Podcasts about fgf

In this episode of Skin Anarchy, host Dr. Ekta sits down with Tony J. Abboud, Chief Commercial Officer of Core Biogenesis, for an eye-opening conversation on the cutting-edge science behind bioidentical proteins in skincare. Tony brings a biotech insider's perspective to the world of beauty, revealing how plant-based protein technology is unlocking a new era of truly effective, science-backed formulations.Core Biogenesis is tackling a long-standing challenge in skincare: the instability and inefficiency of traditional proteins and peptides. Tony breaks down how their team uses camelina sativa plants as natural bioreactors to produce high-purity, bioidentical growth factors like EGF and FGF—compounds that naturally support skin repair and collagen synthesis but decline with age. The innovation doesn't stop there: Core Biogenesis' breakthrough delivery system, oleosomes, stabilizes these proteins and enhances their penetration, leading to significantly better efficacy than traditional formats.This isn't just theoretical science—Tony explains how Core Biogenesis' oleosome-bound EGF retained 93% activity under stress conditions, compared to just 8% with standard EGF. With performance like this, consumers could see visible results in just 14 to 30 days. It's a game-changing advancement for skincare brands and users alike.Whether you're a skincare enthusiast, product formulator, or biotech curious, this episode offers a fascinating look into the future of skincare—one where biology, sustainability, and innovation converge. Tune in to discover how Core Biogenesis is rewriting the rules with plant-powered precision.CHAPTERS:(0:00) Introduction to Core Biogenesis(1:23) Tony's Background in Biotech and Skincare (2:04) The Importance of Ingredient Innovation (5:08) Core Biogenesis: Shifting Focus to Plant-Derived Proteins (10:23) The Science Behind Bioidentical Proteins (15:30) Stability Challenges in Skincare Formulations (17:01) The Impact of Bioidentical Proteins on Anti-Aging(22:03) Consumer Expectations and the Need for Faster Results (28:41) The Future of Bioidentical Proteins in Skincare To learn more about Core Biogenesis, visit https://www.corebiogenesis.co/skincareanarchy.Don't forget to subscribe to Skin Anarchy on Apple Podcasts, Spotify, or your preferred platform. Reach out to us through email with any questions.Sign up for our newsletter!Shop all our episodes and products mentioned through our ShopMy Shelf! Hosted on Acast. See acast.com/privacy for more information.

This conversation is the opening segment of SurfingMASH's April discussion, in memory of Stephen A. Harrison, on drug development. In addition to co-hosts Jörn Schattenberg, Louise Campbell and Roger Green, panelists include hepatologists and key opinion leaders Sven Francque and Naim Alkhouri. This opening discussion focuses on exciting advances in one drug class (FGF-21s) and, more broadly, on exploring ways to treat cirrhosis. As Naim points out in his opening comment, these two issues— cirrhosis as a challenge and FGF-21s as a possible solution path —intersect in clear and exciting ways. He notes that the FGF-21 efruxifermin has been reported to have significant improvement in patients with cirrhosis, while the FGF-21 pegozafermin has shared positive results in a small cohort of patients. He also notes that a third FGF-21, efimosfermin alfa, has results in advanced non-cirrhotic MASH that suggest potential for similar efficacy in patients with cirrhosis, but this must be studied and confirmed in clinical trials. He mentions that resmetirom may also be showing signs of efficacy in some patients with cirrhosis. The entire package, he says, is a "game changer."Jörn notes that we are having parallel advances in treatment for advanced, non-cirrhotic patients. Sven concurs and comments that we are seeing effects that are not strictly related to metabolic disease. There is exceptional power that we can demonstrate one-level regression in sicker patients. The three agree that, at the same time, we are seeing cirrhosis trials that will lead to outcomes data; outcomes trials in non-cirrhotic medications may not be far away.Roger asks whether we are making progress in treating patients living with decompensated cirrhosis. Sven discusses what we are learning about treating portal hypertension, which is an important benefit unrelated to fibrosis regression. Simply improving portal hypertension will have an impact on endpoints. Naim points out that some ongoing trials include patients with cirrhosis, including survodutide and belapectin. Louise notes it will require "great P.R." to reverse some of the current perceptions about cirrhosis, but that this is "great." Naim states that even today, we have "a lot to offer" patients with portal hypertension or other symptoms of decompensation. As he concludes, he notes that this is underappreciated today. 

00:00:00 - Surf's Up: Season 6 Episode 5Host Roger Green briefly describes this episode's three sections and introduces Roundtable guests. The Roundtable panel shares groundbreakers. 00:10:39 - Roundtable: A Deep Dive Into Drug Development, Part OneThe opening portion of this month's roundtable centers around two issues: exciting data for FGF-21s and, more generally, treating patients with cirrhosis. Naim Alkhouri sets the tone in his opening comments, which start by focusing on the exciting SYMMETRY data from efruxifermin and then hones in on FGF-21s and resmetirom in cirrhosis. The rest of the conversation features Jörh Schattenberg, Sven Francque and Naim discussing therapies in development for compensated and decompensating cirrhosis.00;24:44 - Newsmaker: Naga Chalasani on Real-World Experience Prescribing ResmetiromNaga joins Roger to discuss the paper Early Experience with resmetirom to treat Metabolic Dysfunction-Associated Steatohepatitis With Fibrosis in a Real-World Setting from his group at Indiana University, which his group authored and Hepatology Communications recently posted. The paper, based on IU Health's experience with its first 113 resmetirom patients, shares the group's practical experience developing processes to work closely with the specialty pharmacies dispensing resmetirom and, finally, concludes that a more engaged patient management strategy might reduce drug discontinuation to a level comparable with clinical trials.  00:47:21 - Expert: Scott Friedman on Gene Therapy, Diversity of Stellate Cell Types, Other Basic Liver ScienceScott and Roger cover a range of basis science topics in a fast-moving 19-minute discussion. It starts with Scott discussing the increasing acceptance that gene therapy is an acceptable way to treat a range of liver diseases, many of which are orphan or ultra-orphan but, in fact, include potential gene therapies for non-cirrhotic MASH and MASH cirrhosis. He notes that in addition to classic gene therapy, which introduces protective gene variants into the systems of patients with the risky variants, gene therapy is now looking to introduce FGF-21 into patients through genetic modification. From there, the conversation covers CAR-T therapy, the increasing ability to identify many different types of stellate cells and the idea that the most effective therapy for eary fibrosis, advanced fibrosis and cirrhosis might require fundamentally different kinds of interventions. The two final elements are the idea that what we now call "MASH" may be several diseases with different etiologies with similar manifestations and a passionate call for all of us to support maintaining NIH funding in whatever ways we can.01:06:45 - Business ReportAs Roger copes with his laryngitis, AI voices deliver an abbreviated business report 

This week's expert, Hepatologist and Key Opinion Leader Mazen Noureddin, joins Roger to discuss major advances in drug development over the past year. He covers a range of different drug classes, focusing on stages of development and the range of options within each class. First, Mazen discusses a tremendously exciting group of FGF-21 agents, specifically mentioning Akero Therapeutics's efruxifermin, 89bio's pegozafermin, and Boston Pharmaceuticals's efimosfermin. He points to efruxifermin's 96-week results to suggest that FGF-21s might be appropriate for a wide range of patients, the idea that the drug's duration of effect may make the idea of “induction therapy” less appropriate, and the exciting early data on cirrhosis patients. He also mentions pegozafermin's publication of data in the New England Journal of Medicine and efimosfermin's promising data based on monthly dosing. Next, Mazen provides some detail on the various incretin agonist options, why hepatologists are particularly excited about combinations that include a glucagon agent, and what kinds of results we might expect in upcoming trials. Finally, Mazen discusses other promising compounds in later-stage development, including the pan-PPAR lanifibranor and the FASN inhibitor denifenstat. He notes ongoing work on new classes and combination therapies. 

00:00:00 - Surf's Up: Season 6 Episode 4 Surfing the MASH Tsunami concludes its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on pivotal messages that attendees took away from the conference and what messages they would like to share with listeners. Our newsmaker, Fatty Liver Alliance and CEO Mike Betel, discusses the lessons he has taken from being invited to a far wider swath of conferences this year and shares the messages he delivers to these new audiences. Finally, our expert, hepatology research and key opinion leader Mazen Noureddin, discusses recent advances in drug development, focusing on agents in Phase 3 trials.00:04:24 - IntroductionHost Roger Green briefly describes this episode's three sections and one key lesson from each.00:06:03 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 4This is the concluding portion of our Emerging Trends Conference Roundtable. The group focuses on key lessons they have learned and messages they would like listeners to take from this conversation.  The pivotal idea is that SLD is a spectrum running from MASLD through MetALD to ALD. Researchers and treaters will all do best in developing and implementing therapies and guidelines with this thought in mind. Aleksander Krag stresses this idea and notes that, with several different classes of drugs demonstrating positive impact, it will be an exciting decade ahead as we learn how to apply these drugs along the spectrum. Jenn Jones and Alex Lalos note the importance of identifying MetALD, although Jenn noted that it does not seem wise to conduct trials solely with MetALD patients at this time.  00:22:04 - Newsmaker: Mike Betel on the Increased Visibility of Patient AdvocatesThis week's newsmaker, Mike Betel, has experienced a significant increase in the number of conferences at which he is invited to speak or appear on a panel. This discussion centers around the reasons Mike believes this is happening and the message(s) he delivers. To Mike, his most important contribution lies in the amount of information he sends back from each event, many of which surpass 30% download rates (and some even hit 50%). He discusses his value in diabetes, endocrinology and obesity meetings, where he brings a "liver" perspective and co-education opportunity to these events. The entire experience has taught him about the need not to stigmatize patients and reinforced his belief in the importance of tailoring care to patients' needs and personalities. 00:49:28 - Expert: Mazen Noureddin on the Exciting MASLD Drug Development EnvironmentHepatologist and Key Opinion Leader Mazen Noureddin joins Roger to discuss major advances in drug development over the past year. He covers a range of different drug classes, focusing on stages of development and the range of options within each class. Specifically, he discusses the FGF-21 agents, the range of patients for whom they might be appropriate, how efruxifermin's 96-week results may make the idea of "induction therapy" less appropriate,  and the exciting early data on cirrhosis patients. He provides some detail on the various incretin agonist options, why hepatologists are particularly excited about combinations that include a glucagon agent, and what kinds of results we might expect in upcoming trials. He goes on to discuss the pan-PPAR lanifibranor, the FASN inhibitor denifenstat, and notes ongoing work on new classes and combination therapies. In general, he paints, I think, not a rosy, but an extremely optimistic picture of what the future will be for patients who need to be treated for fatty liver. 01:09:38 - Business Report Roger discusses the next Roundtable and provides some details on SurfingMASH's coverage of the upcoming EASL Congress.

Surfing the MASH Tsunami continues its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on what studies on bariatric surgery and drugs in development can tell us about future treatment and explore some clinical trial questions. Guest Surfers include Professor Aleksander Krag of the University of Southern Denmark, the current Secretary-General of EALS, hepatologist Alexander Lalos of Robert Wood Johnson hospital, and Jenn Leigh Jones, founder of the Society for Sober Livers Survival, now part of the Fatty Liver Foundation. Aleksander Krag starts by discussing a presentation on what we can learn from bariatric surgery in terms of fibrosis reduction and why pharmacotherapies work (or not). He envisions a day where we have multiple treatment options and understanding how each works for specific types of patients, leading to robust, cost-effective, patient-specific treatment algorithms.  Alex Lalos describes how presentations on FGF-21s in advanced fibrosis and cirrhosis have whetted his appetite and Jenn Jones asks questions regarding ALD patient trial selection and assignment and clinical endpoints for cirrhosis trials. 

00:00:00 - Surf's Up: Season 6 Episode 3Surfing the MASH Tsunami continues its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on what studies on bariatric surgery and drugs in development can tell us about future treatment and explore some clinical trial questions. Our newsmaker, HistoIndex Director of Clinical Development Yukti Choudhury, introduces us to FibroSIGHT, which provides clinicians with highly precise biopsy analysis. Finally, our expert, Global Liver Institute Vice President, Liver Programs Jeff McIntyre, discusses the implications of recent US government job cuts on future MASH treatment options and patient care.00:04:35 - IntroductionHost Roger Green briefly describes this episode's three sections and one key lesson from each.00:05:45 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 3This portion of our Emerging Trends Conference Roundtable looks at how therapy might evolve over time. Aleksander Krag starts by discussing a presentation on what we can learn from bariatric surgery in terms of fibrosis reduction and why pharmacotherapies work (or not). He envisions a day where we have multiple treatment options and understanding how each works for specific types of patients, leading to robust, cost-effective, patient-specific treatment algorithms.  Alex Lalos describes how presentations on FGF-21s in advanced fibrosis and cirrhosis have whetted his appetite and Jenn Jones asks questions regarding ALD patient trial selection and assignment and clinical endpoints for cirrhosis trials. 00:16:55 - Newsmakers: FibroSIGHT Brings Clinical Trial Analytics to Clinical Practice Use of BiopsyYukti Choudhury, Director of Clinical Development at HistoIndex, joins Roger Green to discuss FibroSIGHT, a new HistoIndex service that allows clinicians to use HistoIndex's Second Harmonic Generation (SHG) technology to determine specific CRN fibrosis level for patients with inconclusive NIT results.  Yukti states that demand for this technique could equal 163,000 cases this year and rising to one million by 2028. She provides practical cues on ordering the test and its reimbursement. Roger shares his long-standing respect for SHG and the clarity it produces. He notes the economic benefit of determining whether a patient has F2 fibrosis, which is indicated for pharmacotherapy, vs.F1, which is not indicated. He sees clear benefit, but expresses concern that any option requiring more biopsies will reduce the number of patients treated.00:41:49 - Patient Advocate and Policy Expert Jeff McIntyre Discusses the Implications of FA/NIH Job Cuts on MASLD Patient CareGlobal Liver Institute Vice President, Liver Programs Jeff McIntyre joins Roger to discuss the April 1 job reductions at the FDA, explore implications for the entire MASLD community, and to ask what patients can and should do. Jeff and Roger note that the job changes will create significant uncertainty and probably reduce the government's ability to respond to future health crises. Jeff notes former FDA Commissioner Rob Califf's comment that the FDA as we know it "is dead," and that we have little idea what the future holds. According to Jeff, patients need to become even more vigilant self-advocates and also seek the guidance and support they need from patient advocacies. Finally, the conversation turns to discuss FibroSIGHT. Jeff describes FibroSIGHT as "exactly where we should be and should not be at the same time," a technology that takes a large step forward in understanding and patient support, but one that ties us to biopsy as a standard for clinical care. Jeff and Roger agree this issue will play out over the coming years. 01:09:18 - Business ReportRoger thanks listeners quoting a letter from one of them, and describes the next round of episodes. 

Congresso Técnico da FGF que definiu o formato da Divisão de Acesso e preparação da equipe para a competição.

Congresso Técnico da FGF que definiu o formato da Divisão de Acesso e preparação da equipe para a competição.

In this episode, Naim Alkhouri, Mike Betel, Michelle Long and Jeff McIntyre join Jörn Schattenberg and Roger Green to look back at The Liver Meeting 2024. This conversation reviews the late-breaker presentation on efimosermin, a q4w FGF-21 agent and the "FDA Corner" session. Jörn begins the discussion by highlighting a paper from the later breaker session on efimosfermin alfa, an FGF-21 agent dosed q4w. He notes that after only six doses (24 weeks), efimosfermin alfa demonstrated significant increases in fibrosis regression and lowering NAS score. To Jörn, this result, coupled with others on efruxifermin and pegozafermin, suggest that FGF-21s are likely to play a significant role in MASH therapy once approved. After Roger and Mike note their enthusiasm about the drug class and this study, Jörn mentions a study with 96-week efruxifermin that data demonstrates prolonged efficacy. As he points out, this matters because while studies of an earlier FGF-21 candidate suggested that antibodies might develop in FGF-21 therapy, that does not appear to be an issue here. Mike asks the group why they feel placebo performs so well in clinical trials. Jörn suggests that working with a compassionate clinical care team in dealing with the patient leads to better performance on diet and exercise and, as a result, increased placebo response to what we might find in general community practice.Michelle praises the FDA Corner session, particularly the agency's transparency and willingness to engage industry and academia in finding paths to move away from biopsy. She also notes some of the practical challenges inherent of moving away from biopsy using data from earlier trials with an outmoded histology reader setup. She is optimistic about the scientific community coming together to address these issues. Jeff praises the agency for an "amazing" session. 

00:00:00 – Surf's Up: Season 5 Episode 26 - Last month, close to 8,000 hepatology stakeholders convened in San Diego for The Liver Meeting 2024. Hepatology Key Opinion Leader Naim Alkhouri, Novo Nordisk International Vice President for Medicines Michelle Long, and patient advocates Jeff McIntyre from the Global Liver Institute and Michael Betel from the Fatty Liver Alliance join Jörn Schattenberg and Roger Green to discuss highlights. 00:03:23 - Introduction and Groundbreaker - Highlights include recent travel, cultural events, and the Third Annual Primary Care Summit from the Fatty Liver Alliance.00:11:35 - Describing TLM2024 - Participants shared a word or short phrase they felt best captured their feelings about TLM2024. 00:14:51 - The ESSENCE Trial - Naim starts the session by describing ESSENCE, a Phase 3 trial of semaglutide in non-cirrhotic MASH patients, which he describes as "the most exciting news of the meeting." Panelists describe the benefits of this trial from a variety of perspectives. 00.22.49 - A Challenge to Trial Recruitment? - Roger asks the group whether the presence of two approved MASH medications that do not require biopsy will make recruiting clinical trials that require them more challenging. The group doubts this will not add a significant new challenge to already-challenging trial recruitment. 00:29:22 - Other keys in drug development - Naim begins a discussion of two topics: the value of synergy between resmetirom and the GLP-1 agonist, and the importance of different genetic polymorphisms in predicting the impact of drugs on specific patients. Michelle mentions a recent paper in Nature identifying distinct clusters of patients based on how their SLDs progress over time. Roger identifies two particular challenges in this area, one posed by Lean MASH and the other specific to Hispanics in the US. 00:34:42 - FGF 21s - Jörn highlights a paper from the later breaker session on efimosfermin alfa, an FGF-21 dosed q4w. Roger and Mike comment. To Jörn, this and other studies demonstrate the place FGF-21s are likely to have in MASH therapy.00:40:29 - FDA Corner and the Role of Surrogates - Michelle praises the FDA Corner session, particularly the agency's transparency and willingness to engage industry and academia in finding paths to move away from biopsy. She is optimistic about the scientific community coming together to address these issues. Jeff notes the pivotal role he believes patients must play in this process. 00:48:33 - Patient Insights - Mike describes a poster he presented (and was lead co-author), titled Patient Voice in MASH Initiatives:  Foundational Principles for the Conduct of Patient-Centric MASH Research. He lists the groups participating in this broad effort and the foundational principles that emerged. Michelle and Jörn share their thoughts on which principles have the greatest impact on them in clinical research. Jeff praises a panel that Mike co-chaired on Lifestyle Management of MASLD and MASH. He praises the breadth and quality of speakers and topics. He also comments on the large number of providers and industry executives who attended this patient-centered session. Roger notes a similar distribution of attendees at the Health Livers, Healthy Lives session on building momentum for prevention. 00:58:36 - Wrapping Up - Roger comments on the breadth of modes of action that have produced successful Phase 2/3 trial results. He notes that we may have 4-5 different modes of action available five years from now. In the rest of the session, panelists describe what they believe will be different and exciting at TLM2025.01:06:01 - Question of the WeekListeners and readers, What do you consider the most essential paper or theme of TLM2024??01:06:38 - Business ReportChanges coming in 2025 with SurfingMASH v2.0

Le Xu, Ph.D., examines the intricate processes underlying lung development and disease, with a focus on idiopathic pulmonary fibrosis (IPF). Xu explores the roles of genetic and cellular mechanisms, including the hedgehog pathway, FGF signaling, and epithelial-mesenchymal interactions, in driving lung fibrosis. Xu also highlights links between congenital diaphragmatic hernia (CDH) and lung development, suggesting that both mechanical and genetic factors contribute to lung hypoplasia. The discussion includes the development of advanced mouse models that replicate key aspects of human IPF, offering insights into fibrosis progression. Xu's research ultimately seeks to identify the causes of lung tissue abnormalities and pave the way for targeted therapies. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 39460]

Le Xu, Ph.D., examines the intricate processes underlying lung development and disease, with a focus on idiopathic pulmonary fibrosis (IPF). Xu explores the roles of genetic and cellular mechanisms, including the hedgehog pathway, FGF signaling, and epithelial-mesenchymal interactions, in driving lung fibrosis. Xu also highlights links between congenital diaphragmatic hernia (CDH) and lung development, suggesting that both mechanical and genetic factors contribute to lung hypoplasia. The discussion includes the development of advanced mouse models that replicate key aspects of human IPF, offering insights into fibrosis progression. Xu's research ultimately seeks to identify the causes of lung tissue abnormalities and pave the way for targeted therapies. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 39460]

Le Xu, Ph.D., examines the intricate processes underlying lung development and disease, with a focus on idiopathic pulmonary fibrosis (IPF). Xu explores the roles of genetic and cellular mechanisms, including the hedgehog pathway, FGF signaling, and epithelial-mesenchymal interactions, in driving lung fibrosis. Xu also highlights links between congenital diaphragmatic hernia (CDH) and lung development, suggesting that both mechanical and genetic factors contribute to lung hypoplasia. The discussion includes the development of advanced mouse models that replicate key aspects of human IPF, offering insights into fibrosis progression. Xu's research ultimately seeks to identify the causes of lung tissue abnormalities and pave the way for targeted therapies. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 39460]

Le Xu, Ph.D., examines the intricate processes underlying lung development and disease, with a focus on idiopathic pulmonary fibrosis (IPF). Xu explores the roles of genetic and cellular mechanisms, including the hedgehog pathway, FGF signaling, and epithelial-mesenchymal interactions, in driving lung fibrosis. Xu also highlights links between congenital diaphragmatic hernia (CDH) and lung development, suggesting that both mechanical and genetic factors contribute to lung hypoplasia. The discussion includes the development of advanced mouse models that replicate key aspects of human IPF, offering insights into fibrosis progression. Xu's research ultimately seeks to identify the causes of lung tissue abnormalities and pave the way for targeted therapies. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 39460]

PFAs on an FGF, deer hunting, and our take on RFK's appointment to the cabinet.

David Happel is President and CEO of Sagimet Biosciences, a company developing drugs to treat metabolic diseases by targeting the underlying cause of fat accumulation in the liver. The drug denifanstat limits the activity of fatty acid synthase (FASN), an enzyme that regulates fat accumulation. This approach is a fat inhibitor, not a fat burner, the focus of other MASH drugs.  David explains, "Sagimet was founded back in 2007 as a private company with a group of medicinal chemists that had a particular target in mind, and this particular target was called fatty acid synthase, or FASN. FASN is a rather ubiquitous enzyme throughout the body that functions as a regulating enzyme in many organs. When FASN becomes overactive or overexpressed, it sort of throws things out of balance and, in particular, certain cardiometabolic diseases, such as MASH and in the liver. So, this group of chemists, in order to resolve this overactivity, developed a portfolio of FASN inhibitors, led by our lead program denifanstat, that seek to target the underlying cause of MASH and, therefore, really work to limit the activity of FASN, try to normalize it essentially is what we do." "For us and this particular molecule, it offers a differentiated approach to treating the disease for us and this particular molecule. Our molecule, denifanstat, is the only FASN inhibitor. It's the only fat inhibitor in development for MASH, making it rather unique. All the rest of the molecules or fat burners, fat oxidizers, and fat mobilizers include GLPs, FGF, and THR-beta. They all function by trying to burn fat peripherally and in the liver to a degree. They rely on that fat-burning mechanism to translate into reductions, inflammation, and fibrosis, which is important to treating MASH, but they've had varying degrees of success. Our molecule targets each pathway independently: fat, inflammation, and fibrosis, and has had a rather pronounced treatment effect as a result."  #SagimetBiosciences #MASH #FattyLiverDisease #FASN #FASNInhibitor #Fibrosis #Obesity #NASH #GLP1Agonists sagimet.com Download the transcript here

David Happel is President and CEO of Sagimet Biosciences, a company developing drugs to treat metabolic diseases by targeting the underlying cause of fat accumulation in the liver. The drug denifanstat limits the activity of fatty acid synthase (FASN), an enzyme that regulates fat accumulation. This approach is a fat inhibitor, not a fat burner, the focus of other MASH drugs.  David explains, "Sagimet was founded back in 2007 as a private company with a group of medicinal chemists that had a particular target in mind, and this particular target was called fatty acid synthase, or FASN. FASN is a rather ubiquitous enzyme throughout the body that functions as a regulating enzyme in many organs. When FASN becomes overactive or overexpressed, it sort of throws things out of balance and, in particular, certain cardiometabolic diseases, such as MASH and in the liver. So, this group of chemists, in order to resolve this overactivity, developed a portfolio of FASN inhibitors, led by our lead program denifanstat, that seek to target the underlying cause of MASH and, therefore, really work to limit the activity of FASN, try to normalize it essentially is what we do." "For us and this particular molecule, it offers a differentiated approach to treating the disease for us and this particular molecule. Our molecule, denifanstat, is the only FASN inhibitor. It's the only fat inhibitor in development for MASH, making it rather unique. All the rest of the molecules or fat burners, fat oxidizers, and fat mobilizers include GLPs, FGF, and THR-beta. They all function by trying to burn fat peripherally and in the liver to a degree. They rely on that fat-burning mechanism to translate into reductions, inflammation, and fibrosis, which is important to treating MASH, but they've had varying degrees of success. Our molecule targets each pathway independently: fat, inflammation, and fibrosis, and has had a rather pronounced treatment effect as a result."  #SagimetBiosciences #MASH #FattyLiverDisease #FASN #FASNInhibitor #Fibrosis #Obesity #NASH #GLP1Agonists sagimet.com Listen to the podcast here

(Re-release) On this special episode, join Mel & Miranda as Mel discusses illnesses often faced by first responders, and the long-term impacts still felt by those who survived and responded to the 9/11 Tragedy over 20 years ago. Miranda shares some tips on how to prepare for a successful parent- teacher conference... even though she may have missed one or two on accident... oops! SPOTLIGHT:World Trade Center Health Program The WTC Health Program is dedicated to helping those who were there during and after the attacks of September 11, 2001. The Program provides services to individuals who meet their requirements.https://www.cdc.gov/wtc Feal Good FoundationThe mission of the FGF includes educating elected officials and private entities on the various problems, concerns and issues faced by First Responders in their everyday duties. The FGF is therefore dedicated to advocating for First Responder rights and illuminating, to proper authorities, the serious issues they encounter.https://fealgoodfoundation.com/ SOURCES:Mel-https://en.m.wikipedia.org/wiki/Health_effects_arising_from_the_September_11_attacks https://www.scientificamerican.com/article/health-effects-of-9-11-still-plague-responders-and-survivors/ Miranda-https://www.verywellfamily.com/expect-at-parent-teacher-conference-3545346 https://kidshealth.org/en/parents/parent-conferences.htmlhttps://www.edutopia.org/article/5-strategies-successful-parent-teacher-conferencehttps://www.varsitytutors.com/blog/5+things+to+do+after+a+parentteacher+conference https://www.readingrockets.org/topics/parent-engagement/articles/surviving-difficult-parent-teacher-conference Hosted on Acast. See acast.com/privacy for more information.

From wound healing to cell growth to bone formation, fibroblast growth factors (FGF) and fibroblast growth factor receptors (FGFR) are responsible for a diverse range of biological processes. This episode begins with the basics: the functions of FGFs and FGFRs. We will then move on to an indepth dive into the structure of FGFRs and how they work with FGFs to initiate the desired cellular response. Finally, we will end the episode by exploring the three main pathways used by FGFs and their corresponding receptors.  FGFR Model: https://images.app.goo.gl/FaZjvuh5H1QnTgfa8

This conversation contains the first half of Roger Green's interview with Global Liver Institute Vice President, Liver Programs Jeff McIntyre, during which the two discuss what Jeff considered the key strategic takeaways for GLI from the various EASL Congress presentations, abstracts and discussions. Jeff focuses on the "overriding sense of optimism" coming from the multiple pieces of positive drug data. He cites the data on Boehringer Ingelheim's survodutide, the follow-up work on Madrigal's resmetirom, an anticipated presentation on semaglutide at the AASLD in November, and strong FGF-21 results as proof that we are beginning to develop multiple robust, safe and effective modes of action for drugs to treat (at least pre-cirrhotic) MASH. His second positive point is that due to the drug trials and nomenclature change, GLI and other advocates are starting to have "more enlightened discussions" about MASLD in the context of the whole patient and related metabolic conditions. As a result, he comes to the third point, which is that multiple modes of action will teach us why what works in one patient might not in another and, ultimately, reshape clinical trials so that the target might not be fibrosis (or at least not only fibrosis), but instead exactly how each drug works. Jeff envisions this line of inquiry as a step down the path away from requiring biopsy. 

Mazen Noureddin and Naim Alkhouri join Jörn Schattenberg and Roger Green to focus on the role FGF-21s will play in long-term advanced fibrosis treatment: induction or long-term therapy...or might we even think of the class as being able to produce a "MASH cure?" Responding to Naim's comment closing the previous discussion, Mazen questions why we regard FGF-21 agents as induction therapies given that it appears to be as well tolerated as the oral agents and maintains such efficacy over time. In fact, he adds, its sustained efficacy might make it possible for livers to eliminate fibrosis and return to their "normal" state, almost like a "cure." Jörn adds a comment about pegozafermin, another FGF-21 in development. Jörn notes that this agent is a pegylated molecule, which makes it different from efruxifermin. He notes that NITs show sustained enzyme response at 48 weeks. Mazen reiterates his optimism about the FGF-21 class and reminds us that there is a third FGF-21 in development. Roger raises Michael Charlton's question (Season 5 Episode 11) whether an induction therapy strategy for FGF-21s might not work if removing the drug allows the MAS activity to return. On the other hand, he notes, it might take years for fibrosis to return. Mazen agrees that many unanswered questions exist, but reiterates his belief in long-term therapeutic value.  

In this conversation from July 2023, Stephen Harrison, Jörn Schattenberg and Roger Green discuss the implications of presentations on the FGF-21 agent efruxifermin and the dual GLP/glucagon agonists pemvidutide and efinopegdutide. Here is the description Roger wrote for the original conversation:In this session, conversation shifts from resmetirom to Mazen Noureddin's "NASH Monopoly" game and focuses on the value of FGF-21s and glucagon agents. Stephen posits two comments about GLP-1s. First, there is now adequate data suggesting that GLP-1s will not melt away all liver fat and as a result lead to dramatic fibrosis regression. Second, we know from a small sub-cohort of patients in Akero's SYMMETRY trial that patients already on fairly low doses of GLP-1s saw what Stephen describes as an 'incredible' and incremental benefit for the FGF-21 agent, efruxifermin. The group notes that while glucagon dual and treble agents are likely to produce dramatically more robust results in weight loss and liver defatting than GLP-1s alone, they still seem unlikely to 'usurp the need for other types of agents.' From here discussion considers the FGF-21 class. Stephen notes that two drugs, efruxifermin and pegozafermin, have demonstrated significant efficacy against fibrosis. As the conversation concludes, the panelists agree that earlier, more aggressive screening to arrest cirrhosis will become pivotal and will not occur until the right drug becomes available. 

Naim Alkhouri and Mazen Noureddin join Jörn Schattenberg and Roger Green to discuss issues regarding incretin agonists and results from the efruxiermin late-breaker at the EASL Congress 2024. Naim shares his general excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed further reduction in liver fat vs. the GLP-1 agent. Jörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He goes back to review the survodutide data from the NEJM article. Mazen shares the late-breaker data that Vlad Ratziu presented on behalf of Stephen. This is a 96-week, triple biopsy study showing dramatic, sustained fibrosis improvement with a 30% delta for one level and a 21% delta for two levels. Jörn notes that the triple biopsies are demonstrate the durability of the agent against fibrosis. Roger notes this is particularly encouraging because of the previous pegbelfermin data showing loss of efficacy and tachyphylaxis. Naim concurs and adds that if the two-stage drop in fibrosis can be sustained, this would be a "big deal for the field" that might lead prescribers to think about FGF-21 as indication therapy with a "more tolerated" oral later on.   

00:00:00 Surf's Up, Season 5 Episode 20Naim Alkhouri and Mazen Noureddin join co-hosts Jörn Schattenberg and Roger Green to discuss major drug development stories from the EASL Congress 2024. They pay tribute to Stephen Harrison and proceed to groundbreakers.00:08:16 - Presentations on ResmetiromMazen shares a paper he presented looking at resmetirom dose-response. The 100mg dose performed better than the 80mg dose. Jörn notes that the most important element of the study might be the demonstrated 36-month effect.  00:14:19- Implications of Different Analytical Modes Naim compares different modes of analysis. Intent to Treat, which treats all non-completers as failures, will produce lower rates of response than a "completer" or "modified Intent to Treat" analysis, which either eliminates non-completers or assigns them placebo-level response. 00:16:12 - The "Twin-Cretins"Jörn coined  the name "Twin-cretins" for agents with GLP-1 agonism plus another incretin effect. Tirzepatide is a GLP/GIP while survodutide, pemvuditide, and efinopegdutide, are GLP/glucagons. Naim reviews the tirzepatide late-breaker presentation, which showed high rates of MASH resolution, but, as a completer analysis, might not have proven whether a GLP/GIP can achieve significant fibrosis regression.  Naim notes that Stephen doubted strongly this was possible, but that bariatric surgery's effect creates a paradox. Mazen concurs, and states he is more confident in the GLP/glucagon agents. Jörn agrees. 00:23:09 - Implications of widespread GLP useRoger asks how widespread prior patient use of incretins will affect prescribing. Naim states that many of his Rezdiffra MASH patients have been on GLP-1 already.  He describes a key difference between the three GLP/glucagon agents in development. 00:24:20 - The previous GLP/glucagon studiesNaim expresses his excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed a further reduction in liver fat compared to the GLP-1 agent. 00:26:44 - Safety of survodutide in cirrhosisJörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He reviews survodutide data from the NEJM article.  00:29:41 - FGF-21s, starting with efrux data Focus shifts to FGF-21s. Mazen shares data from the efruxifermin late-breaker, a 96-week, triple biopsy study showing dramatic, sustained one- and two-level fibrosis improvement. Jörn notes the design demonstrates durability, which Roger finds particularly encouraging given the pegbelfermin experience. Naim  adds that a sustainable two-stage drop in fibrosis might position FGF-21 as induction therapy before long-term oral maintenance.   00:35:28 - Is a drug-based MASH "cure" possible? Mazen wonders whether sustained FGF-21 efficacy might return livers to their "normal" state, almost like a "cure." Jörn briefly discusses pegozafermin, and Mazen notes that a third FGF-21 is in development.   00:42:22 - Wrap-up The panel covers three other agents: the FASN inhibitor, denifenstat, Ionis's DGAT-2 antisense inhibitor, ION224, and Takeda's TAK-227, a TG2 inhibitor, plus the results of SPECIAL, a study evaluating the effect of bariatric surgery on people with cirrhosis. After these, Roger asks Mazen and Jörn what they consider likely to be the biggest story at AASLD in November.  00:53:03 - Question of the Week Given this discussion, Roger asks what are likely to be the three most prescribed medications for MASH five years from now.  00:53:36 - Business Report The next EASL Congress review episodes, how to attend recording sessions live, and a vault discussion from last year's EASL Congress wrap-up. 

The most enthralling conversation I've ever had with anyone on cancer. It's with Charlie Swanton who is a senior group leader at the Francis Crick Institute, the Royal Society Napier Professor in Cancer and medical oncologist at University College London, co-director of Cancer Research UK.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio links and many external linksEric Topol (00:07):Well, hello, this is Eric Topol with Ground Truths, and I am really fortunate today to connect us with Charlie Swanton, who is if not the most prolific researcher in the space of oncology and medicine, and he's right up there. Charlie is a physician scientist who is an oncologist at Francis Crick and he heads up the lung cancer area there. So Charlie, welcome.Charles Swanton (00:40):Thank you, Eric. Nice to meet you.Learning from a FailureEric Topol (00:43):Well, it really is a treat because I've been reading your papers and they're diverse. They're not just on cancer. Could be connecting things like air pollution, it could be Covid, it could be AI, all sorts of things. And it's really quite extraordinary. So I thought I'd start out with a really interesting short paper you wrote towards the end of last year to give a sense about you. It was called Turning a failing PhD around. And that's good because it's kind of historical anchoring. Before we get into some of your latest contributions, maybe can you tell us about that story about what you went through with your PhD?Charles Swanton (01:26):Yeah, well thank you, Eric. I got into research quite early. I did what you in the US would call the MD PhD program. So in my twenties I started a PhD in a molecular biology lab at what was then called the Imperial Cancer Research Fund, which was the sort of the mecca for DNA tumor viruses, if you like. It was really the place to go if you wanted to study how DNA tumor viruses worked, and many of the components of the cell cycle were discovered there in the 80s and 90s. Of course, Paul Nurse was the director of the institute at the time who discovered cdc2, the archetypal regulator of the cell cycle that led to his Nobel Prize. So it was a very exciting place to work, but my PhD wasn't going terribly well. And sort of 18, 19 months into my PhD, I was summoned for my midterm reports and it was not materializing rapidly enough.(02:25):And I sat down with my graduate student supervisors who were very kind, very generous, but basically said, Charlie, this isn't going well, is it? You've got two choices. You can either go back to medical school or change PhD projects. What do you want to do? And I said, well, I can't go back to medical school because I'm now two years behind. So instead I think what I'll do is I'll change PhD projects. And they asked me what I'd like to do. And back then we didn't know how p21, the CDK inhibitor bound to cyclin D, and I said, that's what I want to understand how these proteins interact biochemically. And they said, how are you going to do that? And I said, I'm not too sure, but maybe we'll try yeast two-hybrid screen and a mutagenesis screen. And that didn't work either. And in the end, something remarkable happened.(03:14):My PhD boss, Nic Jones, who's a great guy, still is, retired though now, but a phenomenal scientist. He put me in touch with a colleague who actually works next door to me now at the Francis Crick Institute called Neil McDonald, a structural biologist. And they had just solved, well, the community had just solved the structure. Pavletich just solved the structure of cyclin A CDK2. And so, Neil could show me this beautiful image of the crystal structure in 3D of cyclin A, and we could mirror cyclin D onto it and find the surface residue. So I spent the whole of my summer holiday mutating every surface exposed acid on cyclin D to an alanine until I found one that failed to interact with p21, but could still bind the CDK. And that little breakthrough, very little breakthrough led to this discovery that I had where the viral cyclins encoded by Kaposi sarcoma herpes virus, very similar to cyclin D, except in this one region that I had found interactive with a CDK inhibitor protein p21.(04:17):And so, I asked my boss, what do you think about the possibility this cyclin could have evolved from cyclin D but now mutated its surface residues in a specific area so that it can't be inhibited by any of the control proteins in the mammalian cell cycle? He said, it's a great idea, Charlie, give it a shot. And it worked. And then six months later, we got a Nature paper. And that for me was like, I cannot tell you how exciting, not the Nature paper so much as the discovery that you were the first person in the world to ever see this beautiful aspect of evolutionary biology at play and how this cyclin had adapted to just drive the cell cycle without being inhibited. For me, just, I mean, it was like a dream come true, and I never experienced anything like it before, and I guess it's sizes the equivalent to me of a class A drug. You get such a buzz out of it and over the years you sort of long for that to happen again. And occasionally it does, and it's just a wonderful profession.Eric Topol (05:20):Well, I thought that it was such a great story because here you were about to fail. I mean literally fail, and you really were able to turn it around and it should give hope to everybody working in science out there that they could just be right around the corner from a significant discovery.Charles Swanton (05:36):I think what doesn't break you makes you stronger. You just got to plow on if you love it enough, you'll find a way forward eventually, I hope.Tracing the Evolution of Cancer (TRACERx)Eric Topol (05:44):Yeah, no question about that. Now, some of your recent contributions, I mean, it's just amazing to me. I just try to keep up with the literature just keeping up with you.Charles Swanton (05:58):Eric, it's sweet of you. The first thing to say is it's not just me. This is a big community of lung cancer researchers we have thanks to Cancer Research UK funded around TRACERx and the lung cancer center. Every one of my papers has three corresponding authors, multiple co-first authors that all contribute in this multidisciplinary team to the sort of series of small incremental discoveries. And it's absolutely not just me. I've got an amazing team of scientists who I work with and learn from, so it's sweet to give me the credit.Eric Topol (06:30):I think what you're saying is really important. It is a team, but I think what I see through it all is that you're an inspiration to the team. You pull people together from all over the world on these projects and it's pretty extraordinary, so that's what I would say.Charles Swanton (06:49):The lung community, Eric, the lung cancer community is just unbelievably conducive to collaboration and advancing understanding of the disease together. It's just such a privilege to be working in this field. I know that sounds terribly corny, but it is true. I don't think I recall a single email to anybody where I've asked if we can collaborate where they've said, no, everybody wants to help. Everybody wants to work together on this challenge. It's just such an amazing field to be working in.Eric Topol (07:19):Yeah. Well I was going to ask you about that. And of course you could have restricted your efforts or focused on different cancers. What made you land in lung cancer? Not that that's only part of what you're working on, but that being the main thing, what drew you to that area?Charles Swanton (07:39):So I think the answer to your question is back in 2008 when I was looking for a niche, back then it was lung cancer was just on the brink of becoming an exciting place to work, but back then nobody wanted to work in that field. So there was a chair position in thoracic oncology and precision medicine open at University College London Hospital that had been open, as I understand it for two years. And I don't think anybody had applied. So I applied and because I was the only one, I got it and the rest is history.(08:16):And of course that was right at the time when the IPASS draft from Tony Mok was published and was just a bit after when the poster child of EGFR TKIs and EGFR mutant lung cancer had finally proven that if you segregate that population of patients with EGFR activating mutation, they do incredibly well on an EGFR inhibitor. And that was sort of the solid tumor poster child along with Herceptin of precision medicine, I think. And you saw the data at ASCO this week of Lorlatinib in re-arranged lung cancer. Patients are living way beyond five years now, and people are actually talking about this disease being more like CML. I mean, it's extraordinary the progress that's been made in the last two decades in my short career.Eric Topol (09:02):Actually, I do want to have you put that in perspective because it's really important what you just mentioned. I was going to ask you about this ASCO study with the AKT subgroup. So the cancer landscape of the lung has changed so much from what used to be a disease of cigarette smoking to now one of, I guess adenocarcinoma, non-small cell carcinoma, not related to cigarettes. We're going to talk about air pollution in a minute. This group that had, as you say, 60 month, five year plus survival versus what the standard therapy was a year plus is so extraordinary. But is that just a small subgroup within small cell lung cancer?Charles Swanton (09:48):Yes, it is, unfortunately. It's just a small subgroup. In our practice, probably less than 1% of all presentations often in never smokers, often in female, never smokers. So it is still in the UK at least a minority subset of adenocarcinomas, but it's still, as you rightly say, a minority of patients that we can make a big difference to with a drug that's pretty well tolerated, crosses the blood-brain barrier and prevents central nervous system relapse and progression. It really is an extraordinary breakthrough, I think. But that said, we're also seeing advances in smoking associated lung cancer with a high mutational burden with checkpoint inhibitor therapy, particularly in the neoadjuvant setting now prior to surgery. That's really, really impressive indeed. And adjuvant checkpoint inhibitor therapies as well as in the metastatic setting are absolutely improving survival times and outcomes now in a way that we couldn't have dreamt of 15 years ago. We've got much more than just platinum-based chemo is basically the bottom line now.Revving Up ImmunotherapyEric Topol (10:56):Right, right. Well that actually gets a natural question about immunotherapy also is one of the moving parts actually just amazing to me how that's really, it's almost like we're just scratching the surface of immunotherapy now with checkpoint inhibitors because the more we get the immune system revved up, the more we're seeing results, whether it's with vaccines or CAR-T, I mean it seems like we're just at the early stages of getting the immune system where it needs to be to tackle the cancer. What's your thought about that?Charles Swanton (11:32):I think you're absolutely right. We are, we're at the beginning of a very long journey thanks to Jim Allison and Honjo. We've got CTLA4 and PD-1/PDL-1 axis to target that's made a dramatic difference across multiple solid tumor types including melanoma and lung cancer. But undoubtedly, there are other targets we've seen LAG-3 and melanoma and then we're seeing new ways, as you rightly put it to mobilize the immune system to target cancers. And that can be done through vaccine based approaches where you stimulate the immune system against the patient's specific mutations in their cancer or adoptive T-cell therapies where you take the T-cells out of the tumor, you prime them against the mutations found in the tumor, you expand them and then give them back to the patient. And colleagues in the US, Steve Rosenberg and John Haanen in the Netherlands have done a remarkable job there in the context of melanoma, we're not a million miles away from European approvals and academic initiated manufacturing of T-cells for patients in national health systems like in the Netherlands.(12:50):John Haanen's work is remarkable in that regard. And then there are really spectacular ways of altering T-cells to be able to either migrate to the tumor or to target specific tumor antigens. You mentioned CAR-T cell therapies in the context of acute leukemia, really extraordinary developments there. And myeloma and diffuse large B-cell lymphoma as well as even in solid tumors are showing efficacy. And I really am very excited about the future of what we call biological therapies, be it vaccines, an antibody drug conjugates and T-cell therapies. I think cancer is a constantly adapting evolutionary force to be reckoned with what better system to combat it than our evolving immune system. It strikes me as being a future solution to many of these refractory cancers we still find difficult to treat.Eric Topol (13:48):Yeah, your point is an interesting parallel how the SARS-CoV-2 virus is constantly mutating and becoming more evasive as is the tumor in a person and the fact that we can try to amp up the immune system with these various means that you just were reviewing. You mentioned the other category that's very hot right now, which is the antibody drug conjugates. Could you explain a bit about how they work and why you think this is an important part of the future for cancer?Antibody-Drug ConjugatesCharles Swanton (14:26):That's a great question. So one of the challenges with chemotherapy, as you know, is the normal tissue toxicity. So for instance, neutropenia, hair loss, bowel dysfunction, diarrhea, epithelial damage, essentially as you know, cytotoxics affect rapidly dividing tissues, so bone marrow, epithelial tissues. And because until relatively recently we had no way of targeting chemotherapy patients experienced side effects associated with them. So over the last decade or so, pioneers in this field have brought together this idea of biological therapies linked with chemotherapy through a biological linker. And so one poster chart of that would be the drug T-DXd, which is essentially Herceptin linked to a chemotherapy drug. And this is just the most extraordinary drug that obviously binds the HER2 receptor, but brings the chemotherapy and proximity of the tumor. The idea being the more drug you can get into the tumor and the less you're releasing into normal tissue, the more on tumor cytotoxicity you'll have and the less off tumor on target normal tissue side effects you'll have. And to a large extent, that's being shown to be the case. That doesn't mean they're completely toxicity free, they're not. And one of the side effects associated with these drugs is pneumonitis.(16:03):But that said, the efficacy is simply extraordinary. And for example, we're having to rewrite the rule books if you like, I think. I mean I'm not a breast cancer physician, I used to be a long time ago, but back in the past in the early 2000s, there was HER2 positive breast cancer and that's it. Now they're talking about HER2 low, HER2 ultra-low, all of which seem to in their own way be sensitive to T-DXd, albeit to a lower extent than HER2 positive disease. But the point is that there doesn't seem to be HER2 completely zero tumor group in breast cancer. And even the HER2-0 seem to benefit from T-DXd to an extent. And the question is why? And I think what people are thinking now is it's a combination of very low cell service expression of HER2 that's undetectable by conventional methods like immunohistochemistry, but also something exquisitely specific about the way in which HER2 is mobilized on the membrane and taken back into the cell. That seems to be specific to the breast cancer cell but not normal tissue. So in other words, the antibody drug conjugate binds the tumor cell, it's thought the whole receptor's internalized into the endosome, and that's where the toxicity then happens. And it's something to do with the endosomal trafficking with the low level expression and internalization of the receptor. That may well be the reason why these HER2 low tumors are so sensitive to this beautiful technology.Eric Topol (17:38):Now I mean it is an amazing technology in all these years where we just were basically indiscriminately trying to kill cells and hoping that the cancer would succumb. And now you're finding whether you want to call it a carry or vector or Trojan horse, whatever you want to call it, but do you see that analogy of the HER2 receptor that's going to be seen across the board in other cancers?Charles Swanton (18:02):That's the big question, Eric. I think, and have we just lucked out with T-DXd, will we find other T-DXd like ADCs targeting other proteins? I mean there are a lot of ADCs being developed against a lot of different cell surface proteins, and I think the jury's still out. I'm confident we will, but we have to bear in mind that biology is a fickle friend and there may be something here related to the internalization of the receptor in breast cancer that makes this disease so exquisitely sensitive. So I think we just don't know yet. I'm reasonably confident that we will find other targets that are as profoundly sensitive as HER2 positive breast cancer, but time will tell.Cancer, A Systemic DiseaseEric Topol (18:49):Right. Now along these lines, well the recent paper that you had in Cell, called embracing cancer complexity, which we've talking about a bit, in fact it's kind of those two words go together awfully well, but hallmarks of systemic disease, this was a masterful review, as you say with the team that you led. But can you tell us about what's your main perspective about this systemic disease? I mean obviously there's been the cancer is like cardiovascular and cancers like this or that, but here you really brought it together with systemic illness. What can you say about that?Charles Swanton (19:42):Well, thanks for the question first of all, Eric. So a lot of this comes from some of my medical experience of treating cancer and thinking to myself over the years, molecular biology has had a major footprint on advances in treating the disease undoubtedly. But there are still aspects of medicine where molecular biology has had very little impact, and often that is in areas of suffering in patients with advanced disease and cancer related to things like cancer cachexia, thrombophilia. What is the reason why patients die blood clots? What is the reason patients die of cancer at all? Even a simple question like that, we don't always know the answer to, on death certificates, we write metastatic disease as a cause of cancer death, but we have patients who die with often limited disease burden and no obvious proximal cause of death sometimes. And that's very perplexing, and we need to understand that process better.(20:41):And we need to understand aspects like cancer pain, for example, circadian rhythms affect biological sensitivity of cancer cells to drugs and what have you. Thinking about cancer rather than just sort of a single group of chaotically proliferating cells to a vision of cancer interacting both locally within a microenvironment but more distantly across organs and how organs communicate with the cancer through neuronal networks, for example, I think is going to be the next big challenge by setting the field over the next decade or two. And I think then thinking about more broadly what I mean by embracing complexity, I think some of that relates to the limitations of the model systems we use, trying to understand inter-organ crosstalk, some of the things you cover in your beautiful Twitter reviews. (←Ground Truths link) I remember recently you highlighted four publications that looked at central nervous system, immune cell crosstalk or central nervous system microbiome crosstalk. It's this sort of long range interaction between organs, between the central nervous system and the immune system and the cancer that I'm hugely interested in because I really think there are vital clues there that will unlock new targets that will enable us to control cancers more effectively if we just understood these complex networks better and had more sophisticated animal model systems to be able to interpret these interactions.Eric Topol (22:11):No, it's so important what you're bringing out, the mysteries that still we have to deal with cancer, why patients have all these issues or dying without really knowing what's happened no less, as you say, these new connects that are being discovered at a remarkable pace, as you mentioned, that ground truths. And also, for example, when I spoke with Michelle Monje, she's amazing on the cancer, where hijacking the brain cells and just pretty extraordinary things. Now that gets me to another line of work of yours. I mean there are many, but the issue of evolution of the tumor, and if you could put that in context, a hot area that's helping us elucidate these mechanisms is known as spatial omics or spatial biology. This whole idea of being able to get the spatial temporal progression through single cell sequencing and single cell nuclei, all the single cell omics. So if you could kind of take us through what have we learned with this technique and spatial omics that now has changed or illuminated our understanding of how cancer evolves?Charles Swanton (23:37):Yeah, great question. Well, I mean I think it helps us sort of rewind a bit and think about evolution in general. Genetic selection brought about by diverse environments and environmental pressures that force evolution, genetic evolution, and speciation down certain evolutionary roots. And I think one can think about cancers in a similar way. They start from a single cell and we can trace the evolutionary paths of cancers by single cell analysis as well as bulk sequencing of spatially separated tumor regions to be able to reconstruct their subclones. And that's taught us to some extent, what are the early events in tumor evolution? What are the biological mechanisms driving branched evolution? How does genome instability begin in tumors? And we found through TRACERx work, whole genome doubling is a major route through to driving chromosome instability along with mutagenic enzymes like APOBEC that drive both mutations and chromosomal instability.(24:44):And then that leads to a sort of adaptive radiation in a sense, not dissimilar to I guess the Cambrian explosion of evolutionary opportunity upon which natural selection can act. And that's when you start to see the hallmarks of immune evasion like loss of HLA, the immune recognition molecules that bind the neoantigens or even loss of the neoantigens altogether or mutation of beta 2 microglobulin that allow the tumor cells to now evolve below the radar, so to speak. But you allude to the sort of spatial technologies that allow us to start to interpret the microenvironments as well. And that then tells us what the evolutionary pressures are upon the tumor. And we're learning from those spatial technologies that these environments are incredibly diverse, actually interestingly seem to be converging on one important aspect I'd like to talk to you a little bit more about, which is the myeloid axis, which is these neutrophils, macrophages, et cetera, that seem to be associated with poor outcome and that will perhaps talk about pollution in a minute.(25:51):But I think they're creating a sort of chronic inflammatory response that allows these early nascent tumor cells to start to initiate into frankly tumor invasive cells and start to grow. And so, what we're seeing from these spatial technologies in lung cancer is that T-cells, predatory T-cells, force tumors to lose their HLA molecules and what have you to evade the immune system. But for reasons we don't understand, high neutrophil infiltration seems to be associated with poor outcome, poor metastasis free survival. And actually, those same neutrophils we've recently found actually even tracked to the metastasis sites of metastasis. So it's almost like this sort of symbiosis between the myeloid cells and the tumor cells in their biology and growth and progression of the tumor cells.Eric Topol (26:46):Yeah, I mean this white cell story, this seems to be getting legs and is relatively new, was this cracked because of the ability to do this type of work to in the past everything was, oh, it's cancer's heterogeneous and now we're getting pinpoint definition of what's going on.Charles Swanton (27:04):I think it's certainly contributed, but it's like everything in science, Eric, when you look back, there's evidence in the literature for pretty much everything we've ever discovered. You just need to put the pieces together. And I mean one example would be the neutrophil lymphocyte ratio in the blood as a hallmark of outcome in cancers and to checkpoint inhibitor blockade, maybe this begins to explain it, high neutrophils, immune suppressive environment, high neutrophils, high macrophages, high immune suppression, less benefit from checkpoint inhibitor therapy, whereas you want lymphocyte. So I think there are biomedical medical insights that help inform the biology we do in the lab that have been known for decades or more. And certainly the myeloid M2 axis in macrophages and what have you was known about way before these spatial technologies really came to fruition, I think.The Impact of Air PollutionEric Topol (28:01):Yeah. Well you touched on this about air pollution and that's another dimension of the work that you and your team have done. As you well know, there was a recent global burden of disease paper in the Lancet, which has now said that air pollution with particulate matter 2.5 less is the leading cause of the burden of disease in the world now.Charles Swanton (28:32):What did you think of that, Eric?Eric Topol (28:34):I mean, I was blown away. Totally blown away. And this is an era you've really worked on. So can you put it in perspective?Charles Swanton (28:42):Yeah. So we got into this because patients of mine, and many of my colleagues would ask the same question, I've never smoked doctor, I'm healthy. I'm in my mid 50s though they're often female and I've got lung cancer. Why is that doctor? I've had a good diet, I exercise, et cetera. And we didn't really have a very good answer for that, and I don't want to pretend for a minute we solved the whole problem. I think hopefully we've contributed to a little bit of understanding of why this may happen. But that aside, we knew that there were risk factors associated with lung cancer that included air pollution, radon exposure, of course, germline genetics, we mustn't forget very important germline variation. And I think there is evidence that all of them are associated with lung cancer risk in different ways. But we wanted to look at air pollution, particularly because there was an awful lot of evidence, several meta-analysis of over half a million individuals showing very convincingly with highly significant results that increasing PM 2.5 micron particulate levels were associated with increased risk of lung cancer.(29:59):To put that into perspective, where you are on the west coast of the US, it's relatively unpolluted. You would be talking about maybe five micrograms per meter cubed of PM2.5 in a place like San Diego or Western California, assuming there aren't any forest fires of course. And we estimate that that would translate to about, we think it's about one extra case of never smoking lung cancer per hundred thousand of the population per year per one microgram per meter cube rise in the pollution levels. So if you go to Beijing for example, on a bad day, the air pollution levels could be upwards of a hundred micrograms per meter cubed because there are so many coal fired power stations in China partly. And there I think the risk is considerably higher. And that's certainly what we've seen in the meta-analyses in our limited and relatively crude epidemiological analyses to be the case.(30:59):So I think the association was pretty certain, we were very confident from people's prior publications  this was important. But of course, association is not causation. So we took a number of animal models and showed that you could promote lung cancer formation in four different oncogene driven lung cancer models. And then the question is how, does air pollution stimulate mutations, which is what I initially thought it would do or something else. It turns out we don't see a significant increase in exogenous like C to A carcinogenic mutations. So that made us put our thinking caps on. And I said to you earlier, often all these discoveries have been made before. Well, Berenblum in 1947, first postulated that actually tumors are initiated through a two-step process, which we now know involves a sort of pre initiated cell with a mutation in that in itself is not sufficient to cause cancer.(31:58):But on top of that you need an inflammatory stimulus. So the question was then, well, okay, is inflammation working here? And we found that there was an interleukin-1 beta axis. And what happens is that the macrophages come into the lung on pollution exposure, engulf phagocytose the air pollutants, and we think what's happening is the air pollutants are puncturing membranes in the lung. That's what we think is happening. And interleukin-1 beta preformed IL-1 beta is being released into the extracellular matrix and then stimulating pre-initiated cells stem cells like the AT2 cells with an activating EGFR mutation to form a tumor. But the EGFR mutation alone is not sufficient to form tumors. It's only when you have the interleukin-1 beta and the activated mutation that a tumor can start.(32:49):And we found that if we sequence normal lung tissue in a healthy adult 60-year-old adult, we will find about half of biopsies will have an activating KRAS mutation in normal tissue, and about 15% will have an activating mutation in EGFR in histologically normal tissue with nerve and of cancer. In fact, my friend and colleague who's a co-author on the paper, James DeGregori, who you should speak to in Colorado, fascinating evolutionary cancer biologists estimates that in a healthy 60-year-old, there are a hundred billion cells in your body that harbor an oncogenic mutation. So that tells you that at the cellular level, cancer is an incredibly rare event and almost never happens. I mean, our lifetime risk of cancer is perhaps one in two. You covered that beautiful pancreas paper recently where they estimated that there may be 80 to 100 KRAS mutations in a normal adult pancreas, and yet our lifetime risk of pancreas cancer is one in 70. So this tells you that oncogenic mutations are rarely sufficient to drive cancer, so something else must be happening. And in the context of air pollution associated lung cancer, we think that's inflammation driven by these white cells, these myeloid cells, the macrophages.Cancer BiomarkersEric Topol (34:06):No, it makes a lot of sense. And this, you mentioned the pancreas paper and also what's going in the lung, and it seems like we have this burden of all you need is a tipping point and air pollution seems to qualify, and you seem to be really in the process of icing the mechanism. And like I would've thought it was just mutagenic and it's not so simple, right? But that gets me to this is such an important aspect of cancer, the fact that we harbor these kind of preconditions. And would you think that cancer takes decades to actually manifest most cancers, or do we really have an opportunity here to be able to track whether it's through blood or other biomarkers? Another area you've worked on a lot whereby let's say you could define people at risk for polygenic risk scores or various cancers or genome sequencing for predisposition genes, whatever, and you could monitor in the future over the course of those high-risk people, whether they were starting to manifest microscopic malignancy. Do you have any thoughts about how long it takes for the average person to actually manifest a typical cancer?Charles Swanton (35:28):That's a cracking question, and the answer is we've got some clues in various cancers. Peter Campbell would be a good person to speak to. He estimates that some of the earliest steps in renal cancer can occur in adolescence. We've had patients who gave up smoking 30 or so years ago where we can still see the clonal smoking mutations in the trunk of the tumor's evolutionary tree. So the initial footprints of the cancer are made 30 years before the cancer presents. That driver mutation itself may also be a KRAS mutation in a smoking cigarette context, G12C mutation. And those mutations can precede the diagnosis of the disease by decades. So the earliest steps in cancer evolution can occur, we think can precede diagnoses by a long time. So to your point, your question which is, is there an opportunity to intervene? I'm hugely optimistic about this actually, this idea of molecular cancer prevention.An Anti-Inflammatory Drug Reduces Fatal Cancer and Lung Cancer(36:41):How can we use data coming out of various studies in the pancreas, mesothelioma, lung, et cetera to understand the inflammatory responses? I don't think we can do very much about the mutations. The mutations unfortunately are a natural consequence of aging. You and I just sitting here talking for an hour will have accumulated multiple mutations in our bodies over that period, I'm afraid and there's no escaping it. And right now there's not much we can do to eradicate those mutant clones. So if we take that as almost an intractable problem, measuring them is hard enough, eradicating them is even harder. And then we go back to Berenblum in 1947 who said, you need an inflammatory stimulus. Well, could we do something about the inflammation and dampen down the inflammation? And of course, this is why we got so excited about IL-1 beta because of the CANTOS trial, which you may remember in 2017 from Ridker and colleagues showed that anti IL-1 beta used as a mechanism of preventing cardiovascular events was associated with a really impressive dose dependent reduction in new lung cancer primaries.(37:49):Really a beautiful example of cancer prevention in action. And that data weren't just a coincidence. The FDA mandated Novartis to collect the solid tumor data and the P-values are 0.001. I mean it's very highly significant dose dependent reduction in lung cancer incidents associated with anti IL-1 beta. So I think that's really the first clue in my mind that something can be done about this problem. And actually they had five years of follow-up, Eric. So that's something about that intervening period where you can treat and then over time see a reduction in new lung cancers forming. So I definitely think there's a window of opportunity here.Eric Topol (38:31):Well, what you're bringing up is fascinating here because this trial, which was a cardiology trial to try to reduce heart attacks, finds a reduction in cancer, and it's been lost. It's been buried. I mean, no one's using this therapy to prevent cancer between ratcheting up the immune system or decreasing inflammation. We have opportunities that we're not even attempting. Are there any trials that are trying to do this sort of thing?Charles Swanton (39:02):So this is the fundamental problem. Nobody wants to invest in prevention because essentially you are dealing with well individuals. It's like the vaccine challenge all over again. And the problem is you never know who you are benefiting. There's no economic model for it. So pharma just won't touch prevention with a barge pole right now. And that's the problem. There's no economic model for it. And yet the community, all my academic colleagues are crying out saying, this has got to be possible. This has got to be possible. So CRUK are putting together a group of like-minded individuals to see if we can do something here and we're gradually making progress, but it is tough.Eric Topol (39:43):And it's interesting that you bring that up because for GRAIL, one of the multicenter cancer early detection companies, they raised billions of dollars. And in fact, their largest trial is ongoing in the UK, but they haven't really focused on high-risk people. They just took anybody over age 50 or that sort of thing. But that's the only foray to try to reboot how we or make an early microscopic diagnosis of cancer and track people differently. And there's an opportunity there. You've written quite a bit on you and colleagues of the blood markers being able to find a cancer where well before, in fact, I was going to ask you about that is, do you think there's people that are not just having all these mutations every minute, every hour, but that are starting to have the early seeds of cancer, but because their immune system then subsequently kicks in that they basically kind of quash it for that period of time?Charles Swanton (40:47):Yeah, I do think that, I mean, the very fact that we see these sort of footprints in the tumor genome of immune evasion tells you that the immune system's having a very profound predatory effect on evolving tumors. So I do think it's very likely that there are tumors occurring that are suppressed by the immune system. There is a clear signature, a signal of negative selection in tumors where clones have been purified during their evolution by the immune system. So I think there's pretty strong evidence for that now. Obviously, it's very difficult to prove something existed when it doesn't now exist, but there absolutely is evidence for that. I think it raises the interesting question of immune system recognizes mutations and our bodies are replete with mutations as we were just discussing. Why is it that we're not just a sort of epithelial lining of autoimmunity with T-cells and immune cells everywhere? And I think what the clever thing about the immune system is it's evolved to target antigens only when they get above a certain burden. Otherwise, I think our epithelial lining, our skin, our guts, all of our tissues will be just full of T-cells eating away our normal clones.(42:09):These have to get to a certain size for antigen to be presented at a certain level for the immune system to recognize it. And it's only then that you get the immune predation occurring.Forever Chemicals and Microplastics Eric Topol (42:20):Yeah, well, I mean this is opportunities galore here. I also wanted to extend the air pollution story a bit. Obviously, we talked about particulate matter and there's ozone and nitric NO2, and there's all sorts of other air pollutants, but then there's also in the air and water these forever chemicals PFAS for abbreviation, and they seem to be incriminated like air pollution. Can you comment about that?Charles Swanton (42:55):Well, I can comment only insofar as to say I'm worried about the situation. Indeed, I'm worried about microplastics actually, and you actually cover that story as well in the New England Journal, the association of microplastics with plaque rupture and atheroma. And indeed, just as in parenthesis, I wanted to just quickly say we currently think the same mechanisms that are driving lung cancer are probably responsible for atheroma and possibly even neurodegenerative disease. And essentially it all comes down to the macrophages and the microglia becoming clogged up with these pollutants or environmental particulars and releasing chronic inflammatory mediators that ultimately lead to disease. And IL-1 beta being one of those in atheroma and probably IL-6 and TNF in neurodegenerative disease and what have you. But I think this issue that you rightly bring up of what is in our environment and how does it cause pathology is really something that epidemiologists have spent a lot of time focusing on.(43:56):But actually in terms of trying to move from association to causation, we've been, I would argue a little bit slow biologically in trying to understand these issues. And I think that is a concern. I mean, to give you an example, Allan Balmain, who works at UCSF quite close to you, published a paper in 2020 showing that 17 out of 20 environmental carcinogens IARC carcinogens class one carcinogens cause tumors in rodent models without driving mutations. So if you take that to a logical conclusion, in my mind, what worries me is that many of the sort of carcinogen assays are based on driving mutagenesis genome instability. But if many carcinogen aren't driving DNA mutagenesis but are still driving cancer, how are they doing it? And do we actually have the right assays to interpret safety of new chemical matter that's being introduced into our environment, these long-lived particles that we're breathing in plastics, pollutants, you name it, until we have the right biological assays, deeming something to be safe I think is tricky.Eric Topol (45:11):Absolutely. And I share your concerns on the nanoplastic microplastic story, as you well know, not only have they been seen in arteries that are inflamed and in blood clots and in various tissues, have they been seen so far or even looked for within tumor tissue?Charles Swanton (45:33):Good question. I'm not sure they have. I need to check. What I can tell you is we've been doing some experiments in the lab with fluorescent microplastics, 2.5 micron microplastics given inhaled microplastics. We find them in every mouse organ a week after. And these pollutants even get through into the brain through the olfactory bulb we think.Charles Swanton (45:57):Permeate every tissue, Eric.Eric Topol (45:59):Yeah, no, this is scary because here we are, we have these potentially ingenious ways to prevent cancer in the future, but we're chasing our tails by not doing anything to deal with our environment.Charles Swanton (46:11):I think that's right. I totally agree. Yeah.Eric Topol (46:15):So I mean, I can talk to you for the rest of the day, but I do want to end up with a topic that we have mutual interest in, which is AI. And also along with that, when you mentioned about aging, I'd like to get your views on these two, how do you see AI fitting into the future of cancer? And then the more general topic is, can we actually at some point modulate the biologic aging process with or without help with from AI? So those are two very dense questions, but maybe you can take us through them.Charles Swanton (46:57):How long have we got?Eric Topol (46:59):Just however long you have.A.I. and CancerCharles Swanton (47:02):AI and cancer. Well, AI and medicine actually in general, whether it's biomedical research or medical care, has just infinite potential. And I'm very, very excited about it. I think what excites me about AI is it's almost the infinite possibilities to work across scale. Some of the challenges we raised in the Cell review that you mentioned, tackling, embracing complexity are perfectly suited for an AI problem. Nonlinear data working, for instance in our fields with CT imaging, MRI imaging, clinical outcome data, blood parameters, genomics, transcriptomes and proteomes and trying to relate this all into something that's understandable that relates to risk of disease or potential identification of a new drug target, for example. There are numerous publications that you and others have covered that allude to the incredible possibilities there that are leading to, for instance, the new identification of drug targets. I mean, Eli Van Allen's published some beautiful work here and in the context of prostate cancer with MDM4 and FGF receptor molecules being intimately related to disease biology.(48:18):But then it's not just that, not just drug target identification, it's also going all the way through to the clinic through drug discovery. It's how you get these small molecules to interact with oncogenic proteins and to inhibit them. And there are some really spectacular developments going on in, for instance, time resolved cryo-electron microscopy, where in combination with modeling and quantum computing and what have you, you can start to find pockets emerging in mutant proteins, but not the wild type ones that are druggable. And then you can use sort of synthetic AI driven libraries to find small molecules that will be predicted to bind these transiently emerging pockets. So it's almost like AI is primed to help at every stage in scientific investigation from the bench all the way through to the bedside. And there are examples all the way through there in the literature that you and others have covered in the last few years. So I could not be more excited about that.Eric Topol (49:29):I couldn't agree with you more. And I think when we get to multimodal AI at the individual level across all their risks for conditions in their future, I hope someday will fulfill that fantasy of primary prevention. And that is getting me to this point that I touched on because I do think they interact to some degree AI and then will we ever be able to have an impact on aging? Most people conflate this because what we've been talking about throughout the hour has been age-related diseases, that is cancer, for example, and cardiovascular and neurodegenerative, which is different than changing aging per se, body wide aging. Do you think we'll ever changed body wide aging?Charles Swanton (50:18):Wow, what a question. Well, if you'd asked me 10 years ago, 15 years ago, do you think we'll ever cure melanoma in my lifetime, I'd have said definitely not. And now look where we are. Half of patients with melanoma, advanced melanoma, even with brain metastasis curd with combination checkpoint therapy. So I never say never in biology anymore. It always comes back to bite you and prove you wrong. So I think it's perfectly possible.Charles Swanton (50:49):We have ways to slow down the aging process. I guess the question is what will be the consequences of that?Eric Topol (50:55):That's what I was going to ask you, because all these things like epigenetic reprogramming and senolytic drugs, and they seem to at least pose some risk for cancer.Charles Swanton (51:09):That's the problem. This is an evolutionary phenomenon. It's a sort of biological response to the onslaught of these malignant cells that are potentially occurring every day in our normal tissue. And so, by tackling one problem, do we create another? And I think that's going to be the big challenge over the next 50 years.Eric Topol (51:31):Yeah, and I think your point about the multi-decade challenge, because if you can promote healthy aging without any risk of cancer, that would be great. But if the tradeoff is close, it's not going to be very favorable. That seems to be the main liability of modulation aging through many of the, there's many shots on goal here, of course, as you well know. But they do seem to pose that risk in general.Charles Swanton (51:58):I think that's right. I think the other thing is, I still find, I don't know if you agree with me, but it is an immense conundrum. What is the underlying molecular basis for somatic aging, for aging of normal tissues? And it may be multifactorial, it may not be just one answer to that question. And different tissues may age in different ways. I don't know. It's a fascinating area of biology, but I think it really needs to be studied more because as you say, it underpins all of these diseases we've been talking about today, cardiovascular, neurodegeneration, cancer, you name it. We absolutely have to understand this. And actually, the more I work in cancer, the more I feel like actually what I'm working on is aging.(52:48):And this is something that James DeGregori and I have discussed a lot. There's an observation that in medicine around patients with alpha-1 antitrypsin deficiency who are at higher risk of lung cancer, but they're also at high risk of COPD, and we know the associations of chronic obstructive pulmonary disease with lung cancer risk. And one of the theories that James had, and I think this is a beautiful idea, actually, is as our tissues age, and COPD is a reflection of aging, to some extent gone wrong. And as our tissues age, they become less good at controlling the expansion of these premalignant clones, harboring, harboring oncogenic mutations in normal tissue. And as those premalignant clones expand, the substrate for evolution also expands. So there's more likely to be a second and third hit genetically. So it may be by disrupting the extracellular matrices through inflammation that triggers COPD through alpha-1 antitrypsin deficiency or smoking, et cetera, you are less effectively controlling these emergent clones that just expand with age, which I think is a fascinating idea actually.Eric Topol (54:01):It really is. Well, I want to tell you, Charlie, this has been the most fascinating, exhilarating discussion I've ever had on cancer. I mean, really, I am indebted to you because not just all the work you've done, but your ability to really express it, articulate it in a way that hopefully everyone can understand who's listening or reading the transcript. So we'll keep following what you're doing because you're doing a lot of stuff. I can't thank you enough for joining me today, and you've given me lots of things to think about. I hope the people that are listening or reading feel the same way. I mean, this has been so mind bending in many respects. We're indebted to you.Charles Swanton (54:49):Well, we all love reading your Twitter feeds. Keep them coming. It helps us keep a broader view of medicine and biological research, not just cancer, which is why I love it so much.******************************************The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

This conversation sees the end of the "hot topics" discussion, followed by Michael Charlton discussing issues and excitement around the FGF-21 class.As we begin, Louise Campbell and Jörn Schattenberg speculate on ways to incorporate metrics like the Dietary Inflammation Index into multifactorial care. Michael asks whether alcohol is figured in the index, given its pro-inflammatory nature, and celebrates the fact that we can now evaluate MetALD patients as a group instead of removing them from classical MASH clinical trials. Louise, who raised the issue in the first place, does not know. As she notes, she first found the issue within the last week. One key question for her is how we can use this in 5-10 years when primary care becomes a key player in MASLD and all metabolic diseases. Roger Green's hot topic involves "Ask the MD" columns in US newspapers and magazines. He gives "two cheers" for help columns in which MDs recommend that MASH patients  "go to your doctor and ask for an ultrasound."  He asks whether the PCP is the right destination and whether "ultrasound is the test to seek. However, he appreciates that all this brings MASH badly-needed visibility in the public eye. Michael and Louise agree that given how few patients are treated today, any such public acknowledgment is positive.Michael discusses the emerging excitement around the FGF-21 class. The recent agents from Akero and 89bio are "emerging as highly potent" in terms of PDFF change and transaminase responses. While we need to learn more, he asks how this will fit in with Rezdiffra and, more generally, how long we can give a patient a "potent" growth factor and what will happen if/when the patient needs to discontinue therapy. Jörn and Michael note adherence challenges with this therapy; Roger comments that even with daily oral drugs, adherence can be a challenge.

This final conversation starts by considering prescribing models for other diseases and how they might work here, shifts to discussing the challenges of keeping a patient enrolled in a long-term clinical trial (or even participating in a trial in the first place), and moves on to the final question for the episode. The conversation picks up on the FG-21 conversation, particularly how FGF-21 might be prescribed alongside Rezdiffra. Roger Green starts by asking whether and how this prescribing pattern might fit in an "oncology" model, where FGF-21 might be an induction drug and Rezdiffra a maintenance drug. Michael Charlton suggests that benefits from FGF-21s are likely to fade once therapy is discontinued, which would make this model suboptimal.Jörn Schattenberg raises the issue of keeping patients in the long-term clinical trials necessary to achieve hard outcomes. Jörn advocates keeping his patients in trials but notes that long-term compliance will become increasingly challenging as more therapeutic options become available and the patient may not be improving. Michael suggests we will find similar challenges in recruitment for new trials if patients have to accept the possibility of receiving a placebo. Roger notes that biopsy requirements increase this challenge. As the episode winds down, Roger asks participants what they believe are exciting studies likely to come to light over the next three months. Their answers vary. You'll have to listen to learn. 

Michael Charlton joins Jörn Schattenberg, Louise Campbell, and Roger Green for a far-reaching conversation that covers ways Rezdiffra is already impacting MASH patient treatment, exciting recent studies and broader issues in clinical trial recruitment.  00:00:00 - Surf's Up: Season 5 Episode 11Opening comments from the panel, including brief quotes taken directly from the episode. 00:02:32 - IntroductionOpening comments (re)introducing listeners to Michael Charlton00:04:34 - GroundbreakersEach panelist shares one piece of good news from the previous week.00:06:56 - Impact of Rezdiffra launch on Michael's clinic Michael hails Rezdiffra as "an amazing thing" in terms of its global impact. He goes on to discuss the challenges his clinic faces in properly defining the target F2/F3 patient. 00:14:40 - Defining positive response and treatment futility In response to a question from Louise, Michael indicates that he will continue patients on Rezdiffra as long as they do not progress. 00:19:44 - LiverRISK scoreThe conversation shifts to focus on progress in translational medicine. The first item Michael cites is LiverRIsk, which he terms "substantially superior" to other biomarkers. Next, he mentions his group's work on the microbiome and the challenges in translating items like these into clinically meaningful interventions.00:23:15 - Low-dose aspirin as anti-MASH medicine Michael discusses the recent JAMA publication of a small RCT suggesting benefits from use of low-dose aspirin in biopsy-confirmed MASLD patients.  He and Jörn agree that while the sample size was small, the "highly promising" results might be worthy of discussion with patients.00:26:29 - Jörn and Louise share their items of interestJörn discusses his excitement about the upcoming Innovations in SLD Think-Tank 2024 and its new format. Louise discusses a study indicating correlation between the Dietary Inflammation index score and kilopascal levels. 00:33:27 – Questions about the Dietary Inflammation Index Louise and Jörn speculate on ways to incorporate this kind of result into multifactorial care. Michael asks whether alcohol figured in the index given that many MASH patients consume alcohol. 00:35:38 - Roger on patient feedbackRoger asks how panelists feel about MD columnists recommending that MASH patients  "go to your doctor and ask for an ultrasound."  Michael and Louise agree that given how few patients are treated today, any such public acknowledgment is positive.00:38:11 - Excitement and questions surrounding FGF-21sMichael discusses the emerging excitement around the FGF-21 class. "emerging as highly potent" and asks questions its use and long-term value to patients. The group discusses adherence challenges with a q1w injectable therapy. 00:41:26 Therapeutic models for MASH prescribing Roger asks whether prescribing for FGF-21s might align with an "oncology" model, with FGF-21 as induction drug and Rezdiffra as maintenance drug. Michael suggests that benefits from FGF-21s are likely to fade once therapy is discontinued. 00:43:08 - Challenges in clinical trial recruitment and adherenceJörn, Michael and Roger all agree on the growing challenge of keeping patients in the long-term clinical trials necessary to achieve hard outcomes.00:47:24 - Closing questionRoger asks participants what they believe are exciting studies likely to come to light over the next three months. 00:49:33 - Question of the WeekThe question asks how much value old standard drugs like aspirin or pioglitazone are likely to bring to MASH or MASLD patient treatment.00:50:22 - Business ReportThis week's news on audience metrics, SurfingMASH sponsorship, spring events and this week's Vault conversation.

Dr. Noah Davidsohn, co-founder and CSO of Rejuvenate Bio, discusses the company's innovative work using gene therapies to treat age-related diseases in dogs and humans. In his conversation with host Chris Patil, he explains his recent groundbreaking study showing that partial cellular reprogramming with Yamanaka factors extended lifespan and healthspan in very old mice. Noah then outlines Rejuvenate's clinical pipeline, including targeting longevity pathways like FGF-21 for heart disease and combining TGF-beta inhibition with klotho for osteoarthritis. By choosing secreted factors deliverable with liver-targeted gene therapy, Rejuvenate hopes to circumvent delivery challenges. Noah conveys an inspiring vision of adding healthy years to dogs' and humans' lives.Key Topics Covered:Rejuvenate Bio's mission to reverse aging and age-related diseaseLifespan doubling in old mice with cyclic Yamanaka factor inductionControllable gene therapy system for in vivo partial reprogrammingChoice of FGF-21 for pleiotropic effects deliverable from liverLead programs for arrhythmogenic cardiomyopathy and mitral valve diseaseAdvantages of treating age-related diseases first in dogsCombination gene therapy for osteoarthritis: TGF-beta and klothoSecreted proteins enable broad effects without broad deliveryVision of expanding healthspan by "squaring the curve"Potential to keep people healthy, active and productive to 100+

In the realm of regenerative medicine, BPC-157 (Body Protection Compound-157) has emerged as a promising peptide for its potential to promote healing and address inflammation. From injuries and inflammation to gut health and brain fog, BPC-157 has been shown to promote a wide range of healing properties in many animal studies.  In this podcast, we'll talk about the intricate mechanisms through which BPC-157 for many different health conditions. Tissue Repair and Injuries: BPC-157 has been shown to accelerate tissue repair and regeneration. It works by stimulating the formation of new blood vessels, a process known as angiogenesis. This increases blood flow to the injured site in order to deliver essential nutrients and oxygen to help facilitate the healing process Additionally, BPC-157 modulates the activity of growth factors involved in tissue regeneration, such as VEGF (Vascular Endothelial Growth Factor) and FGF-2 (Fibroblast Growth Factor 2), thereby promoting the proliferation of fibroblasts and other cells crucial for wound healing. Pain Caused by Inflammation and Joint Pain: Inflammation is a common underlying factor in many painful conditions, including back pain (e.g., muscle strains, degenerative disc disease, or arthritis) and joint pain due to inflammatory disorders (e.g., osteoarthritis or rheumatoid arthritis).  BPC-157 exhibits potent anti-inflammatory properties, suppressing the production of pro-inflammatory cytokines like TNF-alpha and interleukins. By dampening the inflammatory response, BPC-157 helps alleviate pain and discomfort associated with inflammation. Moreover, BPC-157 may exert protective effects on cartilage and joint tissues, contributing to its potential to manage joint pain and promote musculoskeletal health. Gut Health: The gastrointestinal tract is a complex ecosystem that plays a vital role in overall health and well-being. In fact, clinical studies show that your gut health is important for your heart health. It's also associated with many other health conditions like obesity, insulin resistance, diabetes, depression, and inflammatory bowel disease.  BPC-157 has been extensively studied in animals for its gastroprotective effects, particularly in conditions characterized by gut inflammation and injury. This peptide promotes the repair and regeneration of damaged gastrointestinal tissues, enhances mucosal integrity of the stomach lining, and reduces inflammation within the gut. Moreover, BPC-157 may modulate gut microbiota composition, contributing to a healthy gut microbiome and improved digestive function. Skin Burns: Skin burns pose significant challenges in wound healing and tissue regeneration. In animal studies, BPC-157 has shown remarkable efficacy in promoting the healing of skin burns by accelerating the formation of new skin tissue and reducing inflammation. It works by enhancing the migration and proliferation of skin cells, leading to faster wound closure and improved wound healing outcomes. Additionally, BPC-157 exhibits antioxidant properties, protecting skin cells from oxidative stress (when there are too many free radicals and not enough antioxidants). This helps cells survive and speeds up the healing process. Corneal Injuries: The cornea (the clear covering over the front of the eye) is susceptible to injuries and infections that can impair vision. BPC-157 has emerged as a potential therapeutic agent for promoting corneal wound healing and reducing inflammation in the eye. Through its angiogenic and anti-inflammatory effects, BPC-157 accelerates the repair of corneal injuries, enhances epithelial cell proliferation, and promotes tissue regeneration.  Brain Fog: Brain fog, characterized by thinking that feels cloudy or slow, can significantly impact daily functioning. BPC-157 exhibits neuroprotective effects and may help alleviate symptoms of brain fog by promoting neuronal survival and regeneration. Moreover, BPC-157 modulates neurotransmitter activity and reduces neuroinflammation, thereby enhancing cognitive function and mental clarity.  Thanks again for listening to The Peptide Podcast. We love having you as part of our community. If you love this podcast, please share it with your friends and family on social media, and have a happy, healthy week! We're huge advocates of elevating your health game with nutrition, supplements, and vitamins. Whether it's a daily boost or targeted support, we trust and use Momentous products to supercharge our wellness journey.  Momentous only uses the highest-quality ingredients, and every single product is rigorously tested by independent third parties to ensure their products deliver on their promise to bring you the best supplements on the market. 

This is it. The end of Sickboy... as you've come to know it that is. This is the final FGF episode but fear not! We're not going anywhere. We're just evolving. It's been almost ten years and hundreds of episodes since we sat down and recorded our first episode, which is crazy. For those of you who've been listening from the start, we love you so much! And today we have some big news. Starting next week, we're experimenting with a fresh new format to bring you one epic episode a week full of all elements that make Sickboy what it is — We can't begin to express how much we love you for your continued support. With that, lets throw back to the very first Feel Good Friday recording we ever did.

This is it. The end of Sickboy... as you've come to know it that is. This is the final FGF episode but fear not! We're not going anywhere. We're just evolving. It's been almost ten years and hundreds of episodes since we sat down and recorded our first episode, which is crazy. For those of you who've been listening from the start, we love you so much! And today we have some big news. Starting next week, we're experimenting with a fresh new format to bring you one epic episode a week full of all elements that make Sickboy what it is — We can't begin to express how much we love you for your continued support. With that, lets throw back to the very first Feel Good Friday recording we ever did.

Only me today! I talk about big changes to FGF in 2024, Chicago winter depression, the Golden Globes & Emmy's, NFL "Super" Wild Card weekend & more --- Support this podcast: https://podcasters.spotify.com/pod/show/joe-krueger3/support

A lil' FGF throwback to the end of last year! Enjoy folks! We'll be back to basics on Jan. 1st!

Building upon our previous discussion on growth factors like EGF and FGF (featured in episode 84: part 1), we'll explore a range of intriguing peptides that have gained popularity for their skin-enhancing properties. From stimulating collagen production to calming irritated skin and even targeting dynamic wrinkles (acting like "botox in a bottle"), we'll cover a variety of topical peptides that are revolutionizing skincare. Stay tuned for this topical cosmetic peptide guide! Topics: 1. Introduction - Recap of last week's episode on growth factors (EGF and FGF) - Shift in focus to topical peptides - Skin anatomy for context 2. Skin Anatomy Overview - Epidermis - Layers and sublayers - Cornification process - Function of each sublayer - Dermis - Papillary and reticular dermis - Role of fibroblasts - Components and functions of the dermis 3. Topical Peptides - Palmitoyl Tripeptide-1 - Mimicking collagen - Stimulating collagen production - Benefits for skin structure and sagging prevention - Palmitoyl Tetrapeptide-7 - Relation to IgG protein - Reduction of IL-6 secretion and inflammation - Use in calming irritated skin - Palmitoyl Tripeptide-8 - Soothing irritated skin or for sensitive skin - Reduction of inflammatory cytokines like IL-8, edema, and capillaries - Palmitoyl Tetrapeptide-38 (Matrixyl 6000) - Comprehensive stimulation of skin matrix components - Greater collagen production and epidermal support - Benefits for skin structure, firmness - Neurotransmitter-Inhibiting Topical Peptides - Targeting dynamic wrinkles caused by muscle contraction - Reduction of muscle contractions and expression lines - Introduction of Acetyl Hexapeptide-8 and Acetyl Octapeptide-3 4. Other Topical Peptides (Future Episode & Featured on My Instagram) - Eyelash growth and nail growth peptides - Solutions for under-eye bags and dark circles Thanks for tuning in! ⁠⁠⁠Book An Intro Coaching Call with Chloe Porter⁠⁠⁠ Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok ⁠⁠⁠@chloe_c_porter⁠⁠⁠ Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Or visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠linktr.ee/synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

A lil' FGF throwback to the end of last year! Enjoy folks! We'll be back to basics on Jan. 1st!

In this episode, we are getting into all things cosmetic peptides and growth factors (and their impact on skin). We will also quickly review the essential structure of our skin, from the surface epidermis to the underlying dermis and sublayers/cellular components of each. This knowledge will set the stage for our discussion on the pivotal roles of EGF and FGF in anti-aging. Also, stay tuned for Part 2, where we'll delve deeper into these topics. Topics: 1. Introduction - Brief review of the anatomy of the skin - Overview of the topics to be discussed (cosmetic peptides and growth factors) 2. Epidermis - Overview of the epidermis - Sublayers of the epidermis - Stratum Corneum - Stratum Lucidum - Stratum Granulosum - Stratum Spinosum - Stratum Basale - Functions and characteristics of each sublayer - Keratinocyte differentiation and lipids production - Role of melanocytes and Merkel cells 3. Dermis - Overview of the dermis - Sublayers of the dermis - Papillary Dermis - Reticular Dermis - Composition and functions of each sublayer - Role of collagen, elastin, fibroblasts, sebaceous glands, sweat glands, hair follicles, and mast cells 4. Cosmetic Peptides and Growth Factors - Introduction to EGF (Epidermal Growth Factor) - Mechanism of action - Effects on keratinocytes and epidermis - Indirect effects on collagen and elastin production - Application in skincare - Introduction to FGF (Fibroblast Growth Factor) - Mechanism of action - Effects on fibroblasts and dermis - Enhancement of skin firmness and elasticity - Upcoming topics in Part 2 - Other growth factors - Additional cosmetic topical peptides - Tips and tricks for skincare formulations Thanks for tuning in! ⁠⁠Book An Intro Coaching Call with Chloe Porter⁠⁠ Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok ⁠⁠@chloe_c_porter⁠⁠ Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Or visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠linktr.ee/synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations of clinical trial results at TLM2023.  Instead of focusing immediately on MASH drugs, Scott suggested we should not overlook the idea that elafibranor is preparing to come to market in the US as a novel medication for PBC with good efficacy and safety from patients who do not respond well to ursodiol or obeticholic acid. I note that elafibranor is only one of two PPARs speeding toward market in PBC with exciting data given what we all heard in the late-breaker presentation on seladelpar. Scott also mentions to integrin antagonist from Pliant in PSC, a disease with no available solutions today. Laurent agrees with Scott that the rare disease drug advances were more exciting than the advances in more common liver diseases.I bring up papers addressing the value of FGF-21 and FGF-19 agents in cirrhosis, which showed some promise for compensated cirrhotic patients. Scott politely disagrees, feeling that while these agents might hold disease steady, they do not address the challenges and mechanisms necessary to meaningfully regress disease. We agree there is a benefit to any agent that slows or reverses the course of disease even slightly in that this buys the patient more time to be treated with more exciting medications still in the pipeline. Scott notes that for Hepatitis C, a far simpler disease it took 25 years from discovery to cure on a path of incremental process. Scott notes that drug development successes are keeping investors interested, which is encouraging in a challenging environment for investment. Laurent returns to the issue of cirrhosis, noting that there are multiple challenges and concomitant bad behaviors like alcohol consumption. He points out that where good studies exist, these are short studies with small samples. Scott points out that MASH is less like hepatitis and more like inflammatory diseases like IBD, where causes of underlying disease are difficult to determine and there is no single pathway in drug development. He buttresses this by noting that in clinical trials, resmetirom provided benefit to only 25% of patients. 

Hepatology researchers and key opinion leaders Profs. Laurent Castera and Scott Friedman join Louise Campbell and Roger Green in the final element of our review coverage of TLM 2023. This far-ranging conversation moves beyond MASLD/NAFLD and MASH/NASH to consider an array of topics.The episode starts with Roger asking the other guests for their general impressions of the meeting. Three key insights: 1.    "Pre-pandemic" levels of interaction and discussion among attendees2.     Online meeting app was a "fail", becoming a topic of conversation in its own right while fostering confusion3.    In the "frenzy" about the anticipated resmetirom approval and other MASH drugs approaching market,  we shouldn't overlook that patients with PBC will soon have two new exciting PPAR agents, elafibranor and seladelpar. As Scott notes, we also learned about promising modes of action for PSC so, overall, a promising meeting for rare cholestatic diseases. The rest of this discussion covers multiple topics, key among them:  ·      Impact of FGF-21 and FGF-19 agents on patients with compensated cirrhosis. Roger is optimistic that agents might provide improvement. Scott is more pessimistic because we do not have agents addressing the unique mechanistic challenges in cirrhosis vs. advanced fibrosis. Both agree that agents on the horizon can buy time until curative or regressive medications arrive. ·      AI-based analysis. Roger bridges to Stephen Harrison's presentation of HistoIndex analysis of resmetirom that produces an estimate of 54% efficacy vs. 34% placebo. He comments that given this analysis and that bariatric surgery studies tell us fibrosis regression may take five years, the FDA one-year standard might be so stringent as to be misleading. ·      Bariatric surgery. Laurent refers to a presentation from Phillippe Mathurin's group demonstrating that in patients post-bariatric surgery, MASH resolution and fibrosis regression clearly lead to improved outcomes. ·      NITs. Laurent discusses a poster from a multi-country 16,000-patient cohort that did not confirm liver stiffness as leading to a decline in MALO over a two-year period but anticipates more robust findings over time. ·      VCTE-based analysis. Louise discusses two posters with analyses based on FibroScan. The first, from the Virginia Commonwealth University and the VA, found that liver stiffness correlates with success in liver transplant and that CAP can predict the risk of future MI in these patients. She notes that CAP of 270 served as "its own parameter" in predicting time to mortality. ·      Nomenclature. Roger notes that a Saturday morning session resolved the two most pivotal outstanding issues about the effect of nomenclature change on scientific development. FDA signaled that the agency views old and new nomenclature terms as interchangeable. NIMBLE and LITMUS analysis determined that patient mapping is also interchangeable.·      Impact of triple-agents. Presentations at this conference confirm that triple agents addressing GLP-1, glucagon and GIP can have bariatric surgery-level impact on liver fat and reduce the entire disease burden. Interspersed between these topics are a range of insights on cirrhosis disease models, regulatory slowness in moving on from current conditional efficacy metrics, treater supply vs. patient demand, "stigma", and basic science. This is a high-level view of an information-dense conversation. Listen to learn more and hear all the details.  

Last week's posting consisted of 1:1 interviews with four KOL from different spheres, each talking with Roger Green about what they are looking forward to seeing at this week's The Liver Meeting 2023. This week, two of those KOLs, co-host Jörn Schattenberg and hepatology KOL Naim Alkhouri, join Roger and co-host Louise Campbell, FRCP, in a free-wheeling review of key abstracts that will be presented at TLM2023.The discussion begins with Jörn spotlighting the first item in the abstract book, a presentation titled MASH Resolution Without Fibrosis Worsening After Bariatric Surgery Improves Long-Term Survival. Jörn spotlights this study for demonstrating survival benefits, a significant benchmark for drug approval processes. This study of bariatric patients with concomitant MASH and fibrosis reveals that MASH resolution often comes before fibrosis regression. This suggests that MASH resolution itself might predict improved long-term outcomes, contrasting with earlier beliefs that only linked fibrosis regression to positive prognoses. Louise comments that reducing inflammation should logically lead to fibrosis regression, comparing it to the treatment of hepatitis C. Naim agrees, emphasizing the liver's remarkable ability to heal if the initial injury stops, such as with alcohol cessation or hepatitis treatment. However, he points out challenges in clinical definitions and trial inclusions based on the current focus on MASH histology. The conversation shifts as Naim shares his excitement that both the ENLIVEN trial with FGF-21 agent pegozafermin and the ALPINE-4 trial with FGF-19 agent aldafermin demonstrate the potential for these agents to reduce fibrosis one level (and occasionally even two!) in patients with cirrhosis. The group agrees that treating cirrhosis is the most urgent challenge facing MASLD hepatology today because patients are close to decompensation and antifibrotic pharmacotherapy does not exist. This leads Roger to ask whether the presence of these agents will drive more aggressive screening for cirrhosis patients and for the group to list the benefits early screening will offer. Louise shares two papers she intends to follow, both of which focus on gender disparities in liver health. She reminds the group of Roberta Forlano's research (shared in S4 E44) and comments during that discussion that women in liver failure experience higher rates of death that man -- they do not fare as well  on liver transplant lists and exhibit higher rates associated with hepatic renal syndrome. The group concurs that this disparity needs more attention and fits into a broader issue of inequality in medical treatment based on gender and other demographic factors.Roger shares two posters on lanifibranor with an eye toward how payers are likely to assess agents when they come to market. As the group discussed in earlier episodes, there are significant challenges identifying which patients are likely to succeed prospectively on a MASH drug and another on determining in a reasonable timeframe whether the medication is working. Of the two lanifibranor posters, one suggests that changes in adiponectin levels can predict level of therapeutic success, while the other shows that presence of a mutated PNPLA3 gene has minimal or no impact on the likelihood of therapeutic success. The group discusses a few other papers and concepts. One paper of note came from the NAIT-NIT consortium and suggests that biopsy can lead to an overestimation of liver fat levels compared to MRI-PDFF. Naim and Jörn comment on behavioral or attitudinal constructs from hepatologists that might lead to this result.Finally, the group comments on the importance of late-breakers as a vital conduit or cutting edge research and each member notes one other paper or session at the meeting they find intriguing.STAY SAFE AND SURF ON!

FGF bids farewell to our most recurring guest Eric Furlong before he moves to Georgia. We talk about stand-up comedy, aliens, Zach Bryan, Furlong's travels, work hangovers & more. Good luck in Georgia buddy! --- Support this podcast: https://podcasters.spotify.com/pod/show/joe-krueger3/support

Miranda's accidental absenteeism at a parent teacher conference did NOT make a good first impression on her son's kindergarten teacher. Mel unpacks the common, lifelong illnesses of first responders and volunteers at 9/11, and shares ways we can get involved and give back to those who sacrificed everything in rescue and recovery efforts. Miranda discusses some strategies to have a successful parent teacher conference... including showing up for them! SOURCES:Mel-https://en.m.wikipedia.org/wiki/Health_effects_arising_from_the_September_11_attacks https://www.scientificamerican.com/article/health-effects-of-9-11-still-plague-responders-and-survivors/ Miranda-https://www.verywellfamily.com/expect-at-parent-teacher-conference-3545346 https://kidshealth.org/en/parents/parent-conferences.htmlhttps://www.edutopia.org/article/5-strategies-successful-parent-teacher-conferencehttps://www.varsitytutors.com/blog/5+things+to+do+after+a+parentteacher+conference https://www.readingrockets.org/topics/parent-engagement/articles/surviving-difficult-parent-teacher-conference SPOTLIGHTS: World Trade Center Health Program The WTC Health Program is dedicated to helping those who were there during and after the attacks of September 11, 2001. The Program provides services to individuals who meet their requirements. They serve over 110,000 9/11 responders and survivors from the World Trade Center in New York City and related sites; and responders from the Pentagon and Shanksville, Pennsylvania sites. There is no deadline to enroll, it's funded through 2090. https://www.cdc.gov/wtc Feal Good FoundationTo assist all emergency personnel, including but not limited to, firefighters, police officers, nurses, volunteers, sanitation workers, transportation workers and construction workers, within the United States who have been injured, or face serious injury due to action or omission, in the course of their duties or within their everyday lives. The mission of the FGF includes educating elected officials and private entities on the various problems, concerns and issues faced by First Responders in their everyday duties. The FGF is therefore dedicated to advocating for First Responder rights and illuminating, to proper authorities, the serious issues they encounter.https://fealgoodfoundation.com/ Hosted on Acast. See acast.com/privacy for more information.

This week on FGF, Tay & Bri are talking radioactive wastewater, how hangin' with your buds for no reason will save your life, and why planes are almost running into each other a lot more than you would hope they do. Also, the AI revolution is the utopia that Taylor is waiting for. Let's wrap this week up with some good vibes and some heavy laughs. Join the post-episode conversation over on Discord! https://discord.gg/expeUDN

This week on FGF, Tay & Bri are talking radioactive wastewater, how hangin' with your buds for no reason will save your life, and why planes are almost running into each other a lot more than you would hope they do. Also, the AI revolution is the utopia that Taylor is waiting for. Let's wrap this week up with some good vibes and some heavy laughs. Join the post-episode conversation over on Discord! https://discord.gg/expeUDN

Meeting cutz the artist for the first time during our stay in Hamilton recently as we brought FGF out to perform courtesy of jai steels. Tapping us in with the Canadian born star, now we're building that bridge from Hamilton to bay city and it's just getting started

Today we thought we'd celebrate for a minute and give you guys (that don't know it) the backstory of how we met. How the podcast started with just Leslie them Stephanie joining in May of 22. Leslie talks about how she always wanted to start a podcast just to encourage women of all walks of life. Encourage them to do the workout, go after your dream, and find what works for you. She made that dream come true for her in 2021 when she started Hero starts with Her. Leslie is a working mom of four, two in high school and another still in elementary which she homeschools. She also has a foster daughter right now, which is her line of work. Stephanie is also a working mom of three, one high schooler, a elementary and toddler whom she homeschools. Her oldest is going to be a junior this year and attends public school. We met through FB, formed a friendship through our love for health and fitness. And that blossomed into a co-host opportunity. Stephanie would join Leslie a few times on episodes before she decided to join her for good in May of 22. So we're celebrating that one year anniversary this month. We both shared our passions with you guys again today and we hope that our episodes just continue to encourage you. Our Facebook community we share into. Join us: https://www.facebook.com/groups/107794994826764/ Leslie's Social Media: IG: https://instagram.com/_herostartswithher_?igshid=YmMyMTA2M2Y= FB: https://www.facebook.com/herostartswithherblog/  (Hero starts with Her with Leslie) Stephanie's Social Media: IG: https://instagram.com/mrs_smz_?igshid=YmMyMTA2M2Y= FB: https://www.facebook.com/momma.FGF/  (Live a faithful balanced Life with Stephanie)   We want to hear from YOU!! Please email us with topics, that you might want us to talk about. Things we can dive into WITH YOU.  Email us feedback on how we can improve and what you want to hear.  We are here because of YOU and for YOU.  We love being transparent with you all and we hope you will consider writing us because we love hearing from you and hearing your stories.   Please Message either of us. Or email: herostartswithher@outlook.com

One of the coolest parts of hosting the FGF podcast is talking to firefighters from my hometown and across the country. Hearing what is important to them in their communities, and in their firehouses, really broadens my own thinking. This is the whole point of this FGF project - to grow our collective understanding. Episode 87, with Fire Chief Josh Stefancic, is another great episode were we talk to a firefighter from “another town”. And while “the circus may be different, the clowns are the same” and this is what really bonds us together, we are in this business for the same purposes and mission. Stefancic and I talked about so many great things and then we pushed record and captured a great podcast as well! We discussed management, mentoring, education, and the critical importance of relationships.   A little more about our Guest… Josh Stefancic, a native of the Chicagoland area, has been a full-time fire service professional since 2001, most recently serving as the Fire Chief for the Safety Harbor (FL) Fire Department since 2018. Josh is a graduate of the National Fire Academy's Executive Fire Officer Program, sits on the NFPA 1700 committee, and is currently the vice chair of the International Fire Service Training Association (IFSTA). Josh received his Bachelor of Science Degree from Oklahoma State University (OSU) in Fire Protection and Safety Engineering Technology in 2001, and his Master's Degree from OSU in Fire and Emergency Management Administration in 2008. He also has a Master's in Public Administration from Florida Gulf Coast University, and serves as the Secretary/Treasurer of the Pinellas County Fire Chiefs' Association.

John Feal is the President & Chairman of the FealGood Foundation which advocates for all emergency personnel (firefighters, police officers, nurses, volunteers, sanitation workers, transportation workers, construction workers etc.) within the United States who have been injured, or face serious injury due to action or omission, in the course of their duties or within their everyday lives. The mission of the FGF includes educating elected officials and private entities on the various problems, concerns and issues faced by first responders in their everyday duties. John continues to lobby for healthcare & compensation owed to first responders who helped on September 11, 2001. He talks about working with comedian Jon Stewart on this worthy cause and what still needs to be done moving forward to give these heroes lasting peace of mind. --- Support this podcast: https://anchor.fm/jbkonair/support

Taylor is in Europe, Brian is off to Antartica. The fellas need a much needed break. This week for FGF we throw back to an early episode of Feel Good Friday featuring the bad ass Dr. Emily Anhalt! She is the CoFounder of Coa, a psychoanalytic psychologist, emotional fitness consultant and all-around promoter of self-awareness in all forms. We talk about the importance of caring for your mental health during these wickety wack times, how to find a therapist that jives with you and more. Then the gang go deep into Jeremie's current struggles with mental health. Beer butt-chugging and all.