Archive for the ‘Curation’ Category

Live Notes, Real Time Conference Coverage AACR 2020 #AACR20: Tuesday June 23, 2020 Noon-2:45 Educational Sessions

Live Notes, Real Time Conference Coverage AACR 2020: Tuesday June 23, 2020 Noon-2:45 Educational Sessions

Reporter: Stephen J. Williams, PhD

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Presidential Address

Elaine R Mardis, William N Hait


Welcome and introduction

William N Hait


Improving diagnostic yield in pediatric cancer precision medicine

Elaine R Mardis
  • Advent of genomics have revolutionized how we diagnose and treat lung cancer
  • We are currently needing to understand the driver mutations and variants where we can personalize therapy
  • PD-L1 and other checkpoint therapy have not really been used in pediatric cancers even though CAR-T have been successful
  • The incidence rates and mortality rates of pediatric cancers are rising
  • Large scale study of over 700 pediatric cancers show cancers driven by epigenetic drivers or fusion proteins. Need for transcriptomics.  Also study demonstrated that we have underestimated germ line mutations and hereditary factors.
  • They put together a database to nominate patients on their IGM Cancer protocol. Involves genetic counseling and obtaining germ line samples to determine hereditary factors.  RNA and protein are evaluated as well as exome sequencing. RNASeq and Archer Dx test to identify driver fusions
  • PECAN curated database from St. Jude used to determine driver mutations. They use multiple databases and overlap within these databases and knowledge base to determine or weed out false positives
  • They have used these studies to understand the immune infiltrate into recurrent cancers (CytoCure)
  • They found 40 germline cancer predisposition genes, 47 driver somatic fusion proteins, 81 potential actionable targets, 106 CNV, 196 meaningful somatic driver mutations



Tuesday, June 23

12:00 PM – 12:30 PM EDT

Awards and Lectures

NCI Director’s Address

Norman E Sharpless, Elaine R Mardis


Introduction: Elaine Mardis


NCI Director Address: Norman E Sharpless
  • They are functioning well at NCI with respect to grant reviews, research, and general functions in spite of the COVID pandemic and the massive demonstrations on also focusing on the disparities which occur in cancer research field and cancer care
  • There are ongoing efforts at NCI to make a positive difference in racial injustice, diversity in the cancer workforce, and for patients as well
  • Need a diverse workforce across the cancer research and care spectrum
  • Data show that areas where the clinicians are successful in putting African Americans on clinical trials are areas (geographic and site specific) where health disparities are narrowing
  • Grants through NCI new SeroNet for COVID-19 serologic testing funded by two RFAs through NIAD (RFA-CA-30-038 and RFA-CA-20-039) and will close on July 22, 2020


Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Immunology, Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Tumor Immunology and Immunotherapy for Nonimmunologists: Innovation and Discovery in Immune-Oncology

This educational session will update cancer researchers and clinicians about the latest developments in the detailed understanding of the types and roles of immune cells in tumors. It will summarize current knowledge about the types of T cells, natural killer cells, B cells, and myeloid cells in tumors and discuss current knowledge about the roles these cells play in the antitumor immune response. The session will feature some of the most promising up-and-coming cancer immunologists who will inform about their latest strategies to harness the immune system to promote more effective therapies.

Judith A Varner, Yuliya Pylayeva-Gupta



Judith A Varner
New techniques reveal critical roles of myeloid cells in tumor development and progression
  • Different type of cells are becoming targets for immune checkpoint like myeloid cells
  • In T cell excluded or desert tumors T cells are held at periphery so myeloid cells can infiltrate though so macrophages might be effective in these immune t cell naïve tumors, macrophages are most abundant types of immune cells in tumors
  • CXCLs are potential targets
  • PI3K delta inhibitors,
  • Reduce the infiltrate of myeloid tumor suppressor cells like macrophages
  • When should we give myeloid or T cell therapy is the issue
Judith A Varner
Novel strategies to harness T-cell biology for cancer therapy
Positive and negative roles of B cells in cancer
Yuliya Pylayeva-Gupta
New approaches in cancer immunotherapy: Programming bacteria to induce systemic antitumor immunity



Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Cancer Chemistry

Chemistry to the Clinic: Part 2: Irreversible Inhibitors as Potential Anticancer Agents

There are numerous examples of highly successful covalent drugs such as aspirin and penicillin that have been in use for a long period of time. Despite historical success, there was a period of reluctance among many to purse covalent drugs based on concerns about toxicity. With advances in understanding features of a well-designed covalent drug, new techniques to discover and characterize covalent inhibitors, and clinical success of new covalent cancer drugs in recent years, there is renewed interest in covalent compounds. This session will provide a broad look at covalent probe compounds and drug development, including a historical perspective, examination of warheads and electrophilic amino acids, the role of chemoproteomics, and case studies.

Benjamin F Cravatt, Richard A. Ward, Sara J Buhrlage


Discovering and optimizing covalent small-molecule ligands by chemical proteomics

Benjamin F Cravatt
  • Multiple approaches are being investigated to find new covalent inhibitors such as: 1) cysteine reactivity mapping, 2) mapping cysteine ligandability, 3) and functional screening in phenotypic assays for electrophilic compounds
  • Using fluorescent activity probes in proteomic screens; have broad useability in the proteome but can be specific
  • They screened quiescent versus stimulated T cells to determine reactive cysteines in a phenotypic screen and analyzed by MS proteomics (cysteine reactivity profiling); can quantitate 15000 to 20,000 reactive cysteines
  • Isocitrate dehydrogenase 1 and adapter protein LCP-1 are two examples of changes in reactive cysteines they have seen using this method
  • They use scout molecules to target ligands or proteins with reactive cysteines
  • For phenotypic screens they first use a cytotoxic assay to screen out toxic compounds which just kill cells without causing T cell activation (like IL10 secretion)
  • INTERESTINGLY coupling these MS reactive cysteine screens with phenotypic screens you can find NONCANONICAL mechanisms of many of these target proteins (many of the compounds found targets which were not predicted or known)

Electrophilic warheads and nucleophilic amino acids: A chemical and computational perspective on covalent modifier

The covalent targeting of cysteine residues in drug discovery and its application to the discovery of Osimertinib

Richard A. Ward
  • Cysteine activation: thiolate form of cysteine is a strong nucleophile
  • Thiolate form preferred in polar environment
  • Activation can be assisted by neighboring residues; pKA will have an effect on deprotonation
  • pKas of cysteine vary in EGFR
  • cysteine that are too reactive give toxicity while not reactive enough are ineffective


Accelerating drug discovery with lysine-targeted covalent probes


Tuesday, June 23

12:45 PM – 2:15 PM EDT

Virtual Educational Session

Molecular and Cellular Biology/Genetics

Virtual Educational Session

Tumor Biology, Immunology

Metabolism and Tumor Microenvironment

This Educational Session aims to guide discussion on the heterogeneous cells and metabolism in the tumor microenvironment. It is now clear that the diversity of cells in tumors each require distinct metabolic programs to survive and proliferate. Tumors, however, are genetically programmed for high rates of metabolism and can present a metabolically hostile environment in which nutrient competition and hypoxia can limit antitumor immunity.

Jeffrey C Rathmell, Lydia Lynch, Mara H Sherman, Greg M Delgoffe


T-cell metabolism and metabolic reprogramming antitumor immunity

Jeffrey C Rathmell


Jeffrey C Rathmell

Metabolic functions of cancer-associated fibroblasts

Mara H Sherman

Tumor microenvironment metabolism and its effects on antitumor immunity and immunotherapeutic response

Greg M Delgoffe
  • Multiple metabolites, reactive oxygen species within the tumor microenvironment; is there heterogeneity within the TME metabolome which can predict their ability to be immunosensitive
  • Took melanoma cells and looked at metabolism using Seahorse (glycolysis): and there was vast heterogeneity in melanoma tumor cells; some just do oxphos and no glycolytic metabolism (inverse Warburg)
  • As they profiled whole tumors they could separate out the metabolism of each cell type within the tumor and could look at T cells versus stromal CAFs or tumor cells and characterized cells as indolent or metabolic
  • T cells from hyerglycolytic tumors were fine but from high glycolysis the T cells were more indolent
  • When knock down glucose transporter the cells become more glycolytic
  • If patient had high oxidative metabolism had low PDL1 sensitivity
  • Showed this result in head and neck cancer as well
  • Metformin a complex 1 inhibitor which is not as toxic as most mito oxphos inhibitors the T cells have less hypoxia and can remodel the TME and stimulate the immune response
  • Metformin now in clinical trials
  • T cells though seem metabolically restricted; T cells that infiltrate tumors are low mitochondrial phosph cells
  • T cells from tumors have defective mitochondria or little respiratory capacity
  • They have some preliminary findings that metabolic inhibitors may help with CAR-T therapy

Obesity, lipids and suppression of anti-tumor immunity

Lydia Lynch
  • Hypothesis: obesity causes issues with anti tumor immunity
  • Less NK cells in obese people; also produce less IFN gamma
  • RNASeq on NOD mice; granzymes and perforins at top of list of obese downregulated
  • Upregulated genes that were upregulated involved in lipid metabolism
  • All were PPAR target genes
  • NK cells from obese patients takes up palmitate and this reduces their glycolysis but OXPHOS also reduced; they think increased FFA basically overloads mitochondria
  • PPAR alpha gamma activation mimics obesity



Tuesday, June 23

12:45 PM – 2:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials

The Evolving Role of the Pathologist in Cancer Research

Long recognized for their role in cancer diagnosis and prognostication, pathologists are beginning to leverage a variety of digital imaging technologies and computational tools to improve both clinical practice and cancer research. Remarkably, the emergence of artificial intelligence (AI) and machine learning algorithms for analyzing pathology specimens is poised to not only augment the resolution and accuracy of clinical diagnosis, but also fundamentally transform the role of the pathologist in cancer science and precision oncology. This session will discuss what pathologists are currently able to achieve with these new technologies, present their challenges and barriers, and overview their future possibilities in cancer diagnosis and research. The session will also include discussions of what is practical and doable in the clinic for diagnostic and clinical oncology in comparison to technologies and approaches primarily utilized to accelerate cancer research.


Jorge S Reis-Filho, Thomas J Fuchs, David L Rimm, Jayanta Debnath


Tuesday, June 23

12:45 PM – 2:45 PM EDT


High-dimensional imaging technologies in cancer research

David L Rimm

  • Using old methods and new methods; so cell counting you use to find the cells then phenotype; with quantification like with Aqua use densitometry of positive signal to determine a threshold to determine presence of a cell for counting
  • Hiplex versus multiplex imaging where you have ten channels to measure by cycling of flour on antibody (can get up to 20plex)
  • Hiplex can be coupled with Mass spectrometry (Imaging Mass spectrometry, based on heavy metal tags on mAbs)
  • However it will still take a trained pathologist to define regions of interest or field of desired view



Jayanta Debnath

Challenges and barriers of implementing AI tools for cancer diagnostics

Jorge S Reis-Filho

Implementing robust digital pathology workflows into clinical practice and cancer research

Jayanta Debnath

Invited Speaker

Thomas J Fuchs
  • Founder of spinout of Memorial Sloan Kettering
  • Separates AI from computational algothimic
  • Dealing with not just machines but integrating human intelligence
  • Making decision for the patients must involve human decision making as well
  • How do we get experts to do these decisions faster
  • AI in pathology: what is difficult? =è sandbox scenarios where machines are great,; curated datasets; human decision support systems or maps; or try to predict nature
  • 1) learn rules made by humans; human to human scenario 2)constrained nature 3)unconstrained nature like images and or behavior 4) predict nature response to nature response to itself
  • In sandbox scenario the rules are set in stone and machines are great like chess playing
  • In second scenario can train computer to predict what a human would predict
  • So third scenario is like driving cars
  • System on constrained nature or constrained dataset will take a long time for commuter to get to decision
  • Fourth category is long term data collection project
  • He is finding it is still finding it is still is difficult to predict nature so going from clinical finding to prognosis still does not have good predictability with AI alone; need for human involvement
  • End to end partnering (EPL) is a new way where humans can get more involved with the algorithm and assist with the problem of constrained data
  • An example of a workflow for pathology would be as follows from Campanella et al 2019 Nature Medicine: obtain digital images (they digitized a million slides), train a massive data set with highthroughput computing (needed a lot of time and big software developing effort), and then train it using input be the best expert pathologists (nature to human and unconstrained because no data curation done)
  • Led to first clinically grade machine learning system (Camelyon16 was the challenge for detecting metastatic cells in lymph tissue; tested on 12,000 patients from 45 countries)
  • The first big hurdle was moving from manually annotated slides (which was a big bottleneck) to automatically extracted data from path reports).
  • Now problem is in prediction: How can we bridge the gap from predicting humans to predicting nature?
  • With an AI system pathologist drastically improved the ability to detect very small lesions


Virtual Educational Session


Cancer Increases in Younger Populations: Where Are They Coming from?

Incidence rates of several cancers (e.g., colorectal, pancreatic, and breast cancers) are rising in younger populations, which contrasts with either declining or more slowly rising incidence in older populations. Early-onset cancers are also more aggressive and have different tumor characteristics than those in older populations. Evidence on risk factors and contributors to early-onset cancers is emerging. In this Educational Session, the trends and burden, potential causes, risk factors, and tumor characteristics of early-onset cancers will be covered. Presenters will focus on colorectal and breast cancer, which are among the most common causes of cancer deaths in younger people. Potential mechanisms of early-onset cancers and racial/ethnic differences will also be discussed.

Stacey A. Fedewa, Xavier Llor, Pepper Jo Schedin, Yin Cao

Cancers that are and are not increasing in younger populations

Stacey A. Fedewa


  • Early onset cancers, pediatric cancers and colon cancers are increasing in younger adults
  • Younger people are more likely to be uninsured and these are there most productive years so it is a horrible life event for a young adult to be diagnosed with cancer. They will have more financial hardship and most (70%) of the young adults with cancer have had financial difficulties.  It is very hard for women as they are on their childbearing years so additional stress
  • Types of early onset cancer varies by age as well as geographic locations. For example in 20s thyroid cancer is more common but in 30s it is breast cancer.  Colorectal and testicular most common in US.
  • SCC is decreasing by adenocarcinoma of the cervix is increasing in women’s 40s, potentially due to changing sexual behaviors
  • Breast cancer is increasing in younger women: maybe etiologic distinct like triple negative and larger racial disparities in younger African American women
  • Increased obesity among younger people is becoming a factor in this increasing incidence of early onset cancers



Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM


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Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic


Curator: Stephen J. Williams, Ph.D.


At the onset of the COVID-19 pandemic, epidemiological data from the origin of the Sars-Cov2 outbreak, notably from the Wuhan region in China, was sparse.  In fact, official individual patient data rarely become available early on in an outbreak, when that data is needed most. Epidemiological data was just emerging from China as countries like Italy, Spain, and the United States started to experience a rapid emergence of the outbreak in their respective countries.  China, made of 31 geographical provinces, is a vast and complex country, with both large urban and rural areas.




As a result of this geographical diversity and differences in healthcare coverage across the country, epidemiological data can be challenging.  For instance, cancer incidence data for regions and whole country is difficult to calculate as there are not many regional cancer data collection efforts, contrasted with the cancer statistics collected in the United States, which is meticulously collected by cancer registries in each region, state and municipality.  Therefore, countries like China must depend on hospital record data and autopsy reports in order to back-extrapolate cancer incidence data.  This is the case in some developed countries like Italy where cancer registry is administered by a local government and may not be as extensive (for example in the Napoli region of Italy).







Population density China by province. Source https://www.unicef.cn/en/figure-13-population-density-province-2017




Epidemiologists, in areas in which data collection may be challenging, are relying on alternate means of data collection such as using devices connected to the internet-of-things such as mobile devices, or in some cases, social media is becoming useful to obtain health related data.  Such as effort to acquire pharmacovigilance data, patient engagement, and oral chemotherapeutic adherence using the social media site Twitter has been discussed in earlier posts: (see below)

Twitter is Becoming a Powerful Tool in Science and Medicine at https://pharmaceuticalintelligence.com/2014/11/06/twitter-is-becoming-a-powerful-tool-in-science-and-medicine/






Now epidemiologists are finding crowd-sourced data from social media and social networks becoming useful in collecting COVID-19 related data in those countries where health data collection efforts may be sub-optimal.  In a recent paper in The Lancet Digital Health [1], authors Kaiyuan Sun, Jenny Chen, and Cecile Viboud present data from the COVID-19 outbreak in China using information collected over social network sites as well as public news outlets and find strong correlations with later-released government statistics, showing the usefulness in such social and crowd-sourcing strategies to collect pertinent time-sensitive data.  In particular, the authors aim was to investigate this strategy of data collection to reduce the time delays between infection and detection, isolation and reporting of cases.

The paper is summarized below:

Kaiyuan Sun, PhD Jenny Chen, BScn Cécile Viboud, PhD . (2020).  Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study.  The Lancet: Digital Health; Volume 2, Issue 4, E201-E208.



As the outbreak of coronavirus disease 2019 (COVID-19) progresses, epidemiological data are needed to guide situational awareness and intervention strategies. Here we describe efforts to compile and disseminate epidemiological information on COVID-19 from news media and social networks.


In this population-level observational study, we searched DXY.cn, a health-care-oriented social network that is currently streaming news reports on COVID-19 from local and national Chinese health agencies. We compiled a list of individual patients with COVID-19 and daily province-level case counts between Jan 13 and Jan 31, 2020, in China. We also compiled a list of internationally exported cases of COVID-19 from global news media sources (Kyodo News, The Straits Times, and CNN), national governments, and health authorities. We assessed trends in the epidemiology of COVID-19 and studied the outbreak progression across China, assessing delays between symptom onset, seeking care at a hospital or clinic, and reporting, before and after Jan 18, 2020, as awareness of the outbreak increased. All data were made publicly available in real time.


We collected data for 507 patients with COVID-19 reported between Jan 13 and Jan 31, 2020, including 364 from mainland China and 143 from outside of China. 281 (55%) patients were male and the median age was 46 years (IQR 35–60). Few patients (13 [3%]) were younger than 15 years and the age profile of Chinese patients adjusted for baseline demographics confirmed a deficit of infections among children. Across the analysed period, delays between symptom onset and seeking care at a hospital or clinic were longer in Hubei province than in other provinces in mainland China and internationally. In mainland China, these delays decreased from 5 days before Jan 18, 2020, to 2 days thereafter until Jan 31, 2020 (p=0·0009). Although our sample captures only 507 (5·2%) of 9826 patients with COVID-19 reported by official sources during the analysed period, our data align with an official report published by Chinese authorities on Jan 28, 2020.


News reports and social media can help reconstruct the progression of an outbreak and provide detailed patient-level data in the context of a health emergency. The availability of a central physician-oriented social network facilitated the compilation of publicly available COVID-19 data in China. As the outbreak progresses, social media and news reports will probably capture a diminishing fraction of COVID-19 cases globally due to reporting fatigue and overwhelmed health-care systems. In the early stages of an outbreak, availability of public datasets is important to encourage analytical efforts by independent teams and provide robust evidence to guide interventions.

A Few notes on Methodology:

  • The authors used crowd-sourced reports from DXY.cn, a social network for Chinese physicians, health-care professionals, pharmacies and health-care facilities. This online platform provides real time coverage of the COVID-19 outbreak in China
  • More data was curated from news media, television and includes time-stamped information on COVID-19 cases
  • These reports are publicly available, de-identified patient data
  • No patient consent was needed and no ethics approval was required
  • Data was collected between January 20, 2020 and January 31,2020
  • Sex, age, province of identification, travel history, dates of symptom development was collected
  • Additional data was collected for other international sites of the pandemic including Cambodia, Canada, France, Germany, Hong Kong, India, Italy, Japan, Malaysia, Nepal, Russia, Singapore, UK, and USA
  • All patients in database had laboratory confirmation of infection



  • 507 patient data was collected with 153 visited and 152 resident of Wuhan
  • Reported cases were skewed toward males however the overall population curve is skewed toward males in China
  • Most cases (26%) were from Beijing (urban area) while an equal amount were from rural areas combined (Shaanzi and Yunnan)
  • Age distribution of COVID cases were skewed toward older age groups with median age of 45 HOWEVER there were surprisingly a statistically high amount of cases less than 5 years of age
  • Outbreak progression based on the crowd-sourced patient line was consistent with the data published by the China Center for Disease Control
  • Median reporting delay in the authors crowd-sourcing data was 5 days
  • Crowd-sourced data was able to detect apparent rapid growth of newly reported cases during the collection period in several provinces outside of Hubei province, which is consistent with local government data

The following graphs show age distribution for China in 2017 and predicted for 2050.

projected age distribution China 2050. Source https://chinapower.csis.org/aging-problem/













The authors have previously used this curation of news methodology to analyze the Ebola outbreak[2].

A further use of the crowd-sourced database was availability of travel histories for patients returning from Wuhan and onset of symptoms, allowing for estimation of incubation periods.

The following published literature has also used these datasets:

Backer JA, Klinkenberg D, Wallinga J: Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020, 25(5).

Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J: The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of internal medicine 2020, 172(9):577-582.

Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY et al: Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine 2020, 382(13):1199-1207.

Dataset is available on the Laboratory for the Modeling of Biological and Socio-technical systems website of Northeastern University at https://www.mobs-lab.org/.


  1. Sun K, Chen J, Viboud C: Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. The Lancet Digital health 2020, 2(4):e201-e208.
  2. Cleaton JM, Viboud C, Simonsen L, Hurtado AM, Chowell G: Characterizing Ebola Transmission Patterns Based on Internet News Reports. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016, 62(1):24-31.

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

Reporter: Stephen J. Williams, PhD.

SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer
April 27, 2020, 11:45 AM – 1:30 PM
Virtual Meeting: All Session Times Are U.S. EDT

All session times are U.S. Eastern Daylight Time (EDT). Access to AACR Virtual Annual Meeting I sessions are free with registration. Register now at http://www.aacr.org/virtualam2020

Session Type

Virtual Minisymposium


Molecular and Cellular Biology/Genetics

16 Presentations
11:45 AM – 1:30 PM
– Chairperson

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:45 AM – 1:30 PM
– Chairperson

  • in 80’s and 90’s signaling focused on defects and also oncogene addiction.  Now the field is switching to finding vulnerabilities in signaling cascades in cancer

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

11:45 AM – 11:55 AM
– Introduction

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:55 AM – 12:05 PM
1085 – Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis

Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Duke University, Durham, NC, University of Texas MD Anderson Cancer Center, Houston, TX

Abstract: Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors.




  • different isoforms of ras mutations exist differentially in various tumor types e.g. nras vs kras
  • the C terminal end serve as hotspots of mutations and probably isoform specific functions
  • they determined the interactomes of nras and kras and determined how many candidates are ras specific
  • they overlayed results from proteomic and CRSPR screen; EFR3a was a potential target that stuck out
  • using TCGA patients with higher EFR3a had poorer prognosis
  • EFR3a promotes Ras signaling; and required for RAS driven tumor growth (in RAS addicted tumors?)
  • EGFR3a promotes clustering of oncogenic RAS at plasma membrane


12:05 PM – 12:10 PM
– Discussion

12:10 PM – 12:20 PM
1086 – Downstream kinase signaling is dictated by specific KRAS mutations; Konstantin Budagyan, Jonathan Chernoff. Drexel University College of Medicine, Philadelphia, PA, Fox Chase Cancer Center, Philadelphia, PA @FoxChaseCancer

Abstract: Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC.

  • Flourescent coselection of KRAS edits by CRSPR screen in a colorectal cancer line; a cell that is competent to undergo HR can undergo combination multiple KRAS
  • target only mutant allele while leaving wild type intact;
  • it was KRAS editing event in APC  +/- mouse cell line
  • this enabled a screen for kinase inhibitors that decreased tumor growth in isogenic cell lines; PKC alpha and beta 1 inhibitors, also CDK4 inhibitors inhibited cell growth
  • questions about heterogeneity in KRAS clones; they looked at off target guides and looked at effects in screens; then they used top two clones that did not have off target;  questions about 3D culture- they have not done that; Question ? dependency on AKT activity? perhaps the G12E has different downstream effectors


12:20 PM – 12:25 PM
– Discussion

12:25 PM – 12:35 PM
1087 – NF1 regulates the RAS-related GTPases, RRAS and RRAS2, independent of RAS activity; Jillian M. Silva, Lizzeth Canche, Frank McCormick. University of California, San Francisco, San Francisco, CA @UCSFMedicine

Abstract: Neurofibromin, which is encoded by the neurofibromatosis type 1 (NF1) gene, is a tumor suppressor that acts as a RAS-GTPase activating protein (RAS-GAP) to stimulate the intrinsic GTPase activity of RAS as well as the closely related RAS subfamily members, RRAS, RRAS2, and MRAS. This results in the conversion of the active GTP-bound form of RAS into the inactive GDP-bound state leading to the downregulation of several RAS downstream effector pathways, most notably MAPK signaling. While the region of NF1 that regulates RAS activity represents only a small fraction of the entire protein, a large extent of the NF1 structural domains and their corresponding mechanistic functions remain uncharacterized despite the fact there is a high frequency of NF1 mutations in several different types of cancer. Thus, we wanted to elucidate the underlying biochemical and signaling functions of NF1 that are unrelated to the regulation of RAS and how loss of these functions contributes to the pathogenesis of cancer. To accomplish this objective, we used CRISPR-Cas9 methods to knockout NF1 in an isogenic “RASless” MEF model system, which is devoid of the major oncogenic RAS isoforms (HRAS, KRAS, and NRAS) and reconstituted with the KRAS4b wild-type or mutant KRASG12C or KRASG12D isoform. Loss of NF1 led to elevated RAS-GTP levels, however, this increase was not as profound as the levels in KRAS-mutated cells or provided a proliferative advantage. Although ablation of NF1 resulted in sustained activation of MAPK signaling, it also unexpectedly, resulted in a robust increase in AKT phosphorylation compared to KRAS-mutated cells. Surprisingly, loss of NF1 in KRAS4b wild-type and KRAS-mutated cells potently suppressed the RAS-related GTPases, RRAS and RRAS2, with modest effects on MRAS, at both the transcript and protein levels. A Clariom™D transcriptome microarray analysis revealed a significant downregulation in the NF-κB target genes, insulin-like growth factor binding protein 2 (IGFBP2), argininosuccinate synthetase 1 (ASS1), and DUSP1, in both the NF1 knockout KRAS4b wild-type and KRAS-mutated cells. Moreover, NF1Null melanoma cells also displayed a potent suppression of RRAS and RRAS2 as well as these NF-κB transcription factors. Since RRAS and RRAS2 both contain the same NF-κB transcription factor binding sites, we hypothesize that IGFBP2, ASS1, and/or DUSP1 may contribute to the NF1-mediated regulation of these RAS-related GTPases. More importantly, this study provides the first evidence of at least one novel RAS-independent function of NF1 to regulate the RAS-related subfamily members, RRAS and RRAS2, in a manner exclusive of its RAS-GTPase activity and this may provide insight into new potential biomarkers and molecular targets for treating patients with mutations in NF1.
  • NF1 and SPRED work together to signal from RTK cKIT through RAS
  • NF1 knockout cells had higher KRAS and had increased cell proliferation
  • NF1 -/-  or SPRED loss had increased ERK phosphorylation and some increase in AKT activity compared to parental cells
  • they used isogenic cell lines devoid of all RAS isoforms and then reconstituted with specific RAS WT or mutants
  • NF1 and SPRED KO both reduce RRAS expression; in an AKT independent mannner
  • NF1 SPRED KO cells have almost no IGFBP2 protein expression and SNAIL so maybe affecting EMT?
  • this effect is independent of its RAS GTPAse activity (noncanonical)

12:35 PM – 12:40 PM
– Discussion

12:40 PM – 12:50 PM
1088 – Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling; Kali J. Dale, Martin McMahon. University of Utah, Salt Lake City, UT, Huntsman Cancer Institute, Salt Lake City, UT

Abstract: RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers.

12:50 PM – 12:55 PM
– Discussion

12:55 PM – 1:05 PM
1090 – Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa De Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Memorial Sloan Kettering Cancer Center, New York, NY, Yale University, West Haven, CT, Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center, New York, NY @sloan_kettering

Abstract: The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors.

  • mTOR can be a potent regulator of PTEN and therefore a major issue when developing PI3K inhibitors

1:05 PM – 1:10 PM
– Discussion

1:10 PM – 1:20 PM
1091 – BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan

Daniel Gerlach, Michael Gmachl, Juergen Ramharter, Jessica Teh, Szu-Chin Fu, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Marco H. Hofmann. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, The University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

  • there is rational for developing an SOS1 inhibitor (GEF); BI3406 shows better PK and PD as a candidate
  • most sensitive cell lines to inhibitor carry KRAS mutation; NRAS or BRAF mutations are not sensititve
  • KRAS mutation defines sensitivity so they created KRAS mut isogenic cell lines
  • found best to co inhibit SOS and MEK as observed plasticity with only SOS
  • dual combination in lung NSCLC pancreatic showed enhanced efficacy compared to monotherapy
  • SOS1 inhibition plus irinotecan enhances DNA double strand breaks; no increased DNA damage in normal stroma but preferentially in tumor cells
  • these SOS1 had broad activity against KRAS mutant models;
  • phase 1 started in 2019;


1:20 PM – 1:25 PM
– Discussion

1:25 PM – 1:30 PM
– Closing Remarks

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

SESSION VMS.CH01.01 – Advances in Cancer Drug Design and Discovery

April 27, 2020, 11:45 AM – 1:15 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTIONAll session times are U.S. Eastern Daylight Time (EDT).

Session Type
Virtual Minisymposium
Cancer Chemistry
14 Presentations
11:45 AM – 11:45 AM
– ChairpersonZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:45 AM – 11:45 AM
– ChairpersonChristopher G. Nasveschuk. C4 Therapeutics, Watertown, MA

11:45 AM – 11:50 AM
– IntroductionZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:50 AM – 12:00 PM
1036 – Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Rogel Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI, Ascentage Pharma Group, Taizhou, Jiangsu, China

12:00 PM – 12:05 PM
– Discussion

12:05 PM – 12:15 PM
1037 – Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine productionXiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA

12:15 PM – 12:20 PM
– Discussion

12:20 PM – 12:30 PM
1038 – A potent and selective PARP14 inhibitor decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explantsLaurie Schenkel, Jennifer Molina, Kerren Swinger, Ryan Abo, Danielle Blackwell, Anne Cheung, William Church, Kristy Kuplast-Barr, Alvin Lu, Elena Minissale, Mario Niepel, Melissa Vasbinder, Tim Wigle, Victoria Richon, Heike Keilhack, Kevin Kuntz. Ribon Therapeutics, Cambridge, MA

12:30 PM – 12:35 PM
– Discussion

12:35 PM – 12:45 PM
1039 – Fragment-based drug discovery to identify small molecule allosteric inhibitors of SHP2. Philip J. Day, Valerio Berdini, Juan Castro, Gianni Chessari, Thomas G. Davies, James E. H. Day, Satoshi Fukaya, Chris Hamlett, Keisha Hearn, Steve Hiscock, Rhian Holvey, Satoru Ito, Yasuo Kodama, Kenichi Matsuo, Yoko Nakatsuru, Nick Palmer, Amanda Price, Tadashi Shimamura, Jeffrey D. St. Denis, Nicola G. Wallis, Glyn Williams, Christopher N. Johnson. Astex Pharmaceuticals, Inc., Cambridge, United Kingdom, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan

Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Recent advances have shown that genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signalling and inhibits proliferation of RTK-driven cancer cell lines. SHP2 is now understood to act upstream of RAS and plays a role in KRAS-driven cancers, an area of research which is rapidly growing. Considering that RTK deregulation often leads to a wide range of cancers and the newly appreciated role of SHP2 in KRAS-driven cancers, SHP2 inhibitors are therefore a promising therapeutic approach.
SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase domain and a C-terminal tail. SHP2 switches between “open” active and “closed” inactive forms due to autoinhibitory interactions between the N-SH2 domain and the phosphatase domain. Historically, phosphatases were deemed undruggable as there had been no advancements with active site inhibitors. We hypothesised that fragment screening would be highly applicable and amenable to this target to enable alternative means of inhibition through identification of allosteric binding sites. Here we describe the first reported fragment screen against SHP2.
Using our fragment-based PyramidTM approach, screening was carried out on two constructs of SHP2; a closed autoinhibited C-terminal truncated form (phosphatase and both SH2 domains), as well as the phosphatase-only domain. A combination of screening methods such as X-ray crystallography and NMR were employed to identify fragment hits at multiple sites on SHP2, including the tunnel-like allosteric site reported by Chen et al, 2016. Initial fragment hits had affinities for SHP2 in the range of 1mM as measured by ITC. Binding of these hits was improved using structure-guided design to generate compounds which inhibit SHP2 phosphatase activity and are promising starting points for further optimization.

  • anti estrogen receptor therapy: ER degraders is one class
  • AZ9833 enhances degradation of ER alpha
  • worked in preclinical mouse model (however very specific)
  • PK parameters were good for orally available in rodents;  also in vitro and in vivo correlation correlated in rats but not in dogs so they were not sure if good to go in humans
  • they were below Km in rats but already at saturated in dogs, dogs were high clearance
  • predicted human bioavailability at 40%


12:45 PM – 12:50 PM
– Discussion

12:50 PM – 1:00 PM
1042 – Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. AstraZeneca, Waltham, MA

1:00 PM – 1:05 PM
– Discussion

1:05 PM – 1:15 PM
– Closing RemarksChristopher G. Nasveschuk. MA

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Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education

Curator: Stephen J. Williams, PhD.

Dr. Cathy N. Davidson from Duke University gives a talk entitled: Now You See It.  Why the Future of Learning Demands a Paradigm Shift

In this talk, shown below, Dr. Davidson shows how our current education system has been designed for educating students for the industrial age type careers and skills needed for success in the Industrial Age and how this educational paradigm is failing to prepare students for the challenges they will face in their future careers.

Or as Dr. Davidson summarizes

Designing education not for your past but for their future

As the video is almost an hour I will summarize some of the main points below


Summary of talk

Dr. Davidson starts the talk with a thesis: that Institutions tend to preserve the problems they were created to solve.

All the current work, teaching paradigms that we use today were created for the last information age (19th century)

Our job to to remake the institutions of education work for the future not the one we inherited

Four information ages or technologies that radically changed communication

  1. advent of writing: B.C. in ancient Mesopotamia allowed us to record and transfer knowledge and ideas
  2. movable type – first seen in 10th century China
  3. steam powered press – allowed books to be mass produced and available to the middle class.  First time middle class was able to have unlimited access to literature
  4. internet- ability to publish and share ideas worldwide

Interestingly, in the early phases of each of these information ages, the same four complaints about the new technology/methodology of disseminating information was heard

  • ruins memory
  • creates a distraction
  • ruins interpersonal dialogue and authority
  • reduces complexity of thought

She gives an example of Socrates who hated writing and frequently stated that writing ruins memory, creates a distraction, and worst commits ideas to what one writes down which could not be changed or altered and so destroys ‘free thinking’.

She discusses how our educational institutions are designed for the industrial age.

The need for collaborative (group) learning AND teaching

Designing education not for your past but for the future

In other words preparing students for THEIR future not your past and the future careers that do not exist today.

In the West we were all taught to answer silently and alone.  However in Japan, education is arranged in the han or group think utilizing the best talents of each member in the group.  In Japan you are arranged in such groups at an early age.  The concept is that each member of the group contributes their unique talent and skill for the betterment of the whole group.  The goal is to demonstrate that the group worked well together.

see https://educationinjapan.wordpress.com/education-system-in-japan-general/the-han-at-work-community-spirit-begins-in-elementary-school/ for a description of “in the han”

In the 19th century in institutions had to solve a problem: how to get people out of the farm and into the factory and/or out of the shop and into the firm

Takes a lot of regulation and institutionalization to convince people that independent thought is not the best way in the corporation

keywords for an industrial age

  • timeliness
  • attention to task
  • standards, standardization
  • hierarchy
  • specialization, expertise
  • metrics (measures, management)
  • two cultures: separating curriculum into STEM versus artistic tracts or dividing the world of science and world of art

This effort led to a concept used in scientific labor management derived from this old paradigm in education, an educational system controlled and success measured using

  • grades (A,B,C,D)
  • multiple choice tests

keywords for our age

  • workflow
  • multitasking attention
  • interactive process (Prototype, Feedback)
  • data mining
  • collaboration by difference

Can using a methodology such as scientific curation affect higher education to achieve this goal of teaching students to collaborate in an interactive process using data mining to create a new workflow for any given problem?  Can a methodology of scientific curation be able to affect such changes needed in academic departments to achieve the above goal?

This will be the subject of future curations tested using real-world in class examples.

However, it is important to first discern that scientific content curation takes material from Peer reviewed sources and other expert-vetted sources.  This is unique from other types of content curation in which take from varied sources, some of which are not expert-reviewed, vetted, or possibly ‘fake news’ or highly edited materials such as altered video and audio.  In this respect, the expert acts not only as curator but as referee.  In addition, collaboration is necessary and even compulsory for the methodology of scientific content curation, portending the curator not as the sole expert but revealing the CONTENT from experts as the main focus for learning and edification.

Other article of note on this subject in this Open Access Online Scientific Journal include:

The above articles will give a good background on this NEW Conceived Methodology of Scientific Curation and its Applicability in various areas such as Medical Publishing, and as discussed below Medical Education.

To understand the new paradigm in medical communication and the impact curative networks have or will play in this arena please read the following:

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

This article discusses a history of medical communication and how science and medical communication initially moved from discussions from select individuals to the current open accessible and cooperative structure using Web 2.0 as a platform.


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In Data Science, A Pioneer Practitioner’s Portfolio of Algorithm-based Decision Support Systems for Operations Management in Several Industrial Verticals: Analytics Designer, Aviva Lev-Ari, PhD, RN

An overview of Data Science as a discipline is presented in

Data Science & Analytics: What do Data Scientists Do in 2020 and a Pioneer Practitioner’s Portfolio of Algorithm-based Decision Support Systems for Operations Management in Several Industrial Verticals


On this landscape about IT, The Internet, Analytics, Statistics, Big Data, Data Science and Artificial Intelligence, I am to tell stories on my own pioneering work in data science, Algorithm-based decision support systems design for different organizations in several sectors of the US economy:

Images on 12/7/2019

  • Startups:
  1. TimeØ Group – The leader in Digital Marketplaces Design
  2. Concept Five Technologies, Inc. – Commercialization of DoD funded technologies
  3. MDSS, Inc. – SAAS in Analytical Services
  4. LPBI Group – Pharmaceutical & Media
  • Top Tier Management Consulting: SRI International, Monitor Group;
  • OEM: Amdahl Corporation;
  • Top 6th System Integrator: Perot System Corporation;
  • FFRDC: MITRE Corporation.
  • Publishing industry: was Director of Research at McGraw-Hill/CTB.
  • Northeastern University, Researcher on Cardiovascular Pharmacotherapy at Bouve College of Health Sciences (Independent research guided by Professor of Pharmacology)

Type of institutions:

  • For-Profit corporations: Amdahl Corp, PSC, McGraw-Hill
  • For-Profit Top Tier Consulting: Monitor Company, Now Deloitte
  • Not-for-Profit Top Tier Consulting: SRI International
  • Pharmaceutical & Media Start up in eScientific Publishing: LPBI Group:
  1. Developers of Curation methodology for e-Articles [N = 5,700],
  2. Developers of electronic Table of Contents for e-Books in Medicine [N = 16, https://lnkd.in/ekWGNqA] and
  3. Developers of Methodologies for real time press coverage and production of e-Proceedings of Biotech Conferences [N = 70].


Autobiographical Annotations: Tribute to My Professors


Pioneering implementations of analytics to business decision making: contributions to domain knowledge conceptualization, research design, methodology development, data modeling and statistical data analysis: Aviva Lev-Ari, UCB, PhD’83; HUJI MA’76


Recollections of Years at UC, Berkeley, Part 1 and Part 2

  • Recollections: Part 1 – My days at Berkeley, 9/1978 – 12/1983 – About my doctoral advisor, Allan Pred, other professors and other peers


  • Recollections: Part 2 – “While Rolling” is preceded by “While Enrolling” Autobiographical Alumna Recollections of Berkeley – Aviva Lev-Ari, PhD’83



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

For @AVIVA1950, Founder, LPBI Group @pharma_BI: Twitter Analytics [Engagement Rate, Link Clicks, Retweets, Likes, Replies] & Tweet Highlights [Tweets, Impressions, Profile Visits, Mentions, New Followers] https://analytics.twitter.com/user/AVIVA1950/tweets

Thriving at the Survival Calls during Careers in the Digital Age – An AGE like no Other, also known as, DIGITAL

Professional Self Re-Invention: From Academia to Industry – Opportunities for PhDs in the Business Sector of the Economy

Reflections on a Four-phase Career: Aviva Lev-Ari, PhD, RNMarch 2018

Was prepared for publication in American Friends of the Hebrew University (AFHU), May 2018 Newsletter, Hebrew University’s HUJI Alumni Spotlight Section.

Aviva Lev-Ari’s profile was up on 5/3/2018 on AFHU website under the Alumni Spotlight at https://www.afhu.org/

On 5/11/2018, Excerpts were Published in AFHU e-news.




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Analysis of Utilizing LPBI Group’s Scientific Curation Platform as an Educational Tool: New Paradigm for Student Engagement

Author: Stephen J. Williams, Ph.D.



Use of LBPI Platform for Educational Purposes

Goal:  to offer supplemental information for student lessons in an upper level Biology course on Cell Signaling and Cell Motility with emphasis on disease etiology including cancer, neurological disease, and cardiovascular disease.

Course:  Temple University Department of Biology course Cell Signaling and Motility Spring semester 2019. Forty five students enrolled.

Methodology:  Each weekly lesson was presented to students as a PowerPoint presentation.  After each lesson the powerpoint presentation was originally meant to be disseminated to each class-registered student on the students Canvas account.  Canvas is a cloud based Learning Management Software developed by educational technology company Salt Lake City, Utah company Infrastructure, Inc.  According to rough figures, Canvas® charges a setup fee and at least $30 per user (for a university the size of Temple University: 55,000 students at $30 each = 1.6 million a semester for user fees only).

As a result of a technical issue with uploading the first week lesson on this system, I had informed the class that, as an alternative means, class presentation notes and lectures will be posted on the site www.pharmaceuticalintelligence.com as a separate post and searchable on all search engines including Google, Twitter, Yahoo, Bing, Facebook etc. In addition, I had informed the students that supplemental information, from curated posts and articles from our site, would be added to the class lecture post as supplemental information they could use for further reading on the material as well as helpful information and reference for class projects.

The posted material was tagged with #TUBiol3373 (university abbreviation, department, course number) and disseminated to various social media platforms using our system.  This allowed the students to enter #TUBiol3373 in any search engine to easily find their lecture notes and supplemental information.

This gave students access to lectures on a mobile platform which was easily discoverable due to our ability to do search engine optimization. (#TUBiol3373 was among the first search results on most popular search engines).

From a technical standpoint,  the ease at which posts of this nature can be made as well as the ease of including links to full articles as references as well as media has been noted.  Although students seem to navigate the Canvas software with ease, they had noticed many professors have issues or problems with using this software, especially with navigating the software for their needs.   LBPI’s platform is an easily updated, accessible, and extensive knowledge system which can alleviate many of these technical issues and provide the added value of incorporating media based instructional material as well as downloadable file and allow the instructor ability to expound on the presented material with commentary.  In addition due to the social nature of the platform, feedback can be attained by use of curated site statistics and commentary sections as well as online surveys.



After the first week, all 45 students used LBPI platform to access these lecture notes with 17 out of 45 continuing to refer to the site during every week (week 1-4) to the class notes.  This was evident from our site statistics as well as number of downloads of the material.  The students had used the #TUBIol3373 and were directed to the site mainly from search engines Google and Yahoo.  In addition, students had also clicked on the links corresponding to supplemental information which I had included, from articles on our site.  In addition, because of the ability to incorporate media on our site, additional information including instructional videos and interviews were included in lecture posts, and this material was easily updated on the instructor’s side.

Adoption of the additional material from our site was outstanding, as many students had verbally said that the additional material was very useful in their studies.  This was also evidenced by site statistics owing to the secondary clicks made from the class lecture post going to additional articles, some not even included as links on the original post.

In addition, and  more important, students had incorporated many of the information from the additional site articles posted and referenced in their class group projects.  At end of semester a survey was emailed to each student  to assess the usefulness of such a teaching strategy. Results of the polling are shown below.

Results from polling of students of #TUBiol3373 “Cell Signaling & Motility” Class

Do you find using a web based platform such as a site like this an easier communication platform for posting lecture notes/added information than a platform like Canvas®? (5 votes)

Answer Votes Percent  
Yes 2 40%  
Somewhat but could use some improvement 2 40%  
No 1 20%  
Did not use web site 0 0%  


Do you find using an open access, curated information platform like this site more useful than using multiple sources to find useful extra study/presentation materials? (6 votes)

Answer Votes Percent  
Yes 5 83%  
No 1 17%  


Did you use the search engine on the site (located on the top right of the home page) to find extra information on topics for your presentations/study material? (5 votes)

Answer Votes Percent  
Yes 4 67%  
No 1 17%  
Did not use web site 1 17%  


Were you able to easily find the supplemental information for each lecture on search engines like Google/Yahoo/Bing/Twitter using the hashtag #TUBiol3373? (6 votes)

Answer Votes Percent  
Yes I was able to find the site easily 4 67%  
No 1 17%  
Did not use a search engine to find site, went directly to site 1 17%  
Encountered some difficulty 0 0%  
Did not use the site for supplemental or class information 0 0%  


How did you find the supplemental material included on this site above the Powerpoint presented material for each of the lectures? (7 votes)

Answer Votes Percent  
Very Useful 4 57%  
Did not use supplemental information 2 29%  
Somewhat Useful 1 14%  
Not Useful 0 0%  

How many times did you use the information on this site (https://www.pharmaceuticalintelligence.com) for class/test/project preparation? (7 votes)

Answer Votes Percent  
Frequently 3 43%  
Sparingly 2 29%  
Occasionally 1 14%  
Never 1 14%  








Views of #TUBiol3373 lessons/posts on www.pharmaceuticalintelligence.com                    


Lesson/Title Total # views # views 1st day # views 2nd day % views day 1 and 2 % views  after 1st 2 days
Lesson 1 AND 2 Cell Signaling & Motility: Lessons, Curations and Articles of reference as supplemental information: #TUBiol3373 60 27 15 93% 45%
Lesson 3 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373 56 12 11 51% 93%
Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373 37 17 6 48% 31%
Lesson 5 Cell Signaling And Motility: Cytoskeleton & Actin: Curations and Articles of reference as supplemental information: #TUBiol3373 13 6 2 17% 15%
Lesson 8 Cell Signaling and Motility: Lesson and Supplemental Information on Cell Junctions and ECM: #TUBiol3373 16 8 2 22% 13%
Lesson 9 Cell Signaling: Curations and Articles of reference as supplemental information for lecture section on WNTs: #TUBioll3373 20 10 3 28% 15%
Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373 19 11 2 28% 13%
Lesson 10 on Cancer, Oncogenes, and Aberrant Cell Signal Termination in Disease for #TUBiol3373 21 10 2 26% 20%
Totals 247 69 46 31% 62%


Note: for calculation of %views on days 1 and 2 of posting lesson and supplemental material on the journal; %views day1 and 2 = (#views day 1 + #views day 2)*100/45 {45 students in class}

For calculation of %views past day 1 and 2 = (total # views – day1 views – day2 views) * 100/45

For calculation in total column last two columns were divided by # of students (45) and # of posts (8)


Overall class engagement was positive with 31% of students interacting with the site during the course on the first two days after posting lessons while 61% of students interacted with the site during the rest of the duration of the course.  The higher number of students interacting with the site after the first two days after lecture and posting may be due to a higher number of students using the posted material for study for the test and using material for presentation purposes.

Engagement with the site for the first two days post lecture ranged from 93% engagement to 22% engagement.  As the class neared the first exam engagement with the site was high however engagement was lower near the end of the class period potentially due to the last exam was a group project and not a written exam.  Students appeared to engage highly with the site to get material for study for the written exam however there still was significant engagement by students for purposes of preparation for oral group projects.  Possibly engagement with the site post 2 days for the later lectures could be higher if a written exam was also given towards the end of the class as well.  This type of analysis allows the professor to understand the level of class engagement week by week.

The results of post-class polling confirm some of the conclusions on engagement.  After the final grades were given out all 45 students received an email with a link to the poll.  Of the 45 students emailed, there were 20 views of the poll with 5-7 answers per question.  Interestingly, most answers were positive on the site and the use of curated material for learning and a source of research project material.   It was very easy finding the posts using the #classname and most students used Google to find the material, which was at the top of Google search results.  Not many students used Twitter or other search engines.  Some went directly to the site.  A majority (71%) found the material useful or somewhat useful for their class presentations and researching topics.

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@PharmaceuticalIntelligence.com Journal: Article Publication by LPBI Group’s FIT Members, January 2019 – June 2019


Reporter: Aviva Lev-Ari, PhD, RN


UPDATED on 2/24/2020


Curator’s Name

1/1/2019 – 6/30/2019

7/1/2019 – 12/31/2019

Dr. Sudipta Saha


Dr. Stephen J. Williams 37 17
Dr. Irina Robu


Dr. Dror Nir


Gail S. Thornton


Amnon Denzig


Rick Mandhal


Dr. Aviva Lev-Ari





Total for 2019:



97+1 (Joel) = 98


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Real Time Coverage @BIOConvention #BIO2019: Understanding the Voices of Patients: Unique Perspectives on Healthcare; June 4 11:00 AM

Reporter: Stephen J. Williams, PhD @StephenJWillia2



The role of the patient has evolved dramatically over the past decade. Not only are patients increasingly more involved in their healthcare decision making, they are also passionate advocates who work tirelessly to advance drug development research and development and secure a public policy environment that is patient-centric. Join a discussion with patient advocates as they discuss their journeys to diagnosis and their viewpoints on our healthcare system. They will share their perspectives on what it means to be a patient and how they are advocating in their own unique ways to achieve a common goal: bringing new treatments to patients.

Christopher Anselmo: affected by MS but did not understand why he should be involved in a study at the time or share your story but he saw others who benefited from both of these and now is fervent patient advocate. Each patient is worth their weight in gold as needed for other patient support.  The why needs to be asked of oneself before go out to other patients or into new trials. Might not see through to end if don’t have that discussion of why doing this.
Eve Bukowski:  she had stomach aches, went to hospital, and diagnosed with constipation, but had stage III colon cancer.  She was campaigning for Hillary Clinton but then started to campaign for her life.  She wound up having multiple therapies and even many I/O trials.  Fighting cancer is a mental challenge.   She has been fighting for eleven years but has an amazing strength and will.
Emily Kramer: cystic fibrosis patient.  Advocates for research as she has a mutant allele (nonsense mut) that is not targeted by the current new therapy against known mutants of CFTR.  So started Emily’s Entourage for this orphan of an orphan disease.  Funded $4 million in grants and helped develop a new startup and get early seed funding.  Noticed that the infrastructure to get these drugs to market was broken and also is investing to shore up these breaks in drug pipeline infrastructure for orphan diseases. For progressive diseases she would like drug developers to shift the timelines or speed with which they get to take a chance and try that new possibility. As a patient advocacy org, they want to partner every step of the way with biotech/pharma, they understand co’s and stakeholders can only do so much but let’s break out of convention.
Julie: many patient advocacy groups go person to person and make a support network.

Please follow LIVE on TWITTER using the following @ handles and # hashtags:





# Hashtags

#BIO2019 (official meeting hashtag)

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Lesson 5 Cell Signaling And Motility: Cytoskeleton & Actin: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Cell motility or migration is an essential cellular process for a variety of biological events. In embryonic development, cells migrate to appropriate locations for the morphogenesis of tissues and organs. Cells need to migrate to heal the wound in repairing damaged tissue. Vascular endothelial cells (ECs) migrate to form new capillaries during angiogenesis. White blood cells migrate to the sites of inflammation to kill bacteria. Cancer cell metastasis involves their migration through the blood vessel wall to invade surrounding tissues.

Please Click on the Following Powerpoint Presentation for Lesson 4 on the Cytoskeleton, Actin, and Filaments


cell signaling 5 lesson

This post will be updated with further information when we get into Lesson 6 and complete our discussion on the Cytoskeleton

Please see the following articles on Actin and the Cytoskeleton in Cellular Signaling

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

This article, constitutes a broad, but not complete review of the emerging discoveries of the critical role of calcium signaling on cell motility and, by extension, embryonic development, cancer metastasis, changes in vascular compliance at the junction between the endothelium and the underlying interstitial layer.  The effect of calcium signaling on the heart in arrhtmogenesis and heart failure will be a third in this series, while the binding of calcium to troponin C in the synchronous contraction of the myocardium had been discussed by Dr. Lev-Ari in Part I.

Universal MOTIFs essential to skeletal muscle, smooth muscle, cardiac syncytial muscle, endothelium, neovascularization, atherosclerosis and hypertension, cell division, embryogenesis, and cancer metastasis. The discussion will be presented in several parts:
1.  Biochemical and signaling cascades in cell motility
2.  Extracellular matrix and cell-ECM adhesions
3.  Actin dynamics in cell-cell adhesion
4.  Effect of intracellular Ca++ action on cell motility
5.  Regulation of the cytoskeleton
6.  Role of thymosin in actin-sequestration
7.  T-lymphocyte signaling and the actin cytoskeleton


Identification of Biomarkers that are Related to the Actin Cytoskeleton

In this article the Dr. Larry Bernstein covers two types of biomarker on the function of actin in cytoskeleton mobility in situ.

  • First, is an application in developing the actin or other component, for a biotarget and then, to be able to follow it as

(a) a biomarker either for diagnosis, or

(b) for the potential treatment prediction of disease free survival.

  • Second, is mostly in the context of MI, for which there is an abundance of work to reference, and a substantial body of knowledge about

(a) treatment and long term effects of diet, exercise, and

(b) underlying effects of therapeutic drugs.

Microtubule-Associated Protein Assembled on Polymerized Microtubules

(This article has a great 3D visualization of a microtuble structure as well as description of genetic diseases which result from mutations in tubulin and effects on intracellular trafficking of proteins.

A latticework of tiny tubes called microtubules gives your cells their shape and also acts like a railroad track that essential proteins travel on. But if there is a glitch in the connection between train and track, diseases can occur. In the November 24, 2015 issue of PNAS, Tatyana Polenova, Ph.D., Professor of Chemistry and Biochemistry, and her team at the University of Delaware (UD), together with John C. Williams, Ph.D., Associate Professor at the Beckman Research Institute of City of Hope in Duarte, California, reveal for the first time — atom by atom — the structure of a protein bound to a microtubule. The protein of focus, CAP-Gly, short for “cytoskeleton-associated protein-glycine-rich domains,” is a component of dynactin, which binds with the motor protein dynein to move cargoes of essential proteins along the microtubule tracks. Mutations in CAP-Gly have been linked to such neurological diseases and disorders as Perry syndrome and distal spinal bulbar muscular dystrophy.


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