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Novel delivery system in REMfresh mimics the way the body naturally releases and maintains melatonin over a 7-hour period

Real-world evidence confirms previous clinical data on improved sleep duration and sleep quality with REMfresh

Reporter: Gail S. Thornton, M.A.

Chronic disorders of sleep and wakefulness affect an estimated 50-70 million adults in the United States.[i] The cumulative long term effects of sleep loss have been associated with a wide range of damaging health consequences, including obesity, diabetes, impaired glucose tolerance, cardiovascular disease, hypertension, anxiety and depression.[ii]In terms of preventing health consequences, sleeping 6-8 hours per night consistently may provide optimal health outcomes.[iii]

This month, real-world evidence from two recently completed patient-reported outcomes (PRO) studies presented at SLEEP 2019 in San Antonio, Texas, confirms previous clinical data demonstrating statistically significant improvements in sleep onset, sleep duration, sleep maintenance and sleep quality with REMfresh®, the first and only continuous release and absorption melatonin (CRA-Melatonin™). This data supports and reinforces the benefits of REMfresh, which is designed to give patients up to 7 hours of sleep support. PRO studies of this kind, which more closely address real-world patient experience, are increasingly being recognized by regulatory authorities and academia in evaluating new therapies.

The REMfresh Duration Validation (REMVAL) study provides further evidence of a correlative relationship between the 7-hour pharmacokinetic profile observed in the earlier clinical study, REM Absorption Kinetics Trial (REMAKT), and the hypnotic effects of REMfresh, observed in subsequent studies, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance, sleep quality and patient satisfaction. This latest study further validates the findings of past studies that have been presented and undergone peer review at major sleep conferences:  

  • REMfresh Patient Reported Outcomes DURation (REMDUR), the first, 500-patient, PRO study of this sleep brand, presented at the annual meeting for sleep specialists, SLEEP 2018, which demonstrated that more than 77 percent of patients achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh (p<.0001)[iv], and
  • REM Absorption Kinetics Trial (REMAKT), a pharmacokinetic study presented at SLEEP 2017 and 2018, which demonstrated that REMfresh mimics the body’s own seven-hour Mesa-Wave® release profile, a natural pattern of melatonin blood levels during a normal night’s sleep cycle.[v] 

An additional PRO subset study, part of REMVAL, called the REMfresh Short Sleep Cohort Assessment (REMSS), assessed improvements in sleep duration and sleep maintenance among 311 patients with morbid or extreme short sleep duration of 4 hours or less.

These two PRO studies (REMVAL and REMSS) were presented at SLEEP 2019, the 33rd Annual Meeting of the Associated Professional Sleep Societies (APSS), which is a joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society, held in San Antonio, Texas, from June 8-12.

“These latest findings provide further confirmation of the potential for nonprescription REMfresh to help address the public health issue of  the cumulative effects of sleep loss,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery as well as Sleep Medicine, Founder and Principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC. “Based on a novel Ion Powered Pump® (IPP®) delivery system that provides a pharmacokinetic (PK) profile that more closely aligns with the body’s own natural sleep pattern, REMfresh has demonstrated once again promising results and high levels of satisfaction in a real-world population of patients who have had chronic difficulties sleeping, providing up to seven hours of sleep support,” said Dr. Brodner.

Topline findings of these studies are as follows:

  • The 1,116 patient-reported outcomes (PRO) study, REMfresh Duration Validation (REMVAL), found that after taking 99 percent ultra-pure, continuous release and absorption melatonin (REMfresh®, CRA-melatonin™), the majority (78.8 percent) of patients involved achieved a sleep duration of greater than or equal to 6 hours (p<.0001), while more than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001).  Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking CRA-melatonin for their sleep issues (p<.0001).
  • REMVAL provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong observed hypnotic effects of CRA-melatonin, as demonstrated by improvements in sleep onset, sleep duration, sleep maintenance and sleep quality.
  • A second PRO subset study, REMfresh Short Sleep Cohort Assessment (REMSS), involving 311 patients who reported sleeping four hours or less nightly from the REMVAL study, found that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001).
  • REMVAL and REMSS also provides validation of the results from the previously peer-reviewed and presented clinical study, REMAKT, which demonstrated that REMfresh mimics the body’s own 7-hour Mesa Wave®, a natural pattern of melatonin blood levels during a normal night’s sleep cycle and the 500-patient, peer-reviewed and presented  REMfresh® Patient Reported Outcomes DURation (REMDUR) study, that demonstrated statistically significant improvements in sleep onset, sleep maintenance and sleep quality.

REMVAL Study Describes Improvements in Sleep Duration and Sleep Quality

The poster entitled, “Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality,” reported findings provides further real-world evidence of a correlative relationship between the originally observed 7-hour pharmacokinetic profile in the REM Absorption Kinetics Trial (REMAKT) and the strong hypnotic effects of CRA-melatonin observed in subsequent studies and may offer a new low-dose, drug-free alternative to prescription hypnotics to treat chronic sleep disturbances.

The 1,116-patient REMVAL study was designed to obtain clinically relevant information about patients’ past usage of melatonin and non-melatonin sleep aids, sleep patterns prior to taking CRA-melatonin, sleep duration before and after taking CRA-melatonin, frequency of CRA-melatonin usage, improvement in sleep onset, sleep maintenance and sleep quality after taking CRA-melatonin, and overall satisfaction with CRA-melatonin.

In the study, patients with sleep disturbances in the general population received a sample of REMfresh from their physicians and were invited to complete a 13-question online survey. After taking REMfresh, the majority (78.8 percent) of patients achieved a sleep duration of greater than or equal to 6 hours (p<.0001). More than 91 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Of the 30.7 percent of patients (342 in total), who reported never having taken other brands of melatonin, 99.4 percent indicated they were likely or very likely to continue taking REMfresh for their sleep issues (p<.0001).

REMSS Study Shows Improvement in Patients with Chronic, Extreme Short Sleep

The poster entitled, “Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study,” highlighted findings from the REMfresh Short Sleep Cohort Assessment (REMSS), involving a cohort of 311 patients from the REMVAL study who reported sleeping four hours or less nightly. This cohort analysis was designed to obtain clinically relevant information from these patients experiencing morbid short sleep disturbances, including sleep patterns and melatonin usage before taking REMfresh, sleep duration before and after taking REMfresh, improvement in sleep onset, sleep maintenance and sleep quality after taking REMfresh, and overall product satisfaction.

Data from this cohort show that 95.8 percent of patients who previously experienced daily, morbid short sleep duration of less than or equal to 4 hours reported an improvement in sleep duration (p<.0001), including more than 46 percent who achieved a sleep duration of greater than or equal to 6 hours (p<.0001). This increase from less than or equal to 4 hours to greater than or equal to 6 hours represents a major sleep duration upgrade in this group facing morbid sleep disturbances. More than 93 percent of patients reported a major/moderate improvement in sleep onset, sleep maintenance and sleep quality (p<.0001). Ninety-nine percent of the patients suffering with morbid short sleep (27.2 percent of whom had never previously tried a melatonin brand) reported that they were very likely or likely to continue using CRA-melatonin. These results provide real-world evidence that CRA-melatonin with its extended 7-hour pharmacokinetic  plateau time and benign safety-profile may be a practical baseline therapy to improve sleep duration and other key sleep parameters, including, sleep maintenance and sleep quality in this group of patients who have a higher risk of all-cause mortality.[vi]˒[vii]˒[viii]˒[ix]

Statistics & Data Corporation (SDC), a top-tier clinical data services provider, has independently determined that the number of participants in the study provides adequate power (>90%) to detect even small improvements in sleep outcomes. This high power, or probability of seeing statistically significant results if CRA-melatonin is truly working to improve sleep outcomes, applies to the overall study population (REMVAL) as well as the cohort of short sleepers (REMSS). SDC has subsequently independently validated the statistical results achieved, (e.g., p-values and statistical language).

The Increasing Appreciation of PRO Studies to Include Patient Experience 
Increasingly, there is an appreciation by the U.S. Congress, regulatory authorities and academia, of the substantive value that real-world patient experience brings to assessing new therapies. In addition to the traditional randomized, placebo-controlled trial studies, regulatory authorities are now incorporating the patient perspective in their decision making, including PRO studies. A PRO study is a measurement based on a report that comes directly from the patient about the status or change in their health condition and without amendment or interpretation of the patient’s response by health-care intermediaries. PRO measures can be used to capture a patient’s everyday experience outside of the clinician’s office, and the effects of a treatment on the patient’s activities of daily living.[x]˒[xi]Together, clinical measures and PRO measures can provide a fuller picture of patient benefit.

REMAKT Clinical Study Presented at Past Medical Meetings 
Pharmacokinetic data on REMfresh® was peer-reviewed and then presented in 2017 and 2018 at SLEEP, the Annual Meeting of the Associated Professional Sleep Societies LLC (APSS), and a joint meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS). 

The study, REM Absorption Kinetics Trial (REMAKT), was a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin). The study found that melatonin levels with REMfresh exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and then had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours. 

Analysis presented at SLEEP 2017 and 2018 showed that REMfresh builds upon the body of evidence from prolonged-release melatonin (PR-M), approved by the European Medicines Agency (EMA) in 2007 as a prescription drug for insomnia, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep onset and quality of life in patients aged 55 years and older compared with placebo.[xv] REMfresh was designed to overcome the challenges of continuous release and absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave®, a flat-topped hill with steep sides).[xvi] There was the desirable fast time to reach the sleep threshold level, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave may help to improve sleep maintenance and morning alertness. 

Over 5,000 healthcare practitioners are estimated to have used REMfresh for their patients and about 320,000 patients are estimated to have purchased and used REMfresh. The continuing, rapid acceptance of REMfresh by patients is observable by several markers, including rapid sales growth and availability among major drug retailers.

###

Data Presented at SLEEP 2019 Poster Sessions:

Monday, June 10, 2019, 5:15-7:15pm

  • (Abstract 0398, Poster Board #135) Improvement in Sleep Duration and Maintenance with Ion Powered Continuous Release and Absorption Melatonin in a Cohort of Patients with Chronic Short Sleep Duration: Results from a Patient-Reported Outcomes Study
    • David J. Seiden, M.D., FAASM,  David Brodner, M.D., Syed M. Shah, Ph.D.
  • (Abstract 0399, Poster Board #136) Observed Hypnotic Effects with a Continuous-Release Ion Powered Pump Melatonin Delivery System: Self-Reported Patient Outcomes Study Results Demonstrating Improvement in Sleep Duration and Quality
    • David J. Brodner, M.D., David J. Seiden, M.D. FAASM, Syed M. Shah, Ph.D.

The abstracts are published in an online supplement of the journal, Sleep, which is available at https://sleepmeeting.org/wp-content/uploads/2019/04/SLEEP_42_S1-Website-Final.pdf.

REFERENCES:


[i] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617

[ii] Cappuccio, F.P., D’Elia, L., Strazzullo, P., & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systemic review and meta-analysis of prospective studies. Sleep, 33(5):585-592.

[iii] Watson, N.F., Badr, M.S., Belenky, G., et al. (2015). Joint Consensus Statement of the American Academy of Sleep  Medicine and Sleep Research Society on the Recommended Amount of Sleep for the Healthy Adult, Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(6); 591-592.

[iv] Seiden,D.J., Brodner, D.C., & Shah, S.M. (2018, June 2-6). Improvement in Sleep Maintenance and Sleep Quality with Ion-Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study (Abstract #0419). Poster presented at SLEEP 2018, Baltimore, Maryland.

[v] Brodner, D.C., Shah, S.M. (2017, June 3-7). REM Absorption Kinetics Trial: A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation versus a Same Strength Immediate-Release Formulation in Healthy Adults (Abstract #0396). Poster presented at: SLEEP 2017, Boston, Massachusetts.

[vi] Knutsen, K.L., Turek,, F.W., Patel, S.R., et al (2006). The u-shaped association between sleep and health: the 2 peaks do not mean the same thing.  Comment on Patel, SR, et al. Sleep, 29(7): 878-879.

[vii] Lubetkin,, E.I., & Haomiao, J. (2018). Burden of disease due to sleep duration and sleep problems in the elderly. Sleep Health, 4; 182-187.

[viii] Hafner M, et al. (2017). Why sleep matters-the economic costs of insufficient sleep: A cross-country comparative analysis, Rand Quarterly.

[ix] Ikehara, S, et al. (2009). Association of Sleep Duration with Mortality  from Cardiovascular Disease and other Causes for Japanese Men and Women: the JACC Study. Sleep, 32(3); 295-301.

[x] U.S. Food and Drug Administration. Real World Evidence. Retrieved from https://www.fda.gov/scienceresearch/specialtopics/realworldevidence/default.htm

[xi] U.S. Food and Drug Administration. 21st Century Cures Act. Retrieved from https://www.fda.gov/regulatoryinformation/lawsenforcedbyfda/significantamendmentstothefdcact/21stcenturycuresact/default.htm.

[xii] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617

[xiii] Cappuccio, F.P., D’Elia, L., Strazzullo, P., & Miller, M.A. (2010). Sleep duration and all-cause mortality: A systemic review and meta-analysis of prospective studies. Sleep, 33(5):585-592.

[xiv] Watson, N.F., Badr, M.S., Belenky, G., et al. (2015). Joint Consensus Statement of the American Academy of Sleep  Medicine and Sleep Research Society on the Recommended Amount of Sleep for the Healthy Adult, Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(6); 591-592.

[xv] European Medicines Agency.(2007). Assessment Report for CIRCADIN.

[xvi] Brodner, D.C. & Shah, S.M. (2017, June 3-7). A Continuous Release Ion Powered Pump Melatonin Delivery System that Overcomes Challenges of Release and Absorption in the Intestines (Abstract #0385). Poster presented at: SLEEP 2017,  Boston, Massachusetts.

SOURCES:

https://finance.yahoo.com/news/significant-real-world-evidence-confirms-123000247.html

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

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

2018

https://pharmaceuticalintelligence.com/2018/06/10/patient-reported-outcomes-study-presented-at-sleep-2018-provides-confirmatory-real-world-evidence-of-the-previously-presented-7-hour-action-of-remfresh-the-first-continuous-release-and-absorp/

2017

https://pharmaceuticalintelligence.com/2017/10/02/2017-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/

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

https://pharmaceuticalintelligence.com/2016/03/16/sleep-science/

2013

https://pharmaceuticalintelligence.com/2013/03/09/melatonin-and-its-effect-on-acetylcholinesterase-activity-in-erythrocytes/

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Pfizer buys out Array BioPharma for $11.4 Billion to beef up its oncology offerings

Reporter: Stephen J. Williams, PhD

As reported in FiercePharma.com:

by Angus Liu |

Three years after purchasing Medivation for $14.3 billion, Pfizer is back with another hefty M&A deal. And once again, it’s betting on oncology.

In the first big M&A deal under new CEO Albert Bourla, Pfizer has agreed to buy oncology specialist Array BioPharma for a total value of about $11.4 billion, the two companies unveiled Monday. The $48-per-share offer represents a premium of about 62% to Array stock’s closing price on Friday.

With the acquisition, Pfizer will beef up its oncology offerings with two marketed drugs, MEK inhibitor Mektovi and BRAF inhibitor Braftovi, which are approved as a combo treatment for melanoma and recently turned up positive results in colon cancer.

The buy will enhance the Pfizer innovative drug business’ “long-term growth trajectory,” Bourla said in a Monday statement, dubbing Mektovi-Braftovi “a potentially industry-leading franchise for colorectal cancer.”

RELATED: Array’s ‘extremely compelling’ new colon cancer data spark blockbuster talk

In a recent interim analysis of a trial in BRAF-mutant metastatic colorectal cancer, the pair, used in tandem with Eli Lilly and Merck KGaA’s Erbitux, produced a benefit in 26% of patients, versus the 2% that chemotherapy helped. The combo also showed it could reduce the risk of death by 48%. SVB Leerink analysts at that time called the data “extremely compelling.”

Right now, one in every three new patients with mutated metastatic melanoma is getting the combo, despite its third-to-market behind combos from Roche and Novartis, Andy Schmeltz, Pfizer’s oncology global president, said during an investor briefing on Monday.

It is being studied in more than 30 clinical studies across several solid tumor indications. Moving forward, Pfizer believes the combo could potentially be used in the adjuvant setting to prevent tumor recurrence after surgery, Pfizer’s chief scientific officer, Mikael Dolsten, said on the call. The company is also keen to know how it could be paired up with Pfizer’s own investigational PD-1, he said, as the combo is already in studies with other PD-1/L1s.

But as Pfizer execs have previously said, the company’s current business development strategy no longer centers on adding revenues “now or soon,” but rather on strengthening Pfizer’s pipeline with earlier-stage assets. And Array can help there, too.

“We are very excited by Array’s impressive track record of successfully discovering and developing innovative small-molecules and targeted cancer therapies,” Dolsten said in a statement.

On top of Mektovi and Braftovi, Array has a long list of out-licensed drugs that could generate big royalties over time. For example, Vitrakvi, the first drug to get an initial FDA approval in tumors with a particular molecular feature regardless of their location, was initially licensed to Loxo Oncology—which was itself snapped up by Eli Lilly for $8 billion—but was taken over by pipeline-hungry Bayer. There are other drugs licensed to the likes of AstraZeneca, Roche, Celgene, Ono Pharmaceutical and Seattle Genetics, among others.

Those drugs are also a manifestation of Array’s strong research capabilities. To keep those Array scientists doing what they do best, Pfizer is keeping a 100-person team in Colorado as a standalone research unit alongside Pfizer’s existing hubs, Schmeltz said.

Pfizer is counting on Array to augment its leadership in breast cancer, an area championed by Ibrance, and prostate cancer, the pharma giant markets Astellas-partnered Xtandi. For 2018, revenues from the Pfizer oncology portfolio jumped to $7.20 billion—up from $6.06 billion in 2017—mainly thanks to those two drugs.

Source: https://www.fiercepharma.com/pharma/pfizer-never-say-never-m-a-buys-oncology-innovator-array-for-11-4b

 

About Array BioPharma

Array markets BRAFTOVI® (encorafenib) capsules in combination with MEKTOVI® (binimetinib)  tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K  mutation in the United States and with partners in other major worldwide markets.* Array’s lead clinical programs, encorafenib and binimetinib, are being investigated in over 30 clinical trials across a number of solid tumor indications, including a Phase 3 trial in BRAF-mutant metastatic colorectal cancer. Array’s pipeline includes several additional programs being advanced by Array or current license-holders, including the following programs currently in registration trials: selumetinib (partnered with AstraZeneca), LOXO-292 (partnered with Eli Lilly), ipatasertib (partnered with Genentech), tucatinib (partnered with Seattle Genetics) and ARRY-797. Vitrakvi® (larotrectinib, partnered with Bayer AG) is approved in the United States and Ganovo® (danoprevir, partnered with Roche) is approved in China.

 

Other Articles of Note of Pfizer Merger and Acquisition deals on this Open Access Journal Include:

From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer; A Curation of Deals, Discovery and the State of Pharma

Pfizer Near Allergan Buyout Deal But Will Fed Allow It?

Pfizer offers legal guarantees over AstraZeneca bid

Re-Creation of the Big Pharma Model via Transformational Deals for Accelerating Innovations: Licensing vs In-house inventions


Tweets, Pictures and Retweets at 18th Annual Cancer Research Symposium – Machine Learning and Cancer, June 14, 2019, MIT by @pharma_BI and @AVIVA1950 for #KIsymposium PharmaceuticalIntelligence.com and Social Media

 

Pictures taken in Real Time

 

Notification from Twitter.com on June 14, 2019 and in the 24 hours following the symposium

 

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eProceedings 18th Symposium 2019 covered in Amazing event, Keynote best talks @avivregev ’er @reginabarzelay

  1. Top lectures by @reginabarzilay @avivaregev

  2. eProceeding 2019 Koch Institute Symposium – 18th Annual Cancer Research Symposium – Machine Learning and Cancer, June 14, 2019, 8:00 AM-5:00 PMET MIT Kresge Auditorium, 48 Massachusetts Ave, Cambridge, MA via

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    eProceedings 18th Symposium 2019 covered in Amazing event, Keynote best talks @avivregev ’er @reginabarzelay

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    Einstein, Curie, Bohr, Planck, Heisenberg, Schrödinger… was this the greatest meeting of minds, ever? Some of the world’s most notable physicists participated in the 1927 Solvay Conference. In fact, 17 of the 29 scientists attending were or became Laureates.

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Featuring Computational and Systems Biology Program at Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute (SKI), The Dana Pe’er Lab

 

Reporter: Aviva Lev-Ari, PhD, RN

A lecture by Dana Pe’er is included, below in the eProceedings which I generated in Real Time on 6/14/2019 @MIT

eProceeding 2019 Koch Institute Symposium – 18th Annual Cancer Research Symposium – Machine Learning and Cancer, June 14, 2019, 8:00 AM-5:00 PM ET MIT Kresge Auditorium, 48 Massachusetts Ave, Cambridge, MA

https://pharmaceuticalintelligence.com/2019/03/12/2019-koch-institute-symposium-machine-learning-and-cancer-june-14-2019-800-am-500-pmet-mit-kresge-auditorium-48-massachusetts-ave-cambridge-ma/

 

 

Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute (SKI

https://www.mskcc.org/research/ski/about

 

Research Programs

Cancer Biology & Genetics Program

Our scientists study the molecular and genetic determinants of cancer predisposition, tumor development, and metastasis.

Cell Biology Program

Our researchers explore the molecular mechanisms that control normal cell behavior and how these mechanisms are disrupted in cancer.

Chemical Biology Program

Our scientists use chemical principles to investigate cutting-edge topics in biology and medicine.

Computational & Systems Biology Program

The goal of our research is to build computer models that simulate biological processes, from the molecular level up to the organism as a whole.

Developmental Biology Program

Our investigators study the mechanisms that control cell proliferation, cell differentiation, tissue patterning, and tissue morphogenesis.

Immunology Program

Our research is geared toward understanding how the immune system functions in all its complexity and how it can be harnessed to fight disease.

Molecular Biology Program

Our research is directed at understanding how cell growth is regulated and how the integrity of the genome is maintained.

Molecular Pharmacology Program

Our research program serves as a conduit for bringing basic science discoveries to preclinical and clinical evaluation.

Structural Biology Program

Our researchers are dedicated to understanding biology at the structural and mechanistic levels, and aiding the development of new cancer therapies.

Book traversal links for Research

 

The Dana Pe’er Lab

 

The Dana Pe'er Lab

The Pe’er lab combines single cell technologies, genomic datasets and machine learning algorithms to address fundamental questions in biomedical science. Empowered by recent breakthrough technologies like massive parallel single cell RNA-sequencing, we ask questions such as: How do multi-cellular organisms develop from a single cell, resulting in the vast diversity of progenitor and terminal cell types? How does a cell’s regulatory circuit control the dynamics of signal processing and how do these circuits rewire over the course of development? How does an ensemble of cells function together to execute a multi-cellular response, such as an immune response to pathogen or cancer? We will also address more medically oriented questions such as: How do regulatory circuits go awry in disease? What is the consequence of intra-tumor heterogeneity? Can we characterize the tumor immune eco-system to gain a better understanding of when or why immunotherapy works or does not work? A key goal is to use this characterization of the tumor immune eco-system to personalize immunotherapy.

Dana Pe'er, PhD

Dana Pe’er, PhD

Chair, Computational and Systems Biology Program, SKI; Scientific Director, Metastasis & Tumor Ecosystems Center

Research Focus

Computational Biologist Dana Pe’er combines single cell technologies, genomic datasets and machine learning techniques to address fundamental questions addressing regulatory cell circuits, cellular development, tumor immune eco-system, genotype to phenotype relations and precision medicine.

Education

PhD, Hebrew University, Jerusalem Israel

 

The Dana Pe’er Lab: Publications

View a full listing of Dana Pe’er’s journal articles.


Palantir characterizes cell fate continuities in human hematopoiesis. Setty M, Kiseliovas V, Levine J, Gayoso A, Mazutis L, Pe’er D. 2019, in press. Nature Biotechnology.

Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, Nainys J, Wu K, Kiseliovas V, Setty M, Choi K, Fromme RM, Dao P, McKenney PT, Wasti RC, Kadaveru K, Mazutis L, Rudensky AY, Pe’er D. Cell. 2018 Aug 23;174(5):1293-1308.e36. doi: 10.1016/j.cell.2018.05.060. PMID: 29961579

Recovering gene interactions from single-cell data using data diffusion. van Dijk D, Sharma R, Nainys J, Yim K, Kathail P, Carr AJ, Burdziak C, Moon KR, Chaffer CL, Pattabiraman D, Bierie B, Mazutis L, Wolf G, Krishnaswamy S, Pe’er D. Cell. 2018 Jul 26;174(3):716-729.e27. doi: 10.1016/j.cell.2018.05.061. PubMed PMID: 29961576

The Human Cell Atlas. Regev A et al. Elife. 2017 Dec 5;6. pii: e27041. doi: 10.7554/eLife.27041. PubMed PMID: 29206104

Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC, Sharma P, Wang J, Wargo JA, Pe’er D, Allison JP. Cell. 2017 Sep 7;170(6):1120-1133.e17. doi: 10.1016/j.cell.2017.07.024. PMID: 28803728

Wishbone identifies bifurcating developmental trajectories from single-cell data. Setty M, Tadmor MD, Reich-Zeliger S, Angel O, Salame TM, Kathail P, Choi K, Bendall S, Friedman N, Pe’er D. Nat Biotechnol. 2016 Jun;34(6):637-45. doi: 10.1038/nbt.3569. PMID: 27136076

Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis. Levine JH, Simonds EF, Bendall SC, Davis KL, Amir el-AD, Tadmor MD, Litvin O, Fienberg HG, Jager A, Zunder ER, Finck R, Gedman AL, Radtke I, Downing JR, Pe’er D, Nolan GP. Cell. 2015 Jul 2;162(1):184-97. doi: 10.1016/j.cell.2015.05.047. PMID: 26095251

Interferon α/β enhances the cytotoxic response of MEK inhibition in melanoma. Litvin O, Schwartz S, Wan Z, Schild T, Rocco M, Oh NL, Chen BJ, Goddard N, Pratilas C, Pe’er D. Mol Cell. 2015 Mar 5;57(5):784-796. doi: 10.1016/j.molcel.2014.12.030. PMID: 25684207

Integration of genomic data enables selective discovery of breast cancer drivers. Sanchez-Garcia F, Villagrasa P, Matsui J, Kotliar D, Castro V, Akavia UD, Chen BJ, Saucedo-Cuevas L, Rodriguez Barrueco R, Llobet-Navas D, Silva JM, Pe’er D. Cell. 2014 Dec 4;159(6):1461-75. doi: 10.1016/j.cell.2014.10.048. PMID: 25433701

Conditional density-based analysis of T cell signaling in single-cell data. Krishnaswamy S, Spitzer MH, Mingueneau M, Bendall SC, Litvin O, Stone E, Pe’er D, Nolan GP. Systems biology. Science. 2014 Nov 28;346(6213):1250689. doi: 10.1126/science.1250689. PMID: 25342659

Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Bendall SC, Davis KL, Amir el-AD, Tadmor MD, Simonds EF, Chen TJ, Shenfeld DK, Nolan GP, Pe’er D. Cell. 2014 Apr 24;157(3):714-25. doi: 10.1016/j.cell.2014.04.005. PMID: 24766814

Book traversal links for The Dana Pe’er Lab

SOURCE

https://www.mskcc.org/research/ski/labs/dana-pe-er/publications

The Dana Pe’er Lab is one of four Labs of the Computational & Systems Biology Program

Computational biologists combine findings in biology with computer algorithms and databases to conduct biological research on powerful computers, using sophisticated software — so-called “dry” laboratories — in ways that complement and strengthen traditional laboratory and clinical research. The aim is to build computer models that simulate biological processes from the molecular level up to the organism as a whole and to use these models to make useful predictions.

 

Computational biology can help interpret detailed molecular profiles of cancerous and noncancerous cells, molecular response profiles of therapeutic agents, and a person’s genetic profile to assist in the development of better diagnostics and prognostics, as well as improved therapies. Intelligent use of computational methods using detailed molecular and genomic data is expected to reduce the trial and error of drug development and possibly lead to shorter, more accurate clinical trials.

 

The Christina Leslie Lab

The John Chodera Lab

The Dana Pe'er Lab

The Joao Xavier Lab

 


Can Elephants Help Fight Cancer?

Reporter: Gail S. Thornton, M.A.

 

 

This paragraph is excerpted from the American Technion Society Facebook page.

Professor Avi Schroeder and Dr. Josh Schiffman of the The University of Utah are working with elephants at Utah’s Hogle Zoo on a possible new tool to fight against lung, bone, breast, and other cancers. Dr. Schiffman found that p53, a cancer-suppressing protein, is far more prevalent in elephants, which rarely develop cancer. Prof. Schroeder is now working to manufacture the protein in nanoparticles to begin preclinical testing.


This article is excerpted from The Salt Lake Tribune, May 2, 2019.

Earth’s biggest, smallest, oddest life forms are getting new attention from scientists. A Utah author explores what they’re learning.

Published: May 2, 2019

Researchers have long ignored superlative life forms — the biggest, the tiniest, ones that can survive extremes — as outliers, Utah author Matthew D. LaPlante says.

But they’re now realizing the value of studying nature’s “oddballs,” he adds, which are helping scientists discover how to better fight disease and aging, understand the history of life on this planet and how we might reach others.

LaPlante’s new book, “Superlative: The Biology of Extremes” was released this week. On Friday at 7 p.m., the associate professor of journalistic writing at Utah State University will read from “Superlative” and talk about his work at The King’s English Bookshop, 1511 S. 1500 East, Salt Lake City. The event is free and open to the public.

The co-writer of several books on the intersection of scientific discovery and society, LaPlante now is working with Harvard geneticist David Sinclair on a book about human longevity. “Superlative” from BenBella Books is the first solo book by LaPlante, a former reporter for The Salt Lake Tribune.

As he surveys unusual life around the earth, there are stops in Utah — from Pando, the aspen clone in Sevier County believed to be the single most massive living organism known on Earth, to pop-up appearances by researchers at the University of Utah and elephants at Hogle Zoo in Salt Lake City.

Vast sequences of the genetic coding that humans share with elephants still perform similar functions in each species, LaPlante explains. And long after the two diverged, both developed the same genetic solution for the oxygen needs of a larger brain.

So there’s reason to believe that responses elephants have evolved — such as rarely developing cancer — might be spurred in humans.

The potential within a genome for such new traits to develop is at the heart of comparative genomics — and at the work of Utah pediatric oncologist Josh Schiffman.

This excerpt from “Superlative” explains how Schiffman began working with Hogle Zoo’s African elephants — the largest living land mammals — to fight cancer.

It all started in the summer of 2012, when [pediatric oncologist Josh] Schiffman’s beloved dog, Rhody, passed away [due] to histiocytosis, a condition that attacks the cells of skin and connective tissue. “It was the only time my wife has ever seen me cry,” he told me. “Rhody was like our first child.”

Schiffman had heard dogs like his had an elevated risk of cancer, but it wasn’t until after Rhody’s death that he learned just how elevated it was. Bernese mountain dogs who live to the age of ten have a 50 percent risk of dying from cancer.

“Suddenly it dawned on me there was this whole other world, this young field of comparative oncology,” he said, “and I was pulled into the idea of being a pioneer and maybe a leader to help move things along.”

Schiffman had long been intrigued by the fact that size doesn’t appear to correlate to cancer rates — a phenomenon known as “Peto’s Paradox,” named for Oxford University epidemiologist Richard Peto. But when Schiffman took his children on an outing to Utah’s Hogle Zoo — the same place I sometimes go to have lunch with my elephant friend, Zuri — everything came together.

A keeper named Eric Peterson had just finished giving a talk to a crowd of visitors, mentioning in passing that the zoo’s elephants have been trained to allow the veterinary staff to take small samples of blood from a vein behind their ears. As the crowd dispersed, an angular, excited man approached him.

“I’ve got a strange question,” Schiffman said.

“We’ve heard them all,” Peterson replied.

“OK then — how do I get me some of that elephant blood?” Schiffman asked.

Peterson contemplated calling security. Instead, after a bit of explanation from Schiffman, the zookeeper told the inquisitive doctor he’d look into it. Two and a half months later, the zoo’s institutional review board gave its blessing to Schiffman’s request.

Things moved fast after that.

(Steve Griffin | Tribune file photo) Lab specialists Lauren Donovan Cristhian Toruno, Lisa Abegglen and researcher Joshua Schiffman, from left, are testing the effects of elephant gene p53 (EP53) in human cancer cells at the Huntsman Cancer Institute.
(Steve Griffin | Tribune file photo) Lab specialists Lauren Donovan Cristhian Toruno, Lisa Abegglen and researcher Joshua Schiffman, from left, are testing the effects of elephant gene p53 (EP53) in human cancer cells at the Huntsman Cancer Institute.

Cancer develops in part because cells divide. During each division the cells must make a copy of their DNA, and once in a while, for various reasons, those copies include a mistake. The more cells divide, the greater the odds of an error, and the more prone an error is to be duplicated again and again.

And elephant cells? Those things are dividing like crazy. Based on the number of cell divisions elephants need to get from Zuri’s size when we met to the size she is now, in just a few short years, it stands to reason they should get lots of cancer. Yet they almost never do.

“Going from 300 pounds as a calf to more than 10,000 pounds, gaining three-plus pounds a day, they’re growing so quickly, so big and so fast — baby elephants really shouldn’t make it to adulthood,” Schiffman said. “They should have 100 times the cancer. Just by chance alone, elephants should be dropping dead all over the place.” Indeed, he said, they should probably die of cancer before they’re even old enough to reproduce. “They should be extinct!”

Already, comparative oncologists suspected the exceptionally low rate of cancer in elephants had something to do with p53, a gene whose human analog is a known cancer suppressor. Most humans have one copy — two alleles — of the gene. Those with an inherited condition known as Li–Fraumeni syndrome, however, have just one allele — and a nearly 100 percent chance of getting cancer. The logical conclusion is more p53 alleles mean a better chance of staving off cancer. And elephants, it turns out, have twenty of them.

The big find that came from Schiffman’s exploration of the elephant blood he got at the zoo, though, was not just that there were more of these genes in elephants, but that the genes behaved a little bit differently, too.

In humans, the gene’s first approach for suppressing tumor growth is to try to repair faulty cells — the sort that cause cancer. So, at first, Schiffman’s team assumed having more p53 genes meant elephants had bigger repair crews. With the goal of watching those crews in action, the researchers exposed the elephant cells to radiation, causing DNA damage. But they noticed that, instead of trying to fix what was broken, the elephant cells seemed to grow something of a conscience.

To understand this, it’s helpful to think about how you’d respond in a zombie apocalypse. Of course you’d fight long and hard to keep from being infected, right? But if a zombie was about to chomp down on your arm, and there was nothing you could do to stop it, and if you had but one bullet remaining in your gun —and a few moments to consider what you might do to your fellow humans as a part of the legion of the undead — what would you do?

That’s what elephant cells do, too. Under the directive of p53, mutated cells don’t put up a fight. Upon recognizing the inevitability of malignant mutation, they take their own lives in a process known as apoptosis.

And they don’t just do this for one kind of cancer. The p53 gene apparently programs cells to do this in response to all kinds of malignantly mutated cells in elephants—a finding that flies in the face of the conventional assumption that there is no one singular cure for the complex group of disorders we call cancer.

When I first met Schiffman in 2016, he was brimming with excitement about the potential elephants have to help us understand cancer. He was also very cautious not to suggest he was anywhere near a cure, nor that he ever would be.

Just a few years later, though, Schiffman was speaking openly about his intention to rid the world of cancer. And, to that end, what’s happening in his lab is encouraging, to say the least.

He and his team have been injecting cancer cells with a synthetic version of a p53 protein modeled on the DNA he’s drawn from Zuri and other elephants from around the world. Viewed on time-lapse video, the results are unmistakable and amazing.

Breast cancer. Gone.

bone cancer. Gone.

Lung cancer. Gone.

One by one, each type of cancer cell falls victim to zombie-cell hara-kiri, shriveling and then exploding, and leaving nothing behind to mutate. Schiffman is now working with Avi Schroeder, an expert in nanomedical delivery systems at Technion-Israel Institute of Technology, to create tiny delivery vehicles to take the synthetic elephant protein into mammalian tumors.

If this was all the benefit we ever derived from studying elephants, it would be plenty.

But it’s not. Not at all.

Source:

https://www.sltrib.com/artsliving/2019/05/02/earths-biggest-smallest/?fbclid=IwAR09iwADrhUKkuoXDRMBHFIMstUESU3OBXxKeN0dTKwxapTUASWsv1T_kZI


New ways to Heal Damage after a Heart Attack

Reporter: Irina Robu, PhD

More than a million Americans have heart attacks each year. Researchers at Northwestern University and University of California, San Diego have designed a minimally invasive platform to deliver nanomaterial that turns body’s inflammatory response into a signal rather than means of scarring following a heart attack. The researchers from Northwestern-UC San Diego established a novel way to deliver a bioactivated, biodegradable, regenerative substance through a noninvasive catheter without clogging in-vivo in a rat model.

When a person has a heart attack, the extracellular matrix is stripped away and scar tissue forms in its place, decreasing the heart’s functionality. The team injects a self-assembling peptide that seeks out a target, the heart’s damaged extracellular matrix and the solution is then activated by the inflammatory environment itself and gels.

The team’s preclinical research was led in rats and segmented into two proof-of-concept tests. The first test recognized that the material could be fed through a catheter without clogging and without interacting with human blood. The second determined whether the self-assembling peptides could find their way to the damaged tissue, bypassing healthy heart tissue. The scientists attached a fluorescent tag to the self-assembling peptides and imaged the heart to see where the peptides eventually settled.

Researchers now know that when they remove the fluorescent tag and replace it with a therapeutic, the self-assembling peptides will locate to the affected area of the heart. One hurdle is that catheter delivery in a rodent model is far more complicated than the same procedure in a human.

A major innovation occurred when sterically constrained cyclic peptides, which flow freely during delivery and rapidly assemble into hydrogels when they come in contact with disease associated enzymes. The process creates conditions for the peptides to better self-assemble on top one another and form the scaffold that resembles the native extracellular matrix.

SOURCE
https://www.eurekalert.org/pub_releases/2019-04/nu-fab042319.php

 

 


Optimization of CRISPR Gene Editing with Gold Nanoparticles

Reporter: Irina Robu, PhD

The CRISPR-Cas9 gene editing system has been welcomed as a hopeful solution to a range of genetic diseases, but the expertise has proven hard to deliver into cells. One plan is to open the cell membrane using an electric shock, but that can accidentally kill the cell. Another is to use viruses as couriers. Problem is, viruses can cause off-target side effects.

CRISPR-Cas9 is a unique technology that enables geneticists and medical researchers to edit parts of the genome by removing, adding or altering sections of DNA sequence. It is faster, cheaper and more accurate than previous techniques of editing DNA and can have a wide range of potential applications.

The CRISPR-Cas9 system consists of two key molecules that introduce a change into the DNA. One is an enzyme called Cas9 which acts as a pair of molecular scissors that can cut the two strands of DNA at a specific location in the genome where bits of DNA can be added or removed. The other one, is a piece of RNA which consists of a small piece of pre-designed RNA sequence located within a longer RNA scaffold. The scaffold part binds to the DNA and pre-designed sequence which contains Cas9. The RNA sequence is designed to find and locate specific sequence in the DNA. The Cas9 trails the guide RNA to the same location in the DNA sequence and makes a cut across both strands of DNA. At this point the cell distinguishes that the DNA is damaged and tries to repair it.

Researchers at Fred Hutchinson Cancer Research Center published new findings in Nature Materials suggested an alternative delivery method such as gold nanoparticles. The gold nanoparticles are packed with all the CRISPR components necessary to make clean gene edits. When the gold nanoparticles were tested in lab models of inherited blood disorders and HIV, between 10% and 20% of the targeted cells were effectively edited, with no toxic side effects.

The researchers use gold nanoparticles to deliver CRISPR to blood stem cells. Each gold nanoparticle contains four CRISPR components, including the enzyme needed to make the DNA cuts. But Fred Hutchinson researchers chose Cas12a, which they believed would lead to more efficient edits. Plus, Cas12a only needs one molecular guide, while Cas9 requires two.
In one experiment, they sought to disturb the gene CCR5 to make cells resistant to HIV. In the second, they created a gene mutation that can protect against blood disorders, including sickle cell disease. They observed the cells encapsulated the nanoparticles within six hours and began the gene-editing process within 48 hours. In mice, gene editing peaked eight weeks after injection, and the edited cells were still in circulation 22 weeks after the treatment.
Researchers at Fred Hutchinson are now working on improving the efficiency of the gold-based CRISPR delivery system so that 50% or more of the targeted cells are edited and are also looking for a commercial partner to bring the technology to clinical phase in the next few years.

SOURCE:

https://www.fiercebiotech.com/research/fred-hutch-team-uses-gold-nanoparticles-to-improve-crispr-gene-editing