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Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Below please find the link to the Powerpoint presentation for lesson #4 for #TUBiol3373.  The lesson first competes the discussion on G Protein Coupled Receptors, including how cells terminate cell signals.  Included are mechanisms of receptor desensitization.  Please NOTE that desensitization mechanisms like B arrestin decoupling of G proteins and receptor endocytosis occur after REPEATED and HIGH exposures to agonist.  Hydrolysis of GTP of the alpha subunit of G proteins, removal of agonist, and the action of phosphodiesterase on the second messenger (cAMP or cGMP) is what results in the downslope of the effect curve, the termination of the signal after agonist-receptor interaction.

 

Click below for PowerPoint of lesson 4

Powerpoint for lesson 4

 

Please Click below for the papers for your Group presentations

paper 1: Membrane interactions of G proteins and other related proteins

paper 2: Macaluso_et_al-2002-Journal_of_Cellular_Physiology

paper 3: Interactions of Ras proteins with the plasma membrane

paper 4: Futosi_et_al-2016-Immunological_Reviews

 

Please find related article on G proteins and Receptor Tyrosine Kinases on this Open Access Online Journal

G Protein–Coupled Receptor and S-Nitrosylation in Cardiac Ischemia and Acute Coronary Syndrome

Action of Hormones on the Circulation

Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses

VEGF activation and signaling, lysine methylation, and activation of receptor tyrosine kinase

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Research about marijuana and fertility is limited but some previous studies suggested that it might harm semen quality. Smoking of any type is also known to be a risk factor for male infertility. So, men who have smoked cannabis are expected to have worse measures of fertility but the data from a recent study suggested the opposite. The finding contradicts all conventional knowledge on how weed affects sperm. This may be because previous research typically focused on men with drug abuse history but this present study simply asked men if they had smoked more than two joints in their life.

 

Analysis of 1,143 semen samples from 662 men collected between 2000 and 2017 at the Fertility Clinic at Massachusetts General Hospital showed that those who had smoked weed at some point in their life had a mean sperm concentration of 62.7 million sperm per milliliter (mL) of ejaculate, while men who avoided marijuana entirely had mean concentrations of 45.4 million/mL. Added to this only 5% of weed smokers had sperm concentrations below the 15 million/mL threshold the World Health Organization has set for a “normal” sperm count, versus 12% of men who never smoked marijuana.

 

The study has some imperfections such as the participants are not necessarily representative of the general population. They were predominantly college educated men with a mean age of 36, and were all seeking treatment at a fertility center. Further research is needed to support the findings. Two possibilities are put forward by the researchers as the reason behind such data. The first is that low levels of marijuana could have a positive effect on the endocannabinoid system, the neurotransmitters in the nervous system that bind to cannabinoid receptors, and are known to regulate fertility. The second is that may be weed-smokers are just bigger risk takers and men with higher testosterone levels and thus have better sperm count.

 

But, there’s certainly no medical recommendation to smoke weed as a fertility treatment but this study, at least, suggests that a little marijuana doesn’t hurt and might benefit sperm production in some way. But, the researchers specified that their finding does not necessarily mean that smoking cannabis increases the chances of fatherhood.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/30726923

 

https://www.bloomberg.com/amp/news/articles/2019-02-06/cannabis-smoking-associated-with-higher-sperm-count-study-finds?__twitter_impression=true

 

https://qz.com/1543564/smoking-weed-linked-to-higher-sperm-count-in-a-harvard-study/

 

https://www.thestar.com.my/news/world/2019/02/06/cannabis-smoking-associated-with-higher-sperm-count-study-finds/

 

http://time.com/5520421/smoking-marijuana-sperm-fertility/

 

https://www.health.com/infertility/marijuana-sperm-count


Unexpected Genetic Vulnerability to Menthol Cigarette Use

Reporter: Irina Robu, PhD

According to a study published in PLOS genetics, a group of international researchers supported by U.S. Food and Drug Administration and the National Institute of Health have found a genetic variant of MRGPRX4 gene in people of African descent that increases a smoker’s preference for cigarettes containing menthol. The FDA determined that

  • nearly 20 million people of African American origin in the United States smoke menthol cigarette.
  • Research has shown that 86 percent of African-American smokers use menthol cigarettes in comparison to the smokers of European descent which are less than 30 percent.

In this study, the researcher Andrew Griffith uncovered clues as to how menthol may reduce the irritation and harshness of smoking cigarettes. The results can help public health agencies to develop strategies to lower the rates of harmful cigarette smoking among groups particularly vulnerable.

At the same time, researchers at University of Texas Southwestern Medical Center led by Dennis Drayna, conducted a detail genetic analyses on 13000 adults using data from a multiethnic, population-based group of smokers from the Dallas Heart Study and from an African-American group of smokers from the Dallas Biobank.

The researchers report that

  • 5 to 8 percent of the African-American study participants had the gene variant.
  • None of the participants of European, Asian, or Native American descent had the variant.
  • Recognizing the genetic variant, pointed the researchers in an unanticipated direction, leading them to offer
  • the first characterization of this naturally-occurring MRGPRX4 variant in humans.
  • The gene codes for a sensor/receptor is believed to be involved in detecting and responding to irritants from the environment in the lungs and airways.

Drayna further stated that while the gene variant can’t explain all of the increased use of menthol cigarettes by African-Americans, the results show that this variant is a theoretically vital factor that motivates the predilection for menthol cigarettes in the population.

Source

https://www.nih.gov/news-events/news-releases/researchers-find-genetic-vulnerability-menthol-cigarette-use

 


  • World Medical Innovation Forum, Partners Innovations, ARTIFICIAL INTELLIGENCE | APRIL 8–10, 2019 | Westin, BOSTON

https://worldmedicalinnovation.org/agenda/

Aviva Lev-Ari, PhD, RN Founder, LPBI Group

will cover this event in Real Time

@AVIVA1950

@pharma_BI

 

 

Monday, April 8, 2019

7:00 am – 8:00 am
7:00 am – 5:00 pm
8:00 am – 9:40 am
Bayer Ballroom

First Look

Nine rapid fire presentations on the applications of AI in Clinical Care

Moderator: Giles Boland, MD
  • Chair, Department of Radiology, BWH; Philip H. Cook Professor of Radiology, HMS
Moderator: Trung Do
  • VP, Business Development, Innovation, PHS
9:40 am – 9:55 am
9:55 am – 11:35 am
Bayer Ballroom

First Look

Nine rapid fire presentations on the applications of AI in Clinical Care

11:45 am – 1:00 pm

Discovery Café Sessions

Lunch with Top Leading Experts: Intensive sessions addressing cutting-edge artificial intelligence topics.

Applying AI to Save Lives During the Opioid Crisis

The U.S. is in the throes of a devastating epidemic of opioid addiction and overdose — some 130 people die in this country every day from opioids, says the National Institute on Drug Abuse. With a total economic cost of more than $78 billion a year, academic and industry organizations are harnessing AI to develop new tools that can help alleviate this national crisis. This session will discuss some of the AI-based strategies that academic and industry teams are leveraging to help clinical and public health officials better predict, identify, and treat opioid addiction, as well as some of the concerns around data privacy.

Moderator: Thomas Sequist, MD, Chief Quality & Safety Officer, PHS

Bob Burgin, CEO, Amplifire Healthcare Alliance

Carm Huntress, CEO, RxRevu Inc

Sarah Wakeman, MD, Medical Director, Substance Use Disorder Initiative, MGH; Assistant Professor, Medicine, HMS

Scott Weiner, MD, Director, Brigham Comprehensive Opioid Response and Education (B-CORE) Program, BWH; Assistant Professor, HMS

 

Community Hospitals: Key Component in Healthcare Transformation

Community hospitals are the largest sources of patient care in the U.S. As such, they represent a critical frontier in the transformation of health care. How are these organizations using AI and digital technologies to drive transformation? What are the key distinctions from academic medical centers? This session will address these and other critical topics that impact community hospitals and their essential, though often overlooked, role in health care.

Moderator: Michael Jaff, DO, President, NWH, PHS, Professor of Medicine, HMS

Fabien Beckers, PhD, CEO, Arterys

Joanna Geisinger, CEO, TORq Interface

Lee Schwamm, MD, Director, Center for TeleHealth and Exec Vice Chair, Neurology, MGH; Professor, Neurology, HMS

Tal Wenderow, CEO, Beyond Verbal

 

Digital Management of Diabetes

Across the full spectrum of patient care, the management of diabetes has been flooded with new technology and treatment options for both type 1 and type 2 diabetes – there is a range of new devices and software, including automatic insulin infusion systems, glucose sensors, AI-based algorithms and decision support tools, with artificial pancreas on the horizon. This session will focus on these areas as well as clinical use cases that highlight the value of AI.

Moderator: Deborah Wexler, MD, Clinical Director, Diabetes Center, MGH; Associate Professor, HMS

Marie McDonnell, MD, Section Chief and Director, Diabetes Program, BWH; Lecturer, HMS

Joshua Riff, MD, CEO, Onduo

 

Emergency Medicine

 

Mental Health and the Promise of AI

Moderator: Sabine Wilhelm, PhD, Chief of Psychology; Director, OCD and Related Disorders Program, MGH; Professor, Psychology, HMS

Thomas McCoy, MD, Director of Research, Center for Quantitative Health, MGH; Assistant Professor, Psychiatry & Medicine, HMS

Christopher Molaro, CEO, Neuroflow

David Silbersweig, MD, Chairman, Department of Psychiatry, BWH; Stanley Cobb Professor of Psychiatry, HMS

 

From Startup to Impact (Pharma and Diagnostics)

With all the hype surrounding AI, this session will focus on what really matters. Impact! Who is really moving the needle in life sciences today? This session will introduce you to five leading companies who will share their client stories over lunch.

Moderator: James Brink, MD, Radiologist-in-Chief, MGH; Juan M. Taveras Professor of Radiology, HMS

1:00 pm – 1:15 pm
1:15 pm – 1:45 pm
Bayer Ballroom
1:45 pm – 2:35 pm
Bayer Ballroom

AMC AI Strategy: AI from the Top

  • Board Member, PHS; President Emerita and Professor of Neuroscience, MIT
  • Chief Data Science Officer, PHS; Vice Chairman, Radiology, MGH; Associate Professor, Radiology, HMS
  • Chief Academic Officer, PHS; Laurie Carrol Guthart Professor of Medicine, Academic Dean for Partners, HMS; 2019 Forum Co-Chair
  • Chief Clinical Officer, PHS; Professor of Medicine, HMS; 2019 Forum Co-Chair
2:35 pm – 3:25 pm
Bayer Ballroom

RWE and Trial Optimization in the AI Era

Moderator: Thomas Lynch, MD
  • EVP and CSO, R&D, Bristol-Myers Squibb
  • CMO, CSO, SVP Oncology, Flatiron Health
  • EVP MA&PV and Bayer CMO, Bayer AG
  • Chief Architect, Microsoft Healthcare
  • CEO, My Own Med Inc.
  • Executive Director, Clinical Trials Office, PHS; Associate Professor of Medicine, HMS
3:25 pm – 4:15 pm
Bayer Ballroom

AI Driven Value-Based Care

Moderator: Timothy Ferris, MD
  • CEO, MGPO; Professor of Medicine, HMS
  • CEO, American Heart Association
  • EVP, President, Network Solutions Change Healthcare
  • Vice Chairman, Investment Banking and Managing Director Lazard Freres
  • CEO, NHS England
4:15 pm – 5:05 pm
Bayer Ballroom

Cardiovascular Care: Reinvented Through AI

  • Vice Chair for Scientific Innovation, Department of Medicine, BWH; Associate Professor of Medicine, HMS
  • President, Bayer Pharma Americas Region, Bayer
  • Director, Cardiac Imaging MR PET CT Program, MGH; Professor, Medicine, HMS
5:15 pm – 6:15 pm

Tuesday, April 9, 2019

7:00 am – 8:00 am
7:00 am – 5:00 pm
7:50 am – 8:00 am
Bayer Ballroom

Opening Remarks

  • Chief Innovation Officer, PHS; President, Partners HealthCare International
8:00 am – 8:50 am
Bayer Ballroom

Implementing AI in Cancer Care

  • Associate Surgeon, BWH; Richard E. Wilson Professor of Surgery in the Field of Surgical Oncology, HMS
  • Chief, Breast Imaging Division, MGH; Professor of Radiology, HMS
  • President and Co-Founder, LunaDNA
  • Delta Electronics Professor, Electrical Engineering and Computer Science Department, MIT
  • Director, Cancer Genome Analysis, Broad Institute; Professor of Pathology, HMS
  • CEO, insitro
8:50 am – 9:40 am
Bayer Ballroom

Imagining Medicine in the Year 2054

In 1984 Isaac Asimov was asked to predict what life in 2019 would be like. Using the same aperture, we as what will health care look like 35 years from now? What capabilities will clinicians have that they now struggle with? And what will be the biggest challenges? Current trends suggest that we will see some significant gains in the areas of cancer immunotherapy, gene therapy for devastating rare diseases, and treatments for common neuropsychiatric conditions, including schizophrenia and depression. Panelists will draw on their visionary perspective and will reflect on what to expect and why.

Moderator: Keith Flaherty, MD
  • Director, Clinical Research, MGH; Professor of Medicine, HMS
  • Vice Chair for Scientific Innovation, Department of Medicine, BWH; Associate Professor of Medicine, HMS
  • Director, Cellular Immunotherapy Program, MGH; Assistant Professor, Medicine, HMS
  • Vice-Chair, Neurology, Director, Genetics and Aging Research Unit, MGH; Joseph P. and Rose F. Kennedy Professor of Neurology, HMS
  • CEO, Biogen
9:40 am – 10:10 am
10:10 am – 10:40 am
Bayer Ballroom
10:40 am – 11:30 am
Bayer Ballroom

CEO Roundtable

Moderator: Anne Klibanski, MD
  • Chief Academic Officer, PHS; Laurie Carrol Guthart Professor of Medicine, Academic Dean for Partners, HMS; 2019 Forum Co-Chair
  • EVP and Chief Commercial Officer, Bristol-Myers Squibb
  • CEO, Philips
  • EVP, Head, Pharmaceuticals Research & Development, Bayer AG
  • CEO, Siemens Healthineers
  • CEO, GE Healthcare
11:45 am – 1:00 pm

Discovery Cafe Sessions

Lunch with Top Leading Experts: Intensive sessions addressing cutting-edge artificial intelligence topics.

Back Office of the Provider Future

Moderator: Peter Markell, EVP, Administration and Finance, CFO and Treasurer, PHS

Kent Ivanoff, CEO, VisitPay

Connie Moser, Chief Operating Officer, Verge Health

 

Chief Digital Strategy Officer Roundtable

With the advent of healthcare AI-enabled technologies, this session brings together several chief digital health officers from a range of organizations. The discussion will address key tradeoffs in sequencing technology across academic medical centers; what technologies are being prioritized; and how consumer expectations are impacting the future delivery model of healthcare.

Moderator: Alistair Erskine, MD, Chief Digital Health Officer, PHS

Michael Anderes, Chief Innovation and Digital Health Officer, Froedtert Health; President, Inception Health

Adam Landman, MD, VP and CIO, Brigham Health; Associate Professor of Emergency Medicine, HMS

Aimee Quirk, CEO, innovationOchsner

Richard Zane, MD, Chief Innovation Officer, UCHealth; Professor and Chair,Department of Emergency Medicine, University of Colorado School of Medicine

 

Innovation Fellows: A New Model of Collaboration

The Innovation Fellows Program provides short-term, experiential career development opportunities for future leaders in health care focused on accelerating collaborative innovation between science and industry. It facilitates personnel exchanges between Harvard Medical School staff from Partners’ hospitals and participating biopharmaceutical, device, venture capital, digital health, payor and consulting firms. A successful example of open innovation, Fellows and Hosts learn from each other as they collaborate on projects ranging from clinical development to digital health & artificial intelligence to new care delivery models and industry disruption. Come listen to the experience and insights of our panelists, including Fellows, Industry Partners and hospital leadership, and learn how this new model of collaboration can deliver value and lead to broader relationships between industry and academia.

 

Last Mile: Fully Implementing AI in Healthcare

Moderator: Keith Dreyer, DO, PhD, Chief Data Science Officer, PHS; Vice Chairman, Radiology, MGH; Associate Professor, Radiology, HMS

Katherine Andriole, PhD, Director of Research Strategy and Operations, MGH & BWH CCDS; Associate Professor, Radiology, HMS

Samuel Aronson, Executive Director, IT, Personalized Medicine, PHS

Seth Hain, VP of R&D, Epic

Jonathan Teich, MD, PhD, Chief Medical Information Officer, InterSystems; Emergency Medicine, BWH

 

Reimagining Disease Management

Moderator: Sree Chaguturu, MD, Chief Population Health Officer, PHS; Assistant Professor, Medicine, HMS

Murray Brozinsky, Chief Strategy Officer, Conversa

Jean Drouin, MD, CEO, Clarify Health Solutions

Sandhya Rao, MD, Senior Medical Director, Population Health, PHS; Assistant Professor, Medicine, HMS

 

Standards and Regulation: The Emerging AI Framework

 

From Startup to Impact (Provider Solutions)

With all the hype surrounding AI, this session will focus on what really matters. Impact! Who is really moving the needle for healthcare providers today? This session will introduce you to five leading companies who will share their client stories over lunch.

Moderator: Meredith Fisher, PhD, Partner, Partners Innovation Fund, PHS

 

1:00 pm – 1:10 pm
1:10 pm – 2:00 pm
Bayer Ballroom

China: AI Enabled Healthcare Leadership

Moderator: James Bradner, MD
  • President, Novartis Institutes for Biomedical Research
  • CEO, Infervision
  • Managing Partner, Qiming Venture Partners
2:00 pm – 2:30 pm
Bayer Ballroom

1:1 Fireside Chat: Mark Benjamin, CEO, Nuance

Moderator: Peter Slavin, MD
  • President, MGH; Professor, Health Care Policy, HMS
  • CEO, Nuance Communications
2:30 pm – 3:00 pm
3:00 pm – 3:50 pm
Bayer Ballroom

Getting to the AI Investment Decision

  • VP, Venture & Managing Partner, Partners Innovation Fund, PHS
  • Managing Director, Bain Capital Life Sciences
  • Managing Partner, Polaris Partners
  • SVP, Strategy, Commercialization & Innovation, Amgen
  • Managing Director, Healthcare Group, Goldman Sachs
  • Partner, Google Ventures
3:50 pm – 4:20 pm
Bayer Ballroom
4:20 pm – 5:10 pm
Bayer Ballroom

Consumer Healthcare and New Models of Care Delivery

Moderator: Diana Nole
  • CEO, Wolters Kluwer Health
  • President, Global Strategy Group, Samsung; Founder, CareVisor
  • VP and Global CTO, Sales, Dell EMC
  • President, Health Platforms, Verily Life Sciences
  • VP and Chief Health Officer, IBM Corporation
  • SVP, Head of Innovation and Health Equity Microsoft Healthcare
5:15 pm – 6:15 pm

Wednesday, April 10, 2019

7:00 am – 12:00 pm
7:30 am – 9:30 am
Bayer Ballroom

Innovation Discovery Grant Awardee Presentations

Twelve clinical AI teams culled through the Innovation Discovery Grant program present their work illustrating how AI can be used to improve patient health and healthcare delivery. This session is designed for investors, entrepreneurs, investigators, and others who are interested in commercializing AI opportunities that are currently in development with support from the Innovation Office.

Moderator: David Louis, MD
  • Pathologist-in-Chief, MGH; Benjamin Castleman Professor of Pathology, HMS
9:30 am – 10:00 am
10:00 am – 10:30 am
Bayer Ballroom

1:1 Fireside Chat: Stefan Oelrich, Member of the Board of Management; President, Pharmaceutical, Bayer AG

Moderator: Betsy Nabel, MD
  • President, Brigham Health; Professor of Medicine, HMS
  • Member of the Board of Management, Bayer AG; President, Pharmaceutical, Bayer AG
10:30 am – 11:00 am
Bayer Ballroom

1:1 Fireside Chat: Deepak Chopra, MD, Founder, The Chopra Foundation

Moderator: Rudolph Tanzi, PhD
  • Vice-Chair, Neurology, Director, Genetics and Aging Research Unit, MGH; Joseph P. and Rose F. Kennedy Professor of Neurology, HMS
  • Founder, The Chopra Foundation
11:00 am – 11:50 am
Bayer Ballroom

Using AI to Predict and Monitor Human Performance and Neurological Disease

  • Chief of Neurology, Co-Director, Neurological Clinical Research Institute, MGH; Julieanne Dorn Professor of Neurology, HMS
  • Chief Scientist, Dolby Laboratories
  • Global Therapeutic Head, Neuroscience Janssen Research & Development
  • EVP and CMO, Biogen
  • CEO, Kitman Labs
11:50 am – 12:50 pm
Bayer Ballroom

Disruptive Dozen: 12 Technologies that will reinvent AI in the Next 12 Months

The culture of innovation throughout Partners HealthCare naturally fosters robust discussions about new “disruptive” technologies and which ones will have the biggest impact on health care. The Disruptive Dozen was created to identify and rank the technologies that Partners faculty feel will break through over the next decade to significantly improve health care. This year, the Disruptive Dozen focuses on relevant advances and opportunities in artificial intelligence (AI).

Moderator: Jeffrey Golden, MD
  • Chair, Department of Pathology, BWH; Ramzi S. Cotran Professor of Pathology, HMS
  • Associate Chief, Infection Control Unit, MGH; Assistant Professor, Medicine, HMS
1:00 pm – 1:10 pm
Bayer Ballroom

Drug Repurposing Hub Library @broadinstitute @MIT @Harvard

Reporter: Aviva Lev-Ari, PhD, RN and Irina Robu, PhD

CLAIMER: most valuable information for Drug Repurposing is found in the following LPBI Group three Intellectual Property Asset Classes

Our intellectual property “IP” consists of three classes of assets as described in detail within live links in the below, listed article.

  • First, the Journal, an ongoing journal of curated, current biomedical research;
  • Second, the books, a collection of 16 volumes of e-books available via Amazon in five specialties of Medicine: Cardiovascular, Genomics, Cancer, Immunology and Precision Medicine; and
  • Third, real-time curation of biotech and medical conferences yielding an e-Proceedings at the end of the conference in One-click operation.

These three IP asset classes are described in details with live links in

eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model

https://pharmaceuticalintelligence.com/2019/02/04/escientific-publishing-a-case-in-point-evolution-of-platform-architecture-methodologies-and-of-intellectual-property-development-content-creation-by-curation-business-model/

 

The Drug Repurposing Hub: A next-generation drug library and information resource

M Corsello, Steven & A Bittker, Joshua & Liu, Zihan & Gould, Joshua & McCarren, Patrick & E Hirschman, Jodi & E Johnston, Stephen & Vrcic, Anita & Wong, Bang & Khan, Mariya & Asiedu, Jacob & Narayan, Rajiv & C Mader, Christopher & Subramanian, Aravind & R Golub, Todd. (2017). The Drug Repurposing Hub: A next-generation drug library and information resource. Nature Medicine. 23. 405-408. 10.1038/nm.4306.

… Published on January 3, 2018 as DOI: 10.1124/mol.117. Downloaded from additional source, we used data from the Broad repurposing hub ( Corsello et al, 2017), which employed high throughput screening to characterize drug-target interactions of approved drugs, natural products and nutraceuticals along with other entities. Our analysis yielded a list of currently ‘druggable’ GPCRs and the drugs that target them. …
… Using a range of ~500 (conservative estimate) to ~700 GPCR-targeted drugs, we estimate that between ~25% and ~36% of approved drugs target GPCRs, with the upper figure the more likely. As additional studies such as the Broad repurposing initiative ( Corsello et al, 2017) characterize GPCR-drug interactions in more detail, we anticipate a growth in this number, as secondary interactions between GPCRs and drugs are defined ( Allen and Roth, 2011). IUPHAR lists more druggable GPCRs than CHEMBL or DRUGBANK but has the smallest number of GPCR-related and overall approved drugs ( Figure 3C shows the number of GPCR-targeted drugs based on target-ligand interactions annotated by either IUPHAR or CHEMBL; of the 476 such drugs listed in one or both sources, only a portion are common to both (50%). …

 

Drug Repurposing Hub Library @broadinstitute  @MIT @Harvard

To date there has not been a systematic effort to identify such opportunities, limited in part by the lack of a comprehensive library of clinical compounds suitable for testing. To address this challenge, we hand-curated a collection of 4,707 compounds, experimentally confirmed their identity, and annotated them with literature-reported targets. The collection includes 3,422 drugs that are marketed around the world or that have been tested in human clinical trials. Compounds were obtained from more than 50 chemical vendors and the purity of each sample was established. We have thus established a blueprint for others to easily assemble such a repurposing library, and we have created an online Drug Repurposing Hub (www.broadinstitute.org/repurposing) containing detailed annotation for each of the compounds.

SOURCE

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568558/

. Author manuscript; available in PMC 2017 Aug 23.
Published in final edited form as:
PMCID: PMC5568558
NIHMSID: NIHMS893143
PMID: 28388612

The Drug Repurposing Hub: a next-generation drug library and information resource

SOURCE
Other Resources

Tumor Ammonia Recycling: How Cancer Cells Use Glutamate Dehydrogenase to Recycle Tumor Microenvironment Waste Products for Biosynthesis

Reporter: Stephen J. Williams, PhD

A feature of the tumorigenic process is the rewiring of the metabolic processes that provides a tumor cell the ability to grow and thrive in conditions of limiting nutrients as well as the ability to utilize waste products in salvage pathways for production of new biomass (amino acids, nucleic acids etc.) required for cellular growth and division 1-8.  A Science article from Spinelli et al. 9 (and corresponding Perspective article in the same issue by Dr. Chi V. Dang entitled Feeding Frenzy for Cancer Cells 10) describes the mechanism by which estrogen-receptor positive (ER+) breast cancer cells convert glutamine to glutamate, release ammonia  into the tumor microenvironment, diffuses into tumor cells and eventually recycle this ammonia by reductive amination of a-ketoglutarate by glutamate dehydrogenase (GDH) to produce glutamic acid and subsequent other amino acids needed for biomass production.   Ammonia can accumulate in the tumor microenvironment in poorly vascularized tumor. Thus ammonia becomes an important nitrogen source for tumor cells.

Mammalian cells have a variety of mechanisms to metabolize ammonia including

  • Glutamate synthetase (GS) in the liver can incorporate ammonia into glutamate to form glutamine
  • glutamate dehydrogenase (GDH) converts glutamate to a-ketoglutarate and ammonia under allosteric regulation (discussed in a post on this site by Dr. Larry H. Berstein; subsection Drugging Glutaminolysis)
  • the reverse reaction of GDH, which was found to occur in ER+ breast cancer cells, a reductive amination of a-ketoglutarate to glutamate11, is similar to the reductive carboxylation of a-ketoglutarate to citrate by isocitrate dehydrogenase (IDH) for fatty acid synthesis (IDH is overexpressed in many tumor types including cancer stem cells 12-15), and involved in immune response and has been developed as a therapeutic target for various cancers. IDH mutations were shown to possess the neomorphic activity to generate the oncometabolite, 2-hydroxyglutarate (2HG) 16-18. With a single codon substitution, the kinetic properties of the mutant IDH isozyme are significantly altered, resulting in an obligatory sequential ordered reaction in the reverse direction 19.

 

In the Science paper, Spinelli et al. report that ER+ breast cancer cells have the ability to utilize ammonia sources from their surroundings in order to produce amino acids and biomass as these ER+ breast cancer cells have elevated levels of GS and GDH with respect to other breast cancer histotypes.

GDH was elevated in ER+ luminal cancer cells and the quiescent epithelial cells in organoid culture

However proliferative cells were dependent on transaminases, which transfers nitrogen from glutamate to pyruvate or oxaloacetate to form a-ketoglutarate and alanine or aspartate. a-ketoglutarate is further metabolized in the citric acid cycle.

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1.    Reductive amination and transamination reactions of glutamic acid.  Source http://www.biologydiscussion.com/organism/metabolism-organism/incorporation-of-ammonia-into-organic-compounds/50870

Spinelli et al. showed GDH is necessary for ammonia reductive incorporation into a-ketoglutarate and also required for ER+ breast cancer cell growth in immunocompromised mice.

In addition, as commented by Dr. Dang in his associated Perspectives article, (quotes indent)

The metabolic tumor microenvironment produced by resident cells, such as fibroblasts and macrophages, can create an immunosuppressive environment 20.  Hence, it will be of great interest to further understand whether products such as ammonia could affect tumor immunity or induce autophagy  (end quote indent)

 

 

 

Figure 2.  Tumor ammonia recycling.  Source:  From Chi V. Dang Feeding Frenzy for cancer cells.  Rights from RightsLink (copyright.com)

Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Jessica B. Spinelli1,2, Haejin Yoon1, Alison E. Ringel1, Sarah Jeanfavre2, Clary B. Clish2, Marcia C. Haigis1 *

1.      1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. 2.      2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

* *Corresponding author. Email: marcia_haigis@hms.harvard.edu

Science  17 Nov 2017:Vol. 358, Issue 6365, pp. 941-946 DOI: 10.1126/science.aam9305

Abstract

Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.

 

 

References

1          Strickaert, A. et al. Cancer heterogeneity is not compatible with one unique cancer cell metabolic map. Oncogene 36, 2637-2642, doi:10.1038/onc.2016.411 (2017).

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Other articles on this Open Access Journal on Cancer Metabolism Include:

 

Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

 

Accumulation of 2-hydroxyglutarate is not a biomarker for malignant progression of IDH-mutated low grade gliomas

 

 

Protein-binding, Protein-Protein interactions & Therapeutic Implications [7.3]

Is the Warburg effect an effect of deregulated space occupancy of methylome?

Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’

New Insights on the Warburg Effect [2.2]

The Inaugural Judith Ann Lippard Memorial Lecture in Cancer Research: PI 3 Kinase & Cancer Metabolism

Renal (Kidney) Cancer: Connections in Metabolism at Krebs cycle and Histone Modulation

Warburg Effect and Mitochondrial Regulation- 2.1.3

Refined Warburg Hypothesis -2.1.2

 


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