Archive for the ‘Innovations in Neurophysiology & Neuropsychology’ Category

2017 Nobel Prize in Physiology or Medicine jointly to Jeffrey C. Hall (ex-Brandeis, University of Maine), Michael Rosbash (Brandeis University) and Michael W. Young (Rockefeller University in New York) for their discoveries of molecular mechanisms controlling the circadian rhythm


Curator: Aviva Lev-Ari, PhD, RN


Press Release


The Nobel Assembly at Karolinska Institutet has today decided to award

the 2017 Nobel Prize in Physiology or Medicine

jointly to

Jeffrey C. Hall, Michael Rosbash and Michael W. Young

for their discoveries of molecular mechanisms controlling the circadian rhythm

READ the Summary


Jeffrey C. Hall was born 1945 in New York, USA. He received his doctoral degree in 1971 at the University of Washington in Seattle and was a postdoctoral fellow at the California Institute of Technology in Pasadena from 1971 to 1973. He joined the faculty at Brandeis University in Waltham in 1974. In 2002, he became associated with University of Maine.

Michael Rosbash was born in 1944 in Kansas City, USA. He received his doctoral degree in 1970 at the Massachusetts Institute of Technology in Cambridge. During the following three years, he was a postdoctoral fellow at the University of Edinburgh in Scotland. Since 1974, he has been on faculty at Brandeis University in Waltham, USA.

Michael W. Young was born in 1949 in Miami, USA. He received his doctoral degree at the University of Texas in Austin in 1975. Between 1975 and 1977, he was a postdoctoral fellow at Stanford University in Palo Alto. From 1978, he has been on faculty at the Rockefeller University in New York.


Key publications

Zehring, W.A., Wheeler, D.A., Reddy, P., Konopka, R.J., Kyriacou, C.P., Rosbash, M., and Hall, J.C. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376.

Bargiello, T.A., Jackson, F.R., and Young, M.W. (1984). Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754.

Siwicki, K.K., Eastman, C., Petersen, G., Rosbash, M., and Hall, J.C. (1988). Antibodies to the period gene product of Drosophila reveal diverse tissue distribution and rhythmic changes in the visual system. Neuron 1, 141–150.

Hardin, P.E., Hall, J.C., and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540.

Liu, X., Zwiebel, L.J., Hinton, D., Benzer, S., Hall, J.C., and Rosbash, M. (1992). The period gene encodes a predominantly nuclear protein in adult Drosophila. J Neurosci 12, 2735–2744.

Vosshall, L.B., Price, J.L., Sehgal, A., Saez, L., and Young, M.W. (1994). Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263, 1606–1609.

Price, J.L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B., and Young, M.W. (1998). double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95.

Keeping time on our human physiology

The biological clock is involved in many aspects of our complex physiology. We now know that all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms. A large proportion of our genes are regulated by the biological clock and, consequently, a carefully calibrated circadian rhythm adapts our physiology to the different phases of the day (Figure 3). Since the seminal discoveries by the three laureates, circadian biology has developed into a vast and highly dynamic research field, with implications for our health and wellbeing.

The circadian clock

Figure 3. The circadian clock anticipates and adapts our physiology to the different phases of the day. Our biological clock helps to regulate sleep patterns, feeding behavior, hormone release, blood pressure, and body temperature.



Medicine Nobel awarded for work on circadian clocks, Jeffrey Hall, Michael Rosbash and Michael Young unpicked molecular workings of cells’ daily rhythms.

Ewen CallawayHeidi Ledford

02 October 2017

Other Related Research 

Charles Weitz, Ph.D., M.D.
Robert Henry Pfeiffer Professor of Neurobiology

Mammalian Circadian Clocks

Circadian clocks are molecular oscillators with ~24-hour periods that drive daily biological rhythms.  Such clocks are found in all of the major branches of life, and they likely represent ancient timekeeping systems important for predicting daily environmental cycles on our rotating planet.  In mammals, circadian clocks are present in most if not all cells. These distributed clocks control a myriad of processes, in aggregate creating coherent 24-hour programs of physiology and behavior.

A picture of how circadian clocks are built has emerged in the last two decades.  The core mechanism is a transcriptional feedback loop, wherein the protein products of several clock genes build the molecular machinery to inhibit the transcription factor responsible for their own production.  The molecular components of circadian clocks are conserved from insects to humans.

The Weitz lab uses molecular biology, biochemistry, genetics, and structural biology to investigate the mammalian circadian clock.  The focus of our efforts at present is to understand the circadian clock in terms of the integrated functions of its several multi-protein machines.  This effort is principally based on the purification of endogenous circadian clock protein complexes from mouse tissues and their biochemical analysis and structural study by cryo-electron microscopy.

Fig. 1.  Class-average electron microscopy images of the mouse nuclear PER complex, a core circadian clock machine.  It is a 1.9-MDa assembly of about thirty proteins that appears as a quasi-spherical, beaded particle of 40-nm diameter. Our current work provides an initial low-resolution view of the structural organization of endogenous clock machinery from a eukaryote.  We aim to obtain high-resolution structures.

Selected papers:

Duong HA, Robles MS, Knutti K, Weitz CJ.  A molecular mechanism for circadian clock negative feedback. Science  332, 1436-1439 (2011).

Padmanabhan K, Robles MS, Westerling T, Weitz CJ.  Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science  337, 599-602 (2012).

Kim JY, Kwak PB, Weitz CJ. Specificity in circadian clock feedback from targeted reconstitution of the NuRD co-repressor.  Mol. Cell  56, 738-748 (2014).

Aryal RA, Kwak PB, Tamayo AG, Chiu PL, Walz T, Weitz CJ.  Macromolecular assemblies of the mammalian circadian clock.  Mol. Cell  (2017, in press).


Circadian Clock’s Inner Gears

Other related articles Published in this Open Access Online Scientific Journal included the following: 

Search Keyword “Sleep” – 161 Scientific Articles

Search Keyword “Circadian” Rhythm

Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours

Curator: Gail S. Thornton, M.A.


Alteration in Reduced Glutathione level in Red Blood Cells: Role of Melatonin

Author: Shilpa Chakrabarti, PhD


Melatonin and its effect on acetylcholinesterase activity in erythrocytes

Author: S. Chakravarty, PhD


Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells

Author: Shilpa Chakravarty, PhD


Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – – Indications for Cardiovascular Chrono-therapeutics

Curator: Aviva Lev-Ari, PhD, RN


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Post-zygotic Mutations, spontaneously arising in an embryonic cell after sperm meets egg, are important players in Autism Spectrum Disorder, a HMS & BCH large study suggests

Reporter: Aviva Lev-Ari, PhD, RN


Based on their findings, they classified 7.5 percent of ASD subjects’ de novo mutations as PZMs. Of these, 83 percent had not been picked up in the original analysis of their genome sequence.

Some PZMs affected genes already known to be linked to autism or other neurodevelopmental disorders (such as SCN2AHNRNPU and SMARCA4), but sometimes affected these genes in different ways. Many other PZMs were in genes known to be active in brain development (such as KLF16 and MSANTD2) but not previously associated with ASD.

Comparing these with the genomic sequencing data (based mostly on blood DNA samples) allowed the researchers estimate the timing of the PZMs and the brain regions they affected. In the image at right, representing the prenatal brain, the region with the most “hits” was the amygdala (AMY, in red), with minor hits in the striatum (STR) and cerebellar cortex (CBC) that did not reach statistical significance.

Image Credit: Mohammed Uddin



Late-breaking mutations may play an important role in autism

Late in the Game, Post-conception mutations may play an important role in autism

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Nature Neuroscience (2017) doi:10.1038/nn.4598
Published online: 17 July 2017

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Cause of Alzheimer’s Discovered: protein SIRT6 role in DNA repair process – low levels enable DNA damage accumulation

Reporter: Aviva Lev-Ari, PhD, RN


According to lead author Dr. Deborah Toiber of the BGU Department of Life Sciences, “If a decrease in SIRT6 and lack of DNA repair is the beginning of the chain that ends in neurodegenerative diseases in seniors, then we should be focusing our research on how to maintain production of SIRT6 and avoid the DNA damage that leads to these diseases.”


Neuroprotective functions for the histone deacetylase SIRT6

Shai Kaluski Miguel Portillo, Antoine Besnard, Daniel Stein, Monica Einav, Lei Zhong, Uwe Ueberham, Thomas Arendt, Raul Mostoslavsky, Amar Sahay, Debra Toiber

Cell Reports 2017 Mar 28;18(13):3052-3062

Long noncoding RNA: noncoding and not coded.

Toiber D, Leprivier G, Rotblat B.

Cell Death Discov. 2017 Jan 9;3:16104. doi: 10.1038/cddiscovery.2016.104.

SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.

Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa S, D’Urso A, Näär AM, Kingston R, Rippe K, Mostoslavsky R.

Mol Cell. 2013 Aug 22;51(4):454-68. doi: 10.1016/j.molcel.2013.06.018.

The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.

Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, Ram O, Truelove J, Guimaraes AR, Toiber D, Cosentino C, Greenson JK, MacDonald AI, McGlynn L, Maxwell F, Edwards J, Giacosa S, Guccione E, Weissleder R, Bernstein BE, Regev A, Shiels PG, Lombard DB, Mostoslavsky R.

Cell. 2012 Dec 7;151(6):1185-99. doi: 10.1016/j.cell.2012.10.047.

Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor.

Cohen-Kfir E, Artsi H, Levin A, Abramowitz E, Bajayo A, Gurt I, Zhong L, D’Urso A, Toiber D, Mostoslavsky R, Dresner-Pollak R.

Endocrinology. 2011 Dec;152(12):4514-24. doi: 10.1210/en.2011-1128.

Characterization of nuclear sirtuins: molecular mechanisms and physiological relevance.

Toiber D, Sebastian C, Mostoslavsky R.

Handb Exp Pharmacol. 2011; 206:189-224. doi: 10.1007/978-3-642-21631-2_9.

A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development.

Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Toiber D, Kulkarni M, Wang Q, Najafi-Shoushtari SH, Mostoslavsky R, Gygi SP, Gill G, Dyson NJ, Näär AM.

Mol Cell. 2011 Jun 10;42(5):689-99. doi: 10.1016/j.molcel.2011.04.020.

Engineering DYRK1A overdosage yields Down syndrome-characteristic cortical splicing aberrations.

Toiber D, Azkona G, Ben-Ari S, Torán N, Soreq H, Dierssen M.

Neurobiol Dis. 2010 Oct;40(1):348-59. doi: 10.1016/j.nbd.2010.06.011.

Acetylcholinesterase variants in Alzheimer’s disease: from neuroprotection to programmed cell death.

Greenberg DS, Toiber D, Berson A, Soreq H.

Neurodegener Dis. 2010;7(1-3):60-3. doi: 10.1159/000285507.

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R.

Cell. 2010 Jan 22;140(2):280-93. doi: 10.1016/j.cell.2009.12.041.

Pro-apoptotic protein-protein interactions of the extended N-AChE terminus.

Toiber D, Greenberg DS, Soreq H.

J Neural Transm 2009 Nov;116(11):1435-42. doi: 10.1007/s00702-009-0249-2.

N-acetylcholinesterase-induced apoptosis in Alzheimer’s disease.

Toiber D, Berson A, Greenberg D, Melamed-Book N, Diamant S, Soreq H.

PLoS One. 2008 Sep 1;3(9):e3108. doi: 10.1371/journal.pone.0003108.

A novel isoform of acetylcholinesterase exacerbates photoreceptors death after photic stress.

Kehat R, Zemel E, Cuenca N, Evron T, Toiber D, Loewenstein A, Soreq H, Perlman I.

Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1290-7.

Modulated splicing-associated gene expression in P19 cells expressing distinct acetylcholinesterase splice variants.

Ben-Ari S*, Toiber D*, Sas AS, Soreq H, Ben-Shaul Y.

J Neurochem. 2006 Apr;97 Suppl 1:24-34.

  • ​*Equal contribution

Cellular stress reactions as putative cholinergic links in Alzheimer’s disease.

Toiber D, Soreq H.

Neurochem Res. 2005 Jun-Jul;30(6-7):909-19.

Function of alternative splicing.

Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D, Thanaraj TA, Soreq H.

Gene. 2005 Jan 3;344:1-20.

Combinatorial complexity of 5′ alternative acetylcholinesterase transcripts and protein products.

Meshorer E, Toiber D, Zurel D, Sahly I, Dori A, Cagnano E, Schreiber L, Grisaru D, Tronche F, Soreq H.

J Biol Chem. 2004 Jul 9;279(28):29740-51.


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2017 award recipients including Thomas S. Kilduff, PhD, Director, Center for Neuroscience at SRI International in Menlo Park, California


Reporter: Aviva Lev-Ari, PhD, RN

I was Director of the Business and Economic Statistics Program at SRI International in Menlo Park, California, 1985-1988.

Sleep Research Society announces 2017 award recipients

Sleep Research Society
Friday, April 28, 2017

DARIEN, IL – Several of the world’s leading sleep and circadian scientists were selected as recipients of the 2017 Sleep Research Society awards, which will be presented Monday, June 5, during the plenary session of SLEEP 2017, the 31st annual meeting of the Associated Professional Sleep Societies LLC (APSS) in Boston.

“The Sleep Research Society awards recognize individuals who have made significant and lasting contributions to sleep and circadian science,” said SRS President Sean P.A. Drummond, PhD. “I congratulate each of the recipients of the 2017 awards and appreciate all that they have done to help the SRS achieve its mission to advance sleep and circadian science.”

The 2017 SRS award recipients, who were selected by the SRS board of directors, are:

Thomas S. Kilduff, PhD
Distinguished Scientist Award for significant, original and sustained scientific contributions of a basic, clinical or theoretical nature to the sleep and circadian research field, made over an entire career
Dr. Kilduff directs the Center for Neuroscience at SRI International in Menlo Park, California. He is co-discoverer of the neuropeptide hypocretin (orexin), a key neurotransmitter in the maintenance of wakefulness. His group at SRI has identified a cortical interneuron population that is activated during sleep in proportion to homeostatic sleep drive, and their work also focuses on therapeutic development for insomnia and narcolepsy.

As the SRS Distinguished Scientist Award recipient, Dr. Kilduff also receives the honor of presenting an invited lecture at the SLEEP 2017 annual meeting. He will present the lecture, “Identifying Novel Sleep/Wake Targets: Hypocretin/Orexin, Cortical nNOS Neurons, and TAAR1,” on Tuesday, June 6, at the Hynes Convention Center in Boston.

Niels C. Rattenborg, PhD
Outstanding Scientific Achievement Award for novel and seminal discoveries of a basic, clinical or theoretical nature that have made a significant impact on the sleep field
Dr. Rattenborg is the leader of the Avian Sleep Group at the Max Planck Institute for Ornithology (MPIO) in Seewiesen, Germany. His research, published in August 2016 in the journal Nature Communications, was the first to demonstrate sleep in flying birds. Using electroencephalogram recordings of great frigatebirds flying over the ocean for up to 10 days, his team found that the birds can sleep with either one hemisphere at a time or both hemispheres simultaneously. However, while in flight they sleep for a much smaller percentage of time than they do while on land, which challenges the dominant view that large daily amounts of sleep are required to maintain adaptive performance.

Colin A. Espie, PhD, DSc
Mary A. Carskadon Outstanding Educator Award for excellence in the field of education related to sleep medicine and sleep research
Dr. Espie is professor of sleep medicine in the Nuffield Department of Clinical Neuroscience and a Fellow of Somerville College at the University of Oxford in England. He is research director of the Experimental and Clinical Sleep Medicine program within the Sleep & Circadian Neuroscience Institute and clinical director of the Oxford Online Program in Sleep Medicine.

Photos are available upon request. For more information, please contact Specialty Society Coordinator Barbara Hoeft at 630-737-9700, ext. 9321, or

About the Sleep Research Society
The Sleep Research Society (SRS) is a professional membership society that advances sleep and circadian science. The SRS provides forums for the exchange of information, establishes and maintains standards of reporting and classifies data in the field of sleep research, and collaborates with other organizations to foster scientific investigation on sleep and its disorders. The SRS also publishes the peer-reviewed, scientific journal SLEEP.


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Drugs that activate this novel stress response pathway, which they call the mitochondrial-to-cytosolic stress response, protected both nematodes and cultured human cells with Huntington´s disease from protein-folding damage.

Reporter: Aviva Lev-Ari, PhD, RN


“Maybe there is a way to use one drug to alter the mitochondrial signal and another drug to alter the communciation signal from the brain,” he said. “You would never see these two effects if you were studying protein folding in a tissue culture dish, because you don’t have the whole organism, C. elegans, in which you can look at the signals being communicated.”

Co-authors of the fat study include Hyun-Eui Kim, Ana Rodrigues Grant, Milos Simic, Rebecca Kohnz, Daniel Nomura, Jenni Durieux, Celine Riera, Melissa Sanchez, Erik Kapernick and Suzanne Wolff at UC Berkeley. The second study was co-authored by Kristen Berendzen, Jenni Durieux, Ye Tian, Hyun-eui Kim and Suzanne Wolff of UC Berkeley, in collaboration with Li-Wa Shao and Ying Liu of Peking University in Beijing.

The studies are supported by the Howard Hughes Medical Institute, National Institutes of Health, Glenn Foundation for Medical Research, and Jane Coffin Childs Memorial Fund for Medical Research.



Can some types of fat protect us from brain disease?


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Real Time Coverage of the AGENDA for Powering Precision Health (PPH) with Science, 9/26/2016, Cambridge Marriott Hotel, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

Boston Marriott Cambridge – September 26, 2016


7:00-8:15         Coffee & Registration

8:30-9:30         Opening
                         Kevin Hrusovsky
                         PPH Summit Founder and Chair, CEO Quanterix    

LIVE @ Marriott, Cambridge Aviva Lev-Ari streaming live from Powering Precision Health Summit

Apple and Steve Jobs – Returned to Apple after Pixar – Jobs has teamed up with Microsoft.

Innovations @Apple: iPhone, iPad, iPod, TV Apple,

Innovations @High Tech Industry in the World: Uber, Facebook, Robots,

Science – leads the revolution and DISRUPTIVE innovations

Medicine – Cardiology, Neurology, Oncology: INFLAMMATION markers

  • Speakers Affiliations
  • Collaborations
  • Leaders in the field
  • 5% Patient Advocacy; 10% Investors, 20% Providers, SCIENTISTS


  • lower costs on HC 40%, shift to prevention, 60% better access
  • Sick care: Japan and France HC more productive – Life expectency is 8 yrs hight than the US
  • Cancer, diabetes, In the US 31 out of 100,ooo reaches +100 yrs of age
  • Cancer Women: BRCA
  • Cancer Men: Prostate Cancer: PSA >10 – riskhigher
  • Sugar consumption in the USA  – 216 Liters/person
  • Obesity and Diabetes
  • Food addiction: Salt, fat, sugar: 2/3 of the populations are obese
  • Omega 6 overload – inflammation
  • Neurological disease:
  1. AD starts at 50 in some cases
  2. Concussions in Sports 5-10% – leading to neurodegenerative diseases
  3. Bicycle accidents at kids: no monitoring
  4. Drug as environmental factor – TOXICITY: depression, Schisophrenia, cardiac Arythmia
  • Digitizing biomarkers & Analytics: extreme specificity and sensitivity of Inflammation markers: Lowest DETECTION marker levels
  • Epigenetics: Twin Studies: Proteins – detections –
  1. Suppression Inflammation Surveilence
  2. Braf mutations – therapy
  3. Cardiology: Mediteranean diet
  4. Troponin-I: Can be seen before symptoms emerges
  5. WEARABLE DEVICES: Detection >> Prevention >> Treatment Sick Care >>> HealthCare
  6. unique opportunity to REVOLUTIONIZE MEDICINE – help patients sooner

Powering Precision Health with Science                          
Compelling technological and scientific advances are fueling a proposition that today’s healthcare can be radically improved and made more effective, accessible and economical by deploying disruptive technologies to carefully guide healthy living.  The potential for shifting our innovation focus from disease diagnostics and treatment (sick care) to early detection and disease prevention (precision healthcare) will be explored in oncology, neurology and cardiology as well as their underlying inflammation pathways.  Mobilizing this transformation requires the democratization of health assessments with digital technology, big data and wellness studies coupled with comprehensive policy and provider reconfiguration that incentivizes healthy living and “accountable” care.  Significant precision health advances are being realized in certain parts of the world and providing a credible blueprint for its potential.   Catalyzing our Precision Health initiative requires scientists, innovators, physicians, providers, regulators, investors and patient advocates to unite and build a collective vision for Precision Health.

9:30- 9:40       Introductions: Oncology Innovator Panel
                        Kevin Hrusovsky PPH Summit Founder and Chair, CEO Quanterix

 David Walt, PhD, Tufts University

Infectious disease 

  1. Single molecule array (simoa) – digitization of signals beads in Alisas – beads loaded on disc array
  2. Serum Cytokines – IL-10 and IL-8: at sub-femtomolar concentrations

Vaccination study: injection of these Cytokines: Human serum cytokine, baseline – COntrol Healthy Samples

Variation inter subjects in cytokine levels: Day One response evolution of th eImmune response

  • day reported illness
  • cytokine fluctuation
  • cytokine expression levels
  • IgG Simoa sensitivity (secondary infection); IgM (primary infection)

ONCOLOGY: Early Detection of Breast Cancer

Future technology:

  • sensitive detection for BRCA
  • 6-12% false positive in Mamography
  • Breast cancer Biomarkers: Singleplex Simeo assays
  • 8X-1000X improved sensitivity
  • Assay tested in commercial kits
  • SimOa for miRNA detection: 66 patients tested, prior to therapy: Marker 1,2,3

Individual protein assay were multiplexed

  1. Three protein Signature: PLS-DA Classification: 84% precision Health vs BRCA Stage II
  2. Sensitivity/specificity: on Biomarkers in BLOOD: 95.9% accuraccy Health vs. diagnosed BRCA

Protein Biomarkers in serum samples – cells secret, cells are invovled with mutations

  • find binding agents


Robert Weinberg, PhD,  MIT /Whitehead Institute

  •  Early detection in colonoscopy is significant
  • Breast CA – early detection  and effect on mortality: 705 OF WOMEN AT 85 have BRCA
  • response to drugs in Cancer; diagnosis of relapse
  • reduce Cancer Mortality ONLY by reduction of inscidence not early detection which – DX and TX does not change mortality – acquired somatic mutation
  • Circulating tumor Cells & CIrculating DNA – Sequencing is very limited in its applicability for BRCA
  • Genomics data integration iwth gene expression
  • Reincentivise the young  – Pharma and Diagnostics — need to fund Postdocs in Academia

John Houston, PhD
                         Formerly SVP Bristol Myers Squibb   

  • What is real and what is doable
  • Advanced   Melanoma: markable accomplishments
  • why some patients respond and why others do not – Biomarkers
  • Combination drug  therapy in Oncology
  • signature for response and non-response is critical
  • Platform to capture data in retrospect

Phil Stephens, PhD
Foundation Medicine

  1. 10,000 patients with cancer mutations
  2. biomarkers for Target Therapy
  3. combinations need be Target and immuno
  4. Bladder Cancer is example were sequencing did help
  5. RNA and DNA and beyond: making sequencing data on metastatic disease
  6. diagnostic Industry needs regulation – Some Texts are not accurate and do not assists

Discussion Moderator: Kevin   – Biomarkers other Technologies mRNA, Liquid Biopsy                                      
9:40-10:00       Keynote Address Oncology:
                         David Walt, PhD
                         Tufts University

Beyond Genomics: Disruptive Approaches to Cancer and Infectious Disease Diagnostics
We have used the single molecule array  technology to screen dozens of potential biomarkers for their ability to diagnose various diseases and predict clinical outcomes.  The single molecule array technology has been used primarily for protein detection but is also applicable to the detection of nucleic acids, including DNA, mRNA, and microRNA, without any amplification.  Ultra-high sensitivity enables the detection of both protein and nucleic acid biomarkers at concentrations previously undetectable in blood. After measuring the candidate biomarkers, we employ classification algorithms to down-select the most informative biomarkers that correlate with the clinical information.  We have employed this approach to discover serum biomarkers for monitoring individuals over extended periods for infectious disease and for early detection of breast cancer.

10:00-10:45     Oncology Innovator Panel Discussion
Revolutionizing Oncology with Disruptive Technologies to Prevent, Detect, and Treat Cancer

10:45-11:15      Coffee break

11:15-12:30     Introductions: Neurology Innovator Panel
                      Kevin Hrusovsky
                      PPH Summit Founder and Chair, CEO Quanterix

Robert Stern, PhD
Boston University, School of Medicine, BU Alzheimer’s Disease and CTE Center

Doug Cole, MD – Neurologist and investor – Flagship Ventures

  1. no powerful tools to understand AD 20 years ago,
  2. Tools are now available – in 5-20 years tools will allow for Treatment development
  3. Societal issue – leadership at University Presidents, Sports organization – grass root pressure like with No Smoking
  4. commonality needs be explore across diseases to establish syndroms shared that will enable development of disease management and treatment


Jesse M. Cedarbaum, MD – Biogen 

  1. Neurologist – worked with MS, Parkinson, AD – did not work with CTE
  2. Soccer – Contact with the ball  – effect the structure of exon, synapsis, beta protein
  3. TOOLS: Genetic risk allowing to play short or long durations
  4. Football, soccer, baseball and tennis
  5. WE NEED LARGE POOLS OF NEUROLOGICAL DISEASES IN PATIENTS – BECAUSE  there are common proteins involved and comorbidities vs present participation in clinical trials by diagnosis
  6. all studies for Parkinson are not analysed in the context of AD
  7. PCP needs tool to diagnose AD better than today the diagnosis is done
  8. in Military training vibrations that causes CTE

Tim Fox
                                               Former NFL Safety, Sports Commentator                                                  
           Peter Cronin
                                               Former NFL Linebacker                                       

11:15-11:25     Tim Fox
                       Former NFL Safety, Sports Commentator  
                       Personal Perspective on The Impact of Repeated Concussions and CTE                 

11:25-11:45      Keynote Address Neurology:
                        Robert Stern, PhD
                        Boston University, School of Medicine, BU Alzheimer’s Disease and CTE Center

Diagnosing Chronic Traumatic Encephalopathy (CTE) During Life: Potential Fluid and Neuroimaging Biomarkers                           
Chronic Traumatic Encephalopathy (CTE) is a unique neurodegenerative disease associated with a history of repetitive head impacts, including concussive and sub-concussive trauma, such as that experienced by contact sport athletes (e.g., American football players, boxers). Currently CTE can only be diagnosed through postmortem neuropathological examination demonstrating the pathognomonic lesions of perivascular phosphorylated tau (p-tau) at the depths of the cortical sulci. The ability to diagnose CTE during life is critically important to understanding the epidemiology of the disease, as well as the examination of specific risk factors (e.g., head impact exposure, genetics) and the ability to conduct clinical trials for treatment and prevention. This talk will describe recent findings in the development of possible in vivo biomarkers for CTE, including Simoa plasma total tau, plasma exosomal tau, as well as tau PET imaging.


  • $60Million NIH Grants
  • Awareness, Prevention, Management
  • Repetitive Head Impacts vs Concussions
  1. effect on neuronal functioning
  2. even one season causes cognitive, physiological changes in the brain
  3. Boxing for long time
  4. long time consecquences – Neuropathology
  5. CTE – brain trauma, leads to progressive neuro-degeneration
  • post consussion disease without symptoms of concussion
  • like AD, microtubule-Associated Protein Tau – misfolded hyperphosphorilated form of tau (p-tau): Perivascular and Depth of Solci — >>>> Spread of areas with distruction
  • Why it was not commonly observed ??
  • CTE and Public Health: Contact Sports – REPETITIVE IMPACT
  • Exposure: Severity and type of trauma
  • rest between hits
  • CTE vs PTSD, other injuries
  • Diagnose during life: develop in vivo biomarkers
  • How to create Biomarkers: DETECT Study: 100 NFL players vs Control – no sport involvement
  • All imaging were not specific to Tau detection –
  • Brain PET Tau Imaging developed: Invasive, expensive, we need a blood test
  • Tau deposits
  • Blood based Biomarkers for CTE – high sensitivity — FOllow up blood screening
  • Plasma Exosomal Tau: Exosomes are cell-derived nanovescicles: Blood, saliva, urine
  • generation of Neuronal Exosomes – extracellular space
  • Exosomes isolation required – Measure Tau in Blood
  • Quanterix_ Plasma total Tau – simoa HD-1
  • Results: plasma T-Tau – difference NFL and control – NFL – Extreme T-Tau COncentration
  • How to refine and validate Plasma T-Tau?
  • relevance to AD – modify early predict sympthoms – Using DIgital Biomarkers
  • Precision Health: Prevention and Tx of CTE:
  • Concussions & subconclusive Hits >>> PreClinical, >>> Clinical CTE not dimented >> CTE Dementia= synaptic loss

11:45-11:55        Peter Cronin
Former NFL Linebacker
Personal Perspective on The Urgent Need For Detection and Treatment of CTE

  • concussion with memory loss, mood changes,

11:55-12:30     Neurology Innovator Panel Discussion
Revolutionizing Neurology with Disruptive Technologies: Prevent, Detect and Treat

  • AD – we know what the proteins are, subtype of diseases – tools and technology
  • Advancement when a test will allow to discern



12:30-1:15       Buffet style lunch

1:15-3:30         Scientific Tracks

Track 1 – Neurology – not attended
1:15-1:40         Jessica Gill, PhD, RN                 The Role of Proteomic Biomarkers of Brain Injuries
                         National Institute of Health
1:40-2:05         Danielle Graham, PhD               Accelerating exploratory fluid biomarker assay development in
Biogen                                       Neurodegenerative Disease
2:05-2:25         Alison Joyce, PhD                      Development of a Sensitive Homebrew Simoa Assay to Detect
Pfizer Inc                                    Leucine-Rich Repeat Kinase 2 (LRRK2)
2:25–3:00         Cheryl Wellington, PhD              Toward Precision Medicine in Canada: Two vignettes
                         University of British Columbia                   
3:00-3:25         Miriam Moscovitch-Lopatin       An Ultra-Sensitive Simoa Immunoassay for Quantifying BDNF
                          MGH                                          Levels in CSF in Early Huntington Disease: A Longitudinal PRE-
CELL Biomarker Study

Track 2 – Cardiology, Oncology, Inflammation, Infectious Disease

1:30-2:00         Ralph McDade, PhD      Ex-Luminex    Myriad RBM     

Triphase approach to biomarker pattern discovery for cancer immunotherapy and autoimmune disease

  • Bi-Polar vs Depression – Diagnosis
  • nostics for Depression Kit to determine which anti-depressant drug to prescribe
  • xMAP Technology – immuno-assays
  • 96 well plate
  • robotic liquid handling – assay precision and reproducability
  • proprietary matrix blockers
  • Myriad Genetics is the Parent company
  • Validation Parameters
  • CLIA certified ELISA Amono assay
  • Analyte: TNF-alpha, IFN-gamma (no marker in RA), IL-1 beta, IL-6, IL-17A
  • DIsease state samples – RA – IL-1Betta
  • Multiplexing

2:00-2:30         John Yan                                     An Ultrasensitive Assay Format for Detecting PD/Biomarkers in
Takeda Pharmaceutical Co          Cell and Xenograft Tumor

  • ULK1 important Autophage Initiating Kinase
  • mTOR – -/+mTor treated with ULK1

2:30-3:00         Rama Boyanapalli, PhD              The long and winding road to a highly sensitive RANKL Assay
                         Shire Company

  • PROTEIN BIOMARKER RANKL AND BONE STRENGTH (bone resorption) and bone formation – Vitamin D PGE@
  • Commercial Kits available:Recombinant and Serum based
  • IMOA technology ultrasensitive
  • Antibody Selection: R&D System DUoSet human RANKL ELISA selection-
  1. Capture Ab sonjugate to beads – MOUSE MONCLONAL
  2. Detector Ab – GOAT POLYCLONAL
  3. tested 12 commercially available Abs
  4. Additional assay optimization
  5. Criteria for QUALIFYING AN ASSAY:
  • Calibration curves with varying calibrator levels – for precision studies
  • Comparing Simoa to ELISA Kit: RANKL concentration


3:00-3:30         Bonnie J. Howell, PhD                 Ultrasensitive Detection of Viral p24 Following Reactivation of
Merck                                          Latent HIV

  • HIV Biology
  • tratment
  • reservoir detection
  • HIV — affects t-Cells — AIDS
  • life cycle of HIV-1
  • Viral RNA, recapaged to virom and start another cycle of infection
  • Treatment of ANtiviral therapies (ART)
  • Persistent replication of the virus
  • HIV Vure Means?
  • Sterilization / eradicated of HIV free
  • Remission/Functional
  • get of ART for few years
  • latent vells survuve deceased activation
  • latent reservoir homeostatic proliferation
  • latent cell reactivation
  • reactivation
  • Where do they hide?
  • HIV – CNS, Gut, GI, GU, Bone marrow,
  • Estimation 1 per million resting CD4 – Quantifying the HIV Rservoir
  1. different PCR- and Culture based assays used to measure reservoir
  2. poor correlation between assay
  3. >95% provirus is defective – does not produce Vyron
  4. Quanterix SImoa digital ELISA for ultrasensitive HIV p24 protein detection
  5. serum convert stage – makes measurement of reservoir difficult
  6. Merck optimized ultrasensitive p24 immunoasay
  7. p24 detectd in gnotypically diverse HIV clinical isolates
  8. HIV-1, CPZ, HIV-2, SIV-MM
  9. Virus to kill strategy: IMMUNO-therapy – measuring protein so importent
  10. Shock and kill
  • Cells with latent HIV with
  • cells with activated HIV
  • Induction in ART-suppresant
  • T-cell activation with stimulation Suppresant p24 Increases with reservoir size in most pt.
  • PMA/Ionomycin, CD4+ T-cell Lysate as measured by TILDA
  • HDACi induces p24 Expression in ART Suppressed HIV + Patients CD4+
  • Latency-Reversing Agents
  • Treatment with Multiple doses of Vorinostat
  • Gag RNA – Assay: Baseline vs Post-VOR – HIV pt received 10 doses VOR administared in 72 hours
  • Two doses of Vorinostat
  • Dilution series


p24 digital ELISA improves assay sensitivity and selectivity

p24 detected in genotypically diverse HIV clinical isolates
3:30-4:00         Coffee Break


Cardiology and Inflammation

4:00-4:10         Introductions: Cardiology/Inflammation Panel
                         Kevin Hrusovsky
PPH Summit Founder and Chair

                                                  Dennis Ausiello, MD
                                                  Mass General HospitalEmeritus
                                                   Petr Jarolim, MD, PhD
Brigham and Women’s HospitalDana Farber Cancer Institute 
Grace Colon, PhD
 InCarda Therapeutics, Inc. and ProterixBio, Inc.                                                            

4:10-4:30        Keynote Address Cardiology/Inflammation
                        Dennis Ausiello, MD
                        Mass General HospitalEmeritus

Mobilizing Precision Health is Within Reach
The data revolution, from genetic to digital, has provided a compelling need to assess wellness and its progression to disease. This is in direct contrast to the long standing approach in medicine of episodic and symptomatic measurement of disease and its progression to morbidity and mortality. Compelling data and science are fueling a proposition that today’s healthcare can be radically improved and made more effective, accessible and economical by deploying disruptive technologies to carefully monitor and guide healthy living.  We will explore the real potential of pre-symptomatic assessment of the human condition independent of time and place, with an improvement in disease prevention. Democratizing health assessments and monitoring with mobile devices, smart phones and community drug stores is an important opportunity for enabling early detection, preventative medicine and precision health.  Establishing disruptive detection technology and sampling strategies across multiple biomarker panels is key to enabling this vision.

4:30 -5:15        Cardiology and Inflammation Innovator Panel Discussion
Revolutionizing Cardiology with Disruptive Technologies: Prevent, Detect and Treat Cardiovascular
Disorders and Diabetes

5:15-5:30         Chair Summary and Summit Close

5:30-7:30         Cocktail Reception


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Postmarketing Safety or Effectiveness Data Needed: The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, a surge in its shares seen after the approval. Eteplirsen will cost patients around $300,000 a year.


Curator: Aviva Lev-Ari, PhD, RN


On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

Factors at play for FDA Approval of eteplirsen

  1. the help of the families of young boys with Duchenne muscular dystrophy, emotional scenes from these families who have campaigned for so long
  2. an executive team from Sarepta who wouldn’t give up,

Ed Kaye, Sarepta, CEO – EK: It’s all about resilience. One of the things we’ve had is a group of people of like minds and anytime one of us gets down, somebody else is there to pick you up. One of the things we’ve always done is: Every time we’ve felt sorry for ourselves, we just need to think about those patients and what they go through. Our struggles in comparison very quickly become meaningless. You end up saying to yourself: What am I complaining about? Quit whining; get up and do your job.


3. an emerging new philosophy from some within the FDA, eteplirsen, now Exondys 51, was approved in patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping.


FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designationPriority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.


The viability of this drug approval depends  on “to be gathered” Postmarketing safety or effectiveness data, aka follow-up confirmatory trials.

Sarepta CEO Ed Kaye on FDA courage, NICE and resilience

BA: When it comes to flexibility, however, the FDA will likely not be flexible if your drug doesn’t prove the desired efficacy in your longer term postmarketing studies. If at the end of this period your drug doesn’t come through, how easy will it be for you to take this off the market? I don’t think anyone, including the FDA, wants a repeat of what happened in 2011 when Roche saw its breast cancer license for Avastin, which had been approved under an accelerated review, pulled after not being safe or effective enough in the follow-up confirmatory trials. But you face this as a possible scenario.

EK: That’s true, but one of the things we’re trying to do to mitigate that is to obviously, with our ongoing studies, prove the efficacy that the FDA wants to see. And you know, if there is a problem with one study then we’d hope to have other data that are supportive. The other thing we’re doing of course is developing that next-generation chemistry in DMD that could prove more effective, so we could certainly consider using that next-gen chemistry to take our work forward and try and make it better.

We have a lot of shots on goal to make sure we can continue to supply a product for these boys, but there is always a risk. If we can’t show efficacy in the way the FDA wants, then yes they have the option to take it off the market.

Need for follow-up confirmatory trials remains outstanding

FDA’s Postmarketing Surveillance Programs

FDA’s Regulations and Policies and Procedures for Postmarketing Surveillance Programs


Positions on Sarepta’s eteplirsen Scientific Approach

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN



Retraction Watch

Tracking retractions as a window into the scientific process

Amid controversial Sarepta approval decision, FDA head calls for key study retraction

with one comment

FDAThe head of the U.S. Food and Drug Administration (FDA) has called for the retraction of a study about a drug that the agency itself approved earlier this week, despite senior staff opposing the approval.

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as ForbesMedPage Today and others reported.

In a lengthy report Commissioner Robert Califf sent to senior FDA officials on September 16 — that was made public on September 19 — he called for the retraction of a 2013 study published in Annals of Neurologyfunded by the seller of eteplirsen, which showed beneficial effects of the drug in DMD patients. Califf writes inthe report:

The publication, now known to be misleading, should probably be retracted by its authors.

In a footnote in the report, Califf adds:

In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report.

The study was not the key factor in the agency’s decision to approve the drug, according to Steve Usdin, Washington editor of the publication BioCentury; still, Usdin told Retraction Watch he is “really surprised” at the call for retraction from top FDA staff, the first he has come across in the last two decades.

The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, which has seen a surge in its shares after the approval. Eteplirsen will cost patients around $300,000 a year.

DMD affects around 1 in 3,600 boys due to a mutation in the gene that codes for the protein dystrophin, which is important for structural stability of muscles. Eteplirsen is the first drug to treat DMD, and was initially given a green light by Janet Woodcock, director of Center for Drug Evaluation and Research, after a split vote from the FDA’s advisory committee. Despite Califf’s issues with the literature supporting the drug’s use in DMD, he did not overturn Woodcock’s decision, and the agency approved the drug this week.

In 2014, an inspection team visited the Nationwide Children’s Hospital in Columbus, Ohio, where the research was conducted, according to the report. In the report, Ellis Unger, director of the Office of Drug Evaluation I in FDA’s Center for Drug Evaluation, notes:

We found the analytical procedures to be typical of an academic research center, seemingly appropriate for what was simply an exploratory phase 1/2 study, but not suitable for an adequate and well controlled study aimed to serve as the basis for a regulatory action. The procedures and controls that one would expect to see in support of a phase 3 registrational trial were not in evidence.

Specifically, Unger describes concerns about blinding during the experiments, and notes:

The immunohistochemistry images were only faintly stained, and had been read by a single technician using an older liquid crystal display (LCD) computer monitor in a windowed room where lighting was not controlled. (The technician had to suspend reading around mid-day, when brighter light began to fill the room and reading became impossible.)

Unger adds:

Having uncovered numerous technical and operational shortcomings in Columbus, our team worked collaboratively with the applicant to develop improved methods for a reassessment of the stored images…This re-analysis, along with the study published in 2013, provides an instructive example of an investigation with extraordinary results that could not be verified.

Luciana Borio, acting chief scientist at the FDA, is cited in the report saying:

I would be remiss if I did not note that the sponsor has exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. Not only was there a misleading published article with respect to the results of Study–which has never been retracted—but Sarepta also issued a press release relying on the misleading article and its findings…As determined by the review team, and as acknowledged by Dr. Woodcock, the article’s scientific findings—with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints—do not withstand proper and objective analyses of the data. Sarepta’s misleading communications led to unrealistic expectations and hope for DMD patients and their families.

Here’s how Sarepta describes the study’s findings in the press release Borio refers to:

Published study results showed that once-weekly treatment with eteplirsen resulted in a statistically significant increase from baseline in novel dystrophin, the protein that is lacking in patients with DMD. In addition, eteplirsen-treated patients evaluable on the 6-minute walk test (6MWT) demonstrated stabilization in walking ability compared to a placebo/delayed-treatment cohort. Eteplirsen was well tolerated in the study with no clinically significant treatment-related adverse events. These data will form the basis of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for eteplirsen planned for the first half of 2014.

However, Usdin noted that the drug’s approval and the study are two independent events, adding that the 2013 study just “got the ball rolling” for eteplirsen, and the FDA conducted many of its own experiments analyses, as detailed in the newly released report.

Jerry Mendell, the corresponding author of the study (which has so far been cited 118 times, according to Thomson Reuters Web of Science) from Ohio State University in Columbus, told us the allegations were “unfounded” and said the data are “valid.” Therefore, he added, he will not be approaching the journal for a retraction, noting that the FDA asked him hundreds of questions about the paper and audited the trials.

Clifford Saper, the editor-in-chief of Annals of Neurology from the Beth Israel Deaconess Medical Center (which is part of Harvard Medical School), said in an email:

It takes more than a call by a politician for retraction of a paper. It takes actual evidence.

He added:

If the FDA commissioner has, or knows of someone who has, evidence for an error in a paper published in Annals of Neurology, I encourage him to send that evidence to me and a copy to the authors of the article, for their reply. At that point we will engage in a scientific review of the evidence and make appropriate responses.

Linda Lowes, sixth author of the present study, is the last author of a 2016 study in Physical Therapy that was retracted months after publication. Its notice reads:

This article has been retracted by the author due to unintentional deviations in the use of the described modified technique to assess plagiocephaly in the study participants, such that the use of the modified technique cannot be defended for the stated purpose in this population at this time.

Califf was a cardiologist at Duke University during the high-profile scandal of researcher Anil Potti at Duke, which led to more than 10 retractions, settled lawsuits, and medical board reprimands. In 2015, he told TheTriangle Business Journal:

I wish I had gotten myself more involved earlier…There were systems that were not adequate, as we stated. … That was a tough one, I think, for the whole institution.

We’ve contacted the FDA for comment, and will update the post with anything else we learn.


Correction 9/21/16 10:44 p.m. eastern: When originally published, this post incorrectly reported that Califf was part of an inspection team that visited the Nationwide Children’s Hospital in Ohio, and attributed quotes from Ellis Unger to Califf. We have made appropriate corrections, and apologize for the error.

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Related Resources on FDA’s Policies on Drugs:

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