Wessels, René Bernards

Cell. Author manuscript; available in PMC 2013 June 5.

Published in final edited form as: Cell. 2012 November 21; 151(5): 937–950.

 

Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

Floris H Groenendijk, Wouter W Mellema, Eline van der Burg, Eva Schut, Michael Hauptmann, Hugo M Horlings, Stefan M Willems, Michel M van den Heuvel, Jos Jonkers, Egbert F Smit, René Bernards

Int J Cancer. 2015 March 15; 136(6): 1434–1444. Published online 2014 August 1.

 

The Corepressor CTBP2 Is a Coactivator of Retinoic Acid Receptor/Retinoid X Receptor in Retinoic Acid Signaling

Prashanth Kumar Bajpe, Guus J. J. E. Heynen, Lorenza Mittempergher, Wipawadee Grernrum, Iris A. de Rink, Wouter Nijkamp, Roderick L. Beijersbergen, Rene Bernards, Sidong Huang

Mol Cell Biol. 2013 August; 33(16): 3343–3353. doi: 10.1128/MCB.01213-12

 

Using Functional Genetics to Understand Breast Cancer Biology

Alan Ashworth, Rene Bernards

Cold Spring Harb Perspect Biol. 2010 July; 2(7): a003327. doi: 10.1101/cshperspect.a003327

 

 

SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer

Andreas I Papadakis, Chong Sun, Theo A Knijnenburg, Yibo Xue, Wipawadee Grernrum, Michael Hölzel, Wouter Nijkamp, Lodewyk FA Wessels, Roderick L Beijersbergen, Rene Bernards, Sidong Huang

Cell Res. 2015 April; 25(4): 445–458. Published online 2015 February 6.

 

The Good, the Bad, and the Ugly: in search of gold standards for assessing functional genetic screen quality

Bastiaan Evers, Rene Bernards, Roderick L Beijersbergen

Mol Syst Biol. 2014 July; 10(7): 738. Published online 2014 July 1.

 

An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer

Katherine Stemke-Hale, Ana Maria Gonzalez-Angulo, Ana Lluch, Richard M. Neve, Wen-Lin Kuo, Michael Davies, Mark Carey, Zhi Hu, Yinghui Guan, Aysegul Sahin, W. Fraser Symmans, Lajos Pusztai, Laura K. Nolden, Hugo Horlings, Katrien Berns, Mien-Chie Hung, Marc J. van de Vijver, Vicente Valero, Joe W. Gray, René Bernards, Gordon B. Mills, Bryan T. Hennessy

Cancer Res. Author manuscript; available in PMC 2009 August 1.

Published in final edited form as: Cancer Res. 2008 August 1; 68(15): 6084–6091.

 

CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies

Brigitte C. Widemann, Maria T. Acosta, Sylvia Ammoun, Allan J. Belzberg, Andre Bernards, Jaishri Blakeley, Antony Bretscher, Karen Cichowski, D. Wade Clapp, Eva Dombi, Gareth D. Evans, Rosalie Ferner, Cristina Fernandez-Valle, Michael J. Fisher, Marco Giovannini, David H. Gutmann, C. Oliver Hanemann, Robert Hennigan, Susan Huson, David Ingram, Joe Kissil, Bruce R. Korf, Eric Legius, Roger J. Packer, Andrea I McClatchey, Frank McCormick, Kathryn North, Minja Pehrsson, Scott R. Plotkin, Vijaya Ramesh, Nancy Ratner, Susann Schirmer, Larry Sherman, Elizabeth Schorry, David Stevenson, Douglas R. Stewart, Nicole Ullrich, Annette C. Bakker, Helen Morrison

Am J Med Genet A. Author manuscript; available in PMC 2014 September 1.

Published in final edited form as: Am J Med Genet A. 2014 March; 0(3): 563–578. Published

 

Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort

Ben S. Wittner, Dennis C. Sgroi, Paula D. Ryan, Tako J. Bruinsma, Annuska M. Glas, Anitha Male, Sonika Dahiya, Karleen Habin, Rene Bernards, Daniel A. Haber, Laura J. Van’t Veer, Sridhar Ramaswamy Clin Cancer Res. Author manuscript; available in PMC 2011 May 7.

 

Guido Kroemer, INSERM U848- Institute Gustave-Roussy, Villejuif, France. A hallmark of successful cancer therapies: Reinstatement of immunosurvelliance.

Immune infiltrate in cancer Gautier Stoll, Laurence Zitvogel, Guido Kroemer

Aging (Albany NY) 2015 June; 7(6): 358–359. Published online 2015 June 25.

 

Corrigendum: “Combinatorial Strategies for the Induction of Immunogenic Cell Death”

Lucillia Bezu, Ligia C. Gomes-da-Silva, Heleen Dewitte, Karine Breckpot, Jitka Fucikova, Radek Spisek, Lorenzo Galluzzi, Oliver Kepp, Guido Kroemer

Front Immunol. 2015; 6: 275. Published online 2015 June 1. doi: 10.3389/fimmu.2015.00275

Corrects: Front Immunol. 2015; 6: 187.

 

Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies

Gautier Stoll, Gabriela Bindea, Bernhard Mlecnik, Jérôme Galon, Laurence Zitvogel, Guido Kroemer

Oncotarget. 2015 May 20; 6(14): 11894–11909. Published online 2015 May 19

 

Other posts on this site on Cytotoxicity and Cancer include

Novel Approaches to Cancer Therapy [11.1]

Misfolded Proteins – from Little Villains to Little Helpers… Against Cancer

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

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

Good and Bad News Reported for Ovarian Cancer Therapy

 

 

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Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle


Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle

Reporter: Stephen J Williams, PhD

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series C: e-Books on Cancer & Oncology

Volume One: Cancer Biology and Genomics for Disease Diagnosis

CancerandOncologyseriesCcoverwhich is now available on Amazon Kindle at                          http://www.amazon.com/dp/B013RVYR2K.

This e-Book is a comprehensive review of recent Original Research on Cancer & Genomics including related opportunities for Targeted Therapy written by Experts, Authors, Writers. This ebook highlights some of the recent trends and discoveries in cancer research and cancer treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about, diagnose, and treat cancer. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon. All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations
  • on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Cancer Biology and Genomics for Disease Diagnosis

Preface

Introduction  The evolution of cancer therapy and cancer research: How we got here?

Part I. Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerge

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

Part II. Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development

Chapter 6:  Treatment Strategies

Chapter 7:  Personalized Medicine and Targeted Therapy

Part III.Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Chapter 8:  Diagnosis                                     

Chapter 9:  Detection

Chapter 10:  Biomarkers

Chapter 11:  Imaging In Cancer

Chapter 12: Nanotechnology Imparts New Advances in Cancer Treatment, Detection, &  Imaging                                 

Epilogue by Larry H. Bernstein, MD, FACP: Envisioning New Insights in Cancer Translational Biology

 

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Notes from Opening Plenary Session – The Genome and Beyond from the 2015 AACR Meeting in Philadelphia PA; Sunday April 19, 2015

 

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 9:30 AM Opening Plenary Session

The Genome and Beyond

Session Chairperson: Lewis C. Cantley, Ph.D.

Speakers: Michael R. Stratton, Tyler Jacks, Stephen B. Baylin, Robert D. Schreiber, Williams R. Sellers

  1. A) Insights From Cancer Genomes: Michael R. Stratton, Ph.D.; Director of the Wellcome Trust Sanger Institute
  • How do we correlate mutations with causative factors of carcinogenesis and exposure?
  • Cancer was thought as a disease of somatic mutations
  • UV skin exposure – see C>T transversion in TP53 while tobacco exposure and lung cancer see more C>A transversion; Is it possible to determine EXPOSURE SIGNATURES?
  • Use a method called non negative matrix factorization (like face pattern recognition but a mutation pattern recognition)
  • Performed sequence analysis producing 12,000 mutation catalogs with 8,000 somatic mutation signatures
  • Found more mutations than expected; some mutation signatures found in all cancers, while some signatures in half of cancers, and some signatures not found in cancer
  • For example found 3 mutation signatures in ovarian cancer but 13 for breast cancers (80,000 mutations); his signatures are actually spectrums of mutations
  • kataegis: defined as localized hypermutation; an example is a signature he found related to AID/APOBEC family (involved in IgG variability); kataegis is more prone in hematologic cancers than solid cancers
  • recurrent tumors show a difference in mutation signatures than primary tumor before drug treatment

 

  1. B) Engineering Cancer Genomes: Tyler Jacks, Ph.D.; Director, Koch Institute for Integrative Cancer Research
  • Cancer GEM’s (genetically engineered mouse models of cancer) had moved from transgenics to defined oncogenes
  • Observation that p53 -/- mice develop spontaneous tumors (lymphomas)
  • then GEMs moved to Cre/Lox systems to generate mice with deletions however these tumor models require lots of animals, much time to create, expensive to keep;
  • figured can use CRSPR/Cas9 as rapid, inexpensive way to generate engineered mice and tumor models
  • he used CRSPR/Cas9 vectors targeting PTEN to introduce PTEN mutations in-vivo to hepatocytes; when they also introduced p53 mutations produced hemangiosarcomas; took ONLY THREE months to produce detectable tumors
  • also produced liver tumors by using CRSPR/Cas9 to introduce gain of function mutation in β-catenin

 

See an article describing this study by MIT News “A New Way To Model Cancer: New gene-editing technique allows scientists to more rapidly study the role of mutations in tumor development.”

The original research article can be found in the August 6, 2014 issue of Nature[1]

And see also on the Jacks Lab site under Research

  1. C) Above the Genome; The Epigenome and its Biology: Stephen B. Baylin
  • Baylin feels epigenetic therapy could be used for cancer cell reprogramming
  • Interplay between Histone (Movers) and epigenetic marks (Writers, Readers) important for developing epigenetic therapy
  • Difference between stem cells and cancer: cancer keeps multiple methylation marks whereas stem cells either keep one on or turn off marks in lineage
  • Corepressor drugs are a new exciting class in chemotherapeutic development
  • (Histone Demythylase {LSD1} inhibitors in clinical trials)
  • Bromodomain (Brd4) enhancers in clinical trials
  1. D) Using Genomes to Personalize Immunotherapy: Robert D. Schreiber, Ph.D.,
  • The three “E’s” of cancer immunoediting: Elimination, Equilibrium, and Escape
  • First evidence for immunoediting came from mice that were immunocompetent resistant to 3 methylcholanthrene (3mca)-induced tumorigenesis but RAG2 -/- form 3mca-induced tumors
  • RAG2-/- unedited (retain immunogenicity); tumors rejected by wild type mice
  • Edited tumors (aren’t immunogenic) led to tolerization of tumors
  • Can use genomic studies to identify mutant proteins which could be cancer specific immunoepitopes
  • MHC (major histocompatibility complex) tetramers: can develop vaccines against epitope and personalize therapy but only good as checkpoint block (anti-PD1 and anti CTLA4) but personalized vaccines can increase therapeutic window so don’t need to start PD1 therapy right away
  • For more details see references Schreiker 2011 Science and Shankaran 2001 in Nature
  1. E) Report on the Melanoma Keynote 006 Trial comparing pembrolizumab and ipilimumab (PD1 inhibitors)

Results of this trial were published the morning of the meeting in the New England Journal of Medicine and can be found here.

A few notes:

From the paper: The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.)

And from Twitter:

Robert Cade, PharmD @VTOncologyPharm

KEYNOTE-006 was presented at this week’s #AACR15 conference. Pembrolizumab blew away ipilimumab as 1st-line therapy for metastatic melanoma.

2:02 PM – 21 Apr 2015

Jeb Keiper @JebKeiper

KEYNOTE-006 at #AACR15 has pembro HR 0.63 in OS over ipi. Issue is ipi is dosed only 4 times over 2 years (per label) vs Q2W for pembro. Hmm

11:55 AM – 19 Apr 2015

OncLive.com @OncLive

Dr Antoni Ribas presenting data from KEYNOTE-006 at #AACR15 – Read more about the findings, at http://ow.ly/LMG6T 

11:25 AM – 19 Apr 2015

Joe @GantosJ

$MRK on 03/24 KEYNOTE-006 vs Yervoy Ph3 stopped early for meeting goals of PFS, OS & full data @ #AACR15 now back to weekend & family

9:05 AM – 19 Apr 2015

Kristen Slangerup @medwritekristen

Keytruda OS benefit over Yervoy in frontline #melanoma $MRK stops Ph3 early & data to come @ #AACR15 #immunotherapy http://yhoo.it/1EYwwq8 

2:40 PM – 26 Mar 2015

Yahoo Finance @YahooFinance

Merck’s Pivotal KEYNOTE-006 Study in First-Line Treatment for…

Merck , known as MSD outside the United States and Canada, today announced that the randomized, pivotal Phase 3 study investigating KEYTRUDA® compared to ipilimumab in the first-line treatment of…

View on web

 

Stephen J Williams @StephenJWillia2

Progression free survival better for pembrolzumab over ipilimumab by 2.5 months #AACR15 @Pharma_BI #Cancer #Immunotherapy

11:56 AM – 19 Apr 2015

 

Stephen J Williams @StephenJWillia2

Melanoma Keynote 006 trial PD1 inhibitor #Immunotherapy 80% responders after 1 year @Pharma_BI #AACR15

 

References

  1. Xue W, Chen S, Yin H, Tammela T, Papagiannakopoulos T, Joshi NS, Cai W, Yang G, Bronson R, Crowley DG et al: CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature 2014, 514(7522):380-384.

 

Other related articles on Cancer Genomics and Social Media Coverage were published in this Open Access Online Scientific Journal, include the following:

Cancer Biology and Genomics for Disease Diagnosis

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

Methodology for Conference Coverage using Social Media: 2014 MassBio Annual Meeting 4/3 – 4/4 2014, Royal Sonesta Hotel, Cambridge, MA

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

2013 American Cancer Research Association Award for Outstanding Achievement in Chemistry in Cancer Research: Professor Alexander Levitzki

Genomics and Epigenetics: Genetic Errors and Methodologies – Cancer and Other Diseases

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Genomics and Metabolomics Advances in Cancer

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

 

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Notes On Tumor Heterogeneity: Targets and Mechanisms, from the 2015 AACR Meeting in Philadelphia PA

Reporter: Stephen J. Williams, Ph.D.

The following contain notes from the Sunday April 19, 2015 AACR Meeting (Pennsylvania Convention Center, Philadelphia PA) 1 PM Major Symposium Session on Tumor Heterogeneity: Targets and Mechanism chaired by Dr. Charles Swanton.

Speakers included: Mark J. Smyth, Charles Swanton, René H. Medema, and Catherine J. Wu

Tumor heterogeneity is a common feature of many malignancies, especially the solid tumors and can drive the evolution and adaptation of the growing tumor, complicating therapy and resulting in therapeutic failure, including resistance. This session at AACR described the mechanisms, both genetic and epigenetic, which precipitate intratumor heterogeneity and how mutational processes and chromosomal instability may impact the tumor progression and the origin of driver events during tumor evolution. Finally the session examined possible therapeutic strategies to take advantage of, and overcome, tumor evolution. The session was chaired by Dr. Charles Swanton. For a more complete description of his work, tumor heterogeneity, and an interview on this site please click on the link below:

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

and

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

 

Notes from Charles Swanton, Cancer Research UK; Identifying Drivers of Cancer Diversity

Dr. Swanton’s lecture focused on data from two recent papers from his lab by Franseco Favero and Nicholas McGranahan:

  1. Glioblastoma adaptation Traced Through Decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome (Annals of Oncology, 2015)[1]

This paper described the longitudinal Whole Genome Sequencing (WGS) study of a 35 year old female whose primary glioblastoma (GBM) was followed through temozolomide treatment and ultimately recurrence.

  • In 2008 patient was diagnosed with primary GBM (three biopsies of unrelated sites were Grade II and Grade IV; temozolomide therapy for three years then relapse in 2011
  • WGS of 2 areas of primary tumor showed extensive mutational and copy number heterogeneity; was able to identify clonal TP53 mutations and clonal IDH1 mutation in primary tumor with different patterns of clonality based on grade
  • Amplifications on chromosome 4 and 12 (PDGFRA, KIT, CDK4)
  • After three years of temozolomide multiple translocations found in chromosome 4 and 12 (6 translocations)
  • Clonal IDH1 R132H mutation in primary tumor only at very low frequency in recurrent tumor
  • The WGS on recurrent tumor (sequencing took ONLY 9 days from tumor resection to sequence results) showed mutation cluster in KIT/PDGFRA.PI3K.mTOR axis so patient treated with imatinib
  • However despite rapid sequencing and a personalized approach based on WGS results, tumor progressed and patient died shortly: tumor evolution is HUGE hurdle for personalized medicine

As Dr. Swanton stated:

“we are underestimating the frequency of polyclonal evolution”

  1. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution (Science Translational Medicine, 2015)[2]
  • analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions.
  • identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches.
  • > 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal
  • Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling

Branched chain can converge on single resistance mechanism; clonal resistance (for example to PI3K inhibitors can get multiple PTEN mutations in various metastases

Targeting Tumor Heterogeneity

  • Identify high risk occupants (have to know case history)
  • Mutational landscape interferes with anti-PD1 therapies
  • Low frequency mutations affect outcome

Notes from Dr. Catherine J. Wu, Dana-Farber Cancer Institute: The evolutionary landscape of CLL: Therapeutic implications

  • Clonal evolution a key feature of cancer progression and relapse
  • Hypothesis: evolutionary dynamics (heterogeneity) in chronic lymphocytic leukemia (CLL) contributes to variations in response and disease “tempo”
  • Used whole exome sequencing and copy number data of 149 CLL cases to discover early and late cancer drivers: clonal patterns (Landau et. al, Cell 2013); some drivers correspond to poor clinical outcome
  • Methylation studies suggest that there is epigenetic heterogeneity which may drive CLL clonal evolution
  • Developing methodology to integrate WES to determine mutations with immunogenic potential for development of personalized immunotherapy for CLL and other malignancies

References

  1. Favero F, McGranahan N, Salm M, Birkbak NJ, Sanborn JZ, Benz SC, Becq J, Peden JF, Kingsbury Z, Grocok RJ et al: Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2015, 26(5):880-887.
  2. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C: Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Science translational medicine 2015, 7(283):283ra254.

 

Other related articles on Tumor Heterogeneity were published in this Open Access Online Scientific Journal, include the following:

 

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

CANCER COMPLEXITY: Heterogeneity in Tumor Progression and Drug Response – 2015 Annual Symposium @Koch Institute for Integrative Cancer Research at MIT – W34, 6/12/2015 9:00 AM EDT – 4:30 PM EDT

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Tumor Imaging and Targeting: Predicting Tumor Response to Treatment: Where we stand?

Mitochondrial Isocitrate Dehydrogenase and Variants

War on Cancer Needs to Refocus to Stay Ahead of Disease Says Cancer Expert

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Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Reporter/Curator: Stephen J. Williams, Ph.D.

 

UPDATED on 9/6/2017

On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).

Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Abstract
Article
References
Citing Articles (22)
Metrics

BACKGROUND

Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.

METHODS

We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.

RESULTS

We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).

CONCLUSIONS

ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

 

Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date

Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).

Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.

There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”

The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.

View Mark Terry’s article here on Biospace.com.

“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”

The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.

Curation of Population Genomic Sequencing Programs/Corporate Partnerships

Click on “Curation of genomic studies” below for full Table

Curation of genomic studies
Study Partners Population Enrolled Disease areas Analysis
Icelandic Genome

Project

deCODE/Amgen Icelandic 2,636 Variants related to: Alzheimer’s, cardiovascular, diabetes WES + EMR; blood samples
Genome Sequencing Study Geisinger Health System/Regeneron Northeast PA, USA 100,000 Variants related to hypercholestemia, autism, obesity, other diseases WES +EMR +MyCode;

– Blood samples

The 100,000 Genomes Project National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche,   Takeda, UCB Rare disorders population UK Starting to recruit 100,000 Initially rare diseases, cancer, infectious diseases WES of blood, saliva and tissue samples

Ref paper

Saudi Human Genome Program 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies General population Saudi Arabia 20,000 genomes over three years First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation Whole genome sequence blood samples + EMR
Genome of the Netherlands (GoNL) Consortium consortium of the UMCG,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. Families in Netherlands 769 Variants, SNV, indels, deletions from apparently healthy individuals, family trios Whole genome NGS of whole blood no EMR

Ref paper in Nat. Genetics

Ref paper describing project

Faroese FarGen project Privately funded Faroe Islands Faroese population 50,000 Small population allows for family analysis Combine NGS with EMR and genealogy reports
Personal Genome Project Canada $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard Canadian Health System Goal: 100,000 ? just started no defined analysis goals yet Whole exome and medical records
Singapore Sequencing Malay Project (SSMP) Singapore Genome Variation Project

Singapore Pharmacogenomics Project

Malaysian 100 healthy Malays from Singapore Pop. Health Study Variant analysis Deep whole genome sequencing
GenomeDenmark four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). 150 complete genomes; first 30 published in Nature Comm. ? See link
Neuromics Consortium University of Tübingen and 18 academic and industrial partners (see link for description) European and Australian 1,100 patients with neuro-

degenerative and neuro-

muscular disease

Moved from SNP to whole exome analysis Whole Exome, RNASeq

References

  1. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
  2. Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
  3. Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
  4. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

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

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

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

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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