Podcasts about cd8 t

Guest: Dr. Shabaana Khader is a Professor and Chair of the Department of Microbiology at the University of Chicago. She discusses how the immune system responds to Mycobacterium tuberculosis, why tuberculosis remains one of the world's deadliest infectious diseases, and the challenges of developing more effective vaccines. She highlights the role of lung-resident immunity, including Th17 responses and lymphoid structures, in controlling infection, and explains how advances in our understanding of host–pathogen interactions are guiding the design of next-generation TB vaccines. Featured Products and Resources: Learn about STEMCELL’s optimized protocols and reagents for immunotherapy research. Download a free Nature Reviews Immunology T cell nomenclature wallpaper. The Immunology Science Round Up Personalized HPV Cancer Vaccine – A multifunctional nanovaccine combining HPV antigens, tumor membranes, and bacterial adjuvants generates durable anti-tumor immunity against HPV-associated cervical cancer. HIV Rewires T Cell Identity – HIV can reprogram infected CD4+ T cells into CD8+ T cells, revealing a previously unrecognized component of the viral reservoir. Decoding Acute Pancreatitis – A single-cell atlas of severe acute pancreatitis identifies a TNF-α–driven immune-endothelial circuit that causes microvascular failure and disease progression. Discovery of Ruptoblasts – A newly discovered cell type, the ruptoblast, protects planarians through an explosive cytotoxic mechanism termed ruptosis. Image courtesy of Dr. Shabaana Khader Subscribe to our newsletter! Never miss updates about new episodes. Subscribe

Creatine causes cancer to spread — that headline is built on a real mouse study. But what does the human data actually say? In this solo explainer, Dr. Robert Lufkin breaks down both halves of the science behind the most studied supplement on the planet.He walks through the 2021 mouse metastasis study behind the viral claim, the surprising evidence that creatine actually powers the immune cells that HUNT cancer (CD8 T cells and, per new UCLA research, dendritic cells), and what the human data — HCAs, NHANES, and the 2025 safety review — really shows. The verdict is more nuanced, and more reassuring, than the headline suggests.Chapters:00:00 — Introduction00:46 — Why This Question Exists01:32 — The Scary Half (2021 Study)02:17 — How Creatine Fuels Tumor Spread03:03 — Creatine Fights Cancer Too03:48 — UCLA June 2026 Dendritic Cells04:35 — Tumor Suppressor or Fuel?05:21 — What Human Data Shows (HCAs)06:08 — NHANES & 2025 Safety Review06:55 — The Honest Caveat07:42 — The TakeawayKey takeaways:The scary headline comes from a 2021 mouse study where dietary creatine promoted metastasis via the MPS1 → SMAD2/3 → TGF-beta pathway — in mice with established, aggressive tumors.The same metabolism fuels your immune system: creatine is essential for CD8 "killer" T cells and the dendritic cells that direct them.In a controlled human trial, creatine did NOT drive carcinogen (HCA) formation.NHANES population data links higher dietary creatine to LOWER cancer risk, and the 2025 safety review calls the human cancer-risk claim "not substantiated."Healthy adults: the human evidence does not support avoiding creatine. Active or metastatic cancer: pause and talk to your oncologist. Always choose third-party tested creatine monohydrate.Studies & sources:Zhang et al., Cell Metabolism 2021 — Creatine promotes cancer metastasis via Smad2/3Geng et al., Int. J. Mol. Sci. 2024 — The multifaceted role of creatine metabolismDi Biase et al., J. Exp. Med. 2019 — Creatine and CD8 T cell antitumor immunityKang et al., iScience 2026 (UCLA) — Creatine and dendritic cell activationPereira et al., Amino Acids 2015 — Creatine and heterocyclic aminesNHANES 2017–2020 — Dietary creatine and cancer riskAntonio et al., Frontiers in Nutrition 2025 — Common safety concerns regarding creatine

There's a single number on your routine blood test that predicts your risk of dying from cancer, heart disease, and infection better than cholesterol — and an FDA-approved drug may now move it.In this Health Longevity Secrets explainer, Robert Lufkin MD breaks down lymphopenia, the IL-15 cytokine, and ANKTIVA (nogapendekin alfa inbakicept) — the first FDA-approved IL-15 super-agonist and possibly one of the most important longevity drugs of the decade.CHAPTERS: 00:00 — Introduction: The Blood Test Number Better Than Cholesterol 00:35 — What Is Lymphopenia and Why It Matters 01:50 — Immunosenescence: Why Your T Cells Decline After Age 20 02:30 — The Mortality Data: Three Studies on Lymphopenia 03:20 — Copenhagen Study: 63% Higher All-Cause Mortality 03:50 — Coronary Angiography Study: Hazard Ratio 1.97 04:25 — Enter IL-15: The Cytokine That Builds Killer Immune Cells 05:15 — IL-15 as a Myokine: Why Resistance Training Protects Against Cancer 06:00 — Four Hallmarks of Aging Hit By One Molecule 06:30 — ANKTIVA Explained: The IL-15 Super-Agonist 07:00 — FDA Approval, Bladder Cancer, and the Soon-Shiong Reframe 08:15 — Is ANKTIVA a Longevity Drug? The Bullish Case 09:00 — The Skeptical Case: Why We Don't Know Yet 10:15 — What You Can Do Today: Track Your Number, Raise IL-15 Naturally 11:30 — Final Take and ClosingKEY TAKEAWAYS:Lymphopenia (absolute lymphocyte count below 1,500/μL) predicts all-cause mortality better than cholesterol in multiple large cohort studiesIL-15 expands NK cells and CD8+ T cells — the same cells that clear senescent "zombie" cells and patrol for cancerResistance training is the single strongest known endogenous IL-15 stimulus; your muscle signals your immune system to stay youngANKTIVA is the first FDA-approved IL-15 super-agonist (April 2024) — currently for bladder cancer but being reframed as a lymphopenia treatmentIL-15 hits four hallmarks of aging at once: immunosenescence, senescent cell accumulation, chronic inflammation, and sarcopeniaHonest take: exciting hypothesis with FDA approval, but zero human longevity trials yet — watch this spaceSTUDIES & SOURCES MENTIONED:Zidar et al., JAMA Network Open 2019 — Lymphopenia and mortality in 31,178 US adults (NHANES)Warny et al., CMAJ 2020 — Copenhagen General Population Study, lymphopenia in 108,135 adultsBawamia et al., Cardiology Journal 2022 — Lymphopenia and 8-year mortality in 15,179 coronary angiography patientsFDA approval, April 22, 2024 — Nogapendekin alfa inbakicept-pmln (ANKTIVA) for BCG-unresponsive non-muscle invasive bladder cancerWatch the full video on YouTube: https://youtu.be/220KHIdFCwg

The ancient fruit sitting in your grocery store right now outperforms rapamycin, rivals caloric restriction, and triggers a cellular cleanup process that most longevity scientists did not even know existed until a lab changed everything 18 years ago. -Watch this episode on YouTube for the full video experience: https://www.youtube.com/@DaveAspreyBPR -Go to timeline.com/Dave or just use code ‘Dave' to get 20% off your next order. Host Dave Asprey sits down with Chris Rinsch, co-founder and President of Timeline Longevity and a PhD cell biologist who has spent nearly two decades doing pharmaceutical quality clinical research on one of the most underrated longevity molecules on earth. Before founding Timeline in 2007, Rinsch worked in venture capital investing in pioneering life sciences companies and in biotechnology developing cell-based therapies at Swiss biotech company ISOTIS SA. He has authored original publications in Nature Medicine, Nature Metabolism, JAMA Open, and Cell Reports Medicine, and holds internationally filed and granted patents on urolithin A. This is the first time a Timeline co-founder has appeared on the show. Together, Dave and Chris break down the full science of urolithin A, the postbiotic compound unlocked from pomegranate by gut bacteria, and why it triggers mitophagy to clear out damaged mitochondria and replace them with high-functioning ones. They cover why only 30 to 40 percent of people can produce urolithin A from food alone, how one month of supplementation measurably improved immune cell populations in people aged 50 to 70, and why Dave has stacked this into his daily longevity protocol alongside NAD precursors and nootropics for years. If you are serious about biohacking your mitochondria, extending healthspan, and doing smarter not harder longevity work, this episode delivers the deep science to back it up. You'll Learn: Why urolithin A outperforms rapamycin in worm lifespan studies and rivals caloric restriction at 45 percent life extension How mitophagy works, why it declines with age, and why it is one of the most important anti-aging mechanisms in the body Why eating pomegranates or taking cheap pomegranate extract does not work for most people and what to take instead How one month of MitoPure improved natural killer cells, CD8 T naive cells, and reduced inflammation in adults aged 50 to 70 Why mitochondria are central to metabolism, brain optimization, immune function, cardiovascular health, and skin aging How Timeline's topical urolithin A produced statistically significant reductions in fine lines and wrinkles after eight weeks Why Dave considers this one of the most clinically validated supplements in his longevity stack alongside NAD and fasting protocols How L'Oreal became a Timeline investor after confirming the mitochondrial science was unlike anything in their existing ingredient library What the XPRIZE Healthspan competition is targeting and why Timeline is competing to reverse biological aging by 10 to 20 years Why the future of functional medicine will require a mitochondrial blood test and how close we are to having one Thank you to our sponsors! - EMR-Tek | https://www.emr-tek.com/DAVE and use code DAVE - Calroy | Go to Calroy.com/DAVE for exclusive discounts on Arterosil HP, Vascanox HP and all Calroy products. - Neuronic | Go to www.neuronic.online Code DAVE for $100 off - ENERGYbits | If you want a simpler, smarter way to support your body… this is it. Head to ENERGYbits.com and use code ASPREY for 20% off your order. Dave Asprey is a four-time New York Times bestselling author, founder of Bulletproof Coffee, and the father of biohacking. With over 1,000 interviews and 1 million monthly listeners, The Human Upgrade brings you the knowledge to take control of your biology, extend your longevity, and optimize every system in your body and mind. Each episode delivers cutting-edge insights inhealth, performance, neuroscience, supplements, nutrition, biohacking, emotional intelligence, and conscious living. New episodes are released every Tuesday, Thursday, Friday, and Sunday (BONUS). Dave asks the questions no one else will and gives you real tools to become stronger, smarter, and more resilient. Keywords: Chris Rinsch, Timeline Longevity, MitoPure, urolithin A, mitochondria, mitophagy, pomegranate, elagitannins, postbiotic, gut microbiome, longevity, anti-aging, healthspan, biohacking, supplements, human performance, metabolism, mitochondrial health, cellular health, autophagy, natural killer cells, immune health, inflammation, NAD, rapamycin, caloric restriction, muscle endurance, collagen, skin aging, fine lines, wrinkles, topical skincare, L'Oreal, XPRIZE Healthspan, Nature Aging, clinical trials, longevity stack, brain optimization, cardiovascular health, biological age, aging clock, fasting, nootropics, functional medicine, Dave Asprey, polyphenols, microbiome diversity Resources: • Go to timeline.com/Dave or just use code ‘Dave' to get 20% off your next order. • Get My 2026 Clean Nicotine Roadmap | Enroll for free at https://daveasprey.com/2026-clean-nicotine-roadmap/ • Dave Asprey's Latest News | Go to https://daveasprey.com/ to join Inside Track today. • Danger Coffee: https://dangercoffee.com/discount/dave15 • My Daily Supplements: SuppGrade Labs (15% Off) • Favorite Blue Light Blocking Glasses: TrueDark (15% Off) • Dave Asprey's BEYOND Conference: https://beyondconference.com • Dave Asprey's New Book – Heavily Meditated: https://daveasprey.com/heavily-meditated • Join My Substack (Live Access To Podcast Recordings): https://substack.daveasprey.com/ • Upgrade Labs: https://upgradelabs.com Timestamps: 00:00 – Trailer 00:37 – Intro 03:57 – Pomegranates 10:03 – Discovering Urolithin A & Mitophagy 20:50 – Science vs. Pomegranate Supplements 25:24 – Topical Skincare Science 26:09 – L'Oreal Partnership & Skin Results 33:38 – 15 Clinical Studies & XPRIZE 43:50 – Nature Aging Immune Study 49:22 – Dosing & Daily Routine 51:29 – Future of Mitochondrial Health See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Guest: Dr. Tullia Bruno is an Assistant Professor at the University of Pittsburgh. She discusses how B cells and tertiary lymphoid structures shape anti-tumor immunity within solid tumors, challenging the traditional T cell–centric view of cancer immunology. She highlights how these immune niches influence responses to immunotherapy, the importance of spatial organization within the tumor microenvironment, and emerging strategies to therapeutically induce tertiary lymphoid structures to improve cancer treatment. Featured Products and Resources: Subscribe for a chance to win a pair of STEMCELL science socks. Request a free EasySep EV isolation kit sample to try in your own lab. The Immunology Science Round Up Feeding Boosts T Cell Immunity – Postprandial metabolism enhances T cell fitness and improves effector and CAR-T cell function through chylomicron-driven metabolic reprogramming. Chemokines Control T Cell Priming – CCR7 signaling limits CD8+ T cell interactions with dendritic cells to preserve effective effector and memory responses. Helminths Boost Offspring Immunity – Maternal helminth-driven microbiome changes protect offspring from respiratory viruses through the metabolite indole-3-propionic acid. Enhancing CAR T Persistence – CAR-modified stem-cell memory T cells show improved persistence, expansion, and anti-tumor responses compared to standard CAR T cells. Image courtesy of Dr. Tullia Bruno. Subscribe to our newsletter! Never miss updates about new episodes. Subscribe

Episode 223: Oncogenic Viruses Introduction Mehr: Hi everyone, welcome back to the Rio Bravo qweek podcast. Back by popular demand is Me, Mehr Boparai a third-year medical student at COMP-NW. Here with me is Jeremy Pan from COMP who is also a third-year medical student. How are you doing Jeremy? Jeremy: I'm doing great Mehr.Thanks for the kind intro; we had a fun time this morning doing street medicine and had some practice giving Toradol injections and wound dressings. So excited to be back for another podcast episode this afternoon! Mehr: This week, we are moving away from bacteria and antibiotics and diving deeper into cancer-causing viruses. Jeremy: Yes, and if you are interested at all in public health, this is one of those areas where medicine overlaps with public health in a really tangible way. I think one of the most underappreciated aspects of this topic is that we have vaccines that can prevent many of these cancers. If you told someone 50 years ago we'd be vaccinating against cancer, they probably wouldn't believe you! It's amazing to see how far medicine has come. How viruses cause cancer: Jeremy: Before jumping into specific viruses, I always think having a mechanism-based framework makes everything stick better. Mehr: Right, because they don't all cause cancer the same way. Medicine can never be easy huh? Jeremy: Yea…this career really is just a lifetime of discovery. So just to start, in broad terms, we can think of three main buckets of how viruses can cause cancer: Direct oncogenesis where viral proteins interfere with tumor suppressors like P53 and Rb. We will go over their specific mechanisms a little later in the discussion. Mehr:  Chronic inflammation where viruses cause repeated injury through production of reactive oxygen species. They also increase the chance of mutation through repeated DNA replication, leading to cancer.  Jeremy: Immune evasion or suppression leads to decreased tumor surveillance. What this means essentially is that our immune system is constantly removing abnormal cells before they become cancerous. This is completed by CD8 T cells and natural killer, or NK, cells. CD8 T cells recognize abnormal peptides presented on Major Histocompatibility Complex, or MHC, class I molecules and induce apoptosis in those cells. Mehr: And NK cells step in when cells decide to stop expressing MHC I, which abnormal cells like to hide to avoid being caught. So just to reiterate, there are two layers to dissect here: if a cell looks suspicious with an abnormal MHC, CD8 T-cells kill them. If the abnormal cell decides to hide its MHC, then the NK cell will kill it instead. Jeremy: So, for the final big picture, we can think of oncogenic viruses as either disabling tumor suppression, causing chronic damage over time through inflammation, and weakening the immune system's ability to catch cancer in time before it develops. HPV Mehr: Let's start with one of the most common viruses afflicting our population – Human Papilloma Virus otherwise known as HPV.  Jeremy: Right, this notorious virus is probably the most clinically impactful oncogenic virus. The key players HPV utilizes are proteins E6 and E7. Mehr: Right! E6 binds to and inhibits p53, which normally acts to induce cell cycle arrest, and E7 inhibits Rb, which normally acts as a tumor suppressor gene that inhibits the G1 to S phase transition in a normal cell cycle. Jeremy: So essentially, we are losing both apoptosis and losing cell cycle control at the same time. What is interesting about HPV is that persistent infection, not just exposure to the virus, is what drives cancer risk.  Mehr: Exactly, most HPV infections clear on their own, but the ones that persist are the problem. Clinically, many end up being asymptomatic. However, for high-risk infections, we can see genital warts that can itch, feel tender, or cause abnormal vaginal bleeding and discharge. Patients are sometimes not able to have a vaginal delivery because of the warts that are present along their genital tract. We can also see warts on the hands and fingers or plantar surface of our feet. Jeremy: Another interesting point is that we are also seeing a shift where there are more cases of oropharyngeal cancers in younger, non-smoking patients. This is why if we see an abnormal neck lymph node or persistent sore throat after swallowing in a young patient, HPV should definitely be on the differential.  Mehr: Screening is very important as well! We typically discover high-risk HPV infections through routine Pap smears and other HPV specific tests through DNA PCR and RNA tests. We also encourage vaccination for effective prevention of both genital warts and high-risk HPV-related cancers. There was also a study in Scotland where there were zero cases of HPV in adults who received the vaccine between 12-13 years of age! Which is crazy!  EBV HBV & HCV Mehr: Now let's shift to viruses that affect the liver, Hepatitis B virus and Hepatitis C virus. Jeremy: Both are strongly associated with hepatocellular carcinoma, but they actually get there in slightlydifferent ways. Mehr: Right. Hepatitis B is a DNA virus that can integrate directly into the host genome, which can disrupttumor suppressor genes and promote oncogenesis. Jeremy: Whereas Hepatitis C is an RNA virus, so it doesn't integrate into the host genome. Instead, it causes chronic inflammation Over time, that leads to repeated cycles of hepatocyte injury and regeneration, along withoxidative stress from reactive oxygen species, which increases the risk of DNA mutations. Mehr: One really important clinical pearl is that Hep B can actually cause hepatocellular carcinoma evenwithout cirrhosis. Whereas with Hep C, the pathway is usually chronic inflammation → fibrosis → cirrhosis → dysplasia→ cancer.  Jeremy: So, screening becomes really important for both of these viruses. For high-risk patients—like those with chronic hepatitis or cirrhosis—we typically dosurveillance with liver ultrasound every 6 months, sometimes with alpha-fetoprotein levels to see if it is elevated. Mehr: From a prevention standpoint, the Hep B vaccine is a huge win. It significantly reduces the risk ofhepatocellular carcinoma. For Hep C, we don't have a vaccine, but direct-acting antivirals can actually cure the infection andreduce long-term cancer risk, which is why we screen between ages 18-79  nowadays. Global Hep B and C account for 65% of all HCC cases! So, it makes sense that primary care itself is increasing the treatment of Hep C cases as well since it is easier to prescribe and that you want to be treated ASAP.  Jeremy: Yea, the ability to treat Hep C is so beneficial to population health. Now let's say you have a patient who develops hepatocellular carcinoma, options can include surgicalresection, liver transplantation, local therapies, or systemic treatments depending on stage.  Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week!  __________________________________ References: Barry H. C. (2024). Scottish Screening: No Cases of Invasive Cervical Cancer in Women Who Received at Least One Dose of Bivalent HPV Vaccine at 12 or 13 Years of Age. American family physician, 110(2), 201–202. https://pubmed.ncbi.nlm.nih.gov/39172683/ Theme song, Works All The Time by Dominik Schwarzer, YouTube ID: CUBDNERZU8HXUHBS, purchased from https://www.premiumbeat.com/. Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week!

Urolithin A (MitoPure)--Mitophagy, Muscle Recovery, Immunity, and Skin Health: Dr. Brad Currier, clinical trial manager at Timeline, a Swiss biotech company, details urolithin A (MitoPure), a postbiotic derived from pomegranate precursors that most people cannot produce due to microbiome differences. Currier explains MitoPure's mechanism—stimulating mitophagy to recycle dysfunctional mitochondria—and reviews evidence from multiple clinical trials. He reveals a Sports Medicine study in elite male distance runners showing reduced creatine kinase and lower perceived exertion, suggesting improved recovery, plus trials in middle-aged and older adults showing improvements in strength, six-minute walk test, and VO2 max at 500 mg–1 g doses. They also cover a Nature Aging immune study reporting rejuvenation of stem-like CD8 T cells with improved mitochondrial fatty acid oxidation, ongoing research directions, supplement quality/testing for athletes, and topical urolithin A skincare trials and partnerships, including L'Oréal Lancôme.

Guest: Dr. Alfred Singer is a Senior Investigator at the National Cancer Institute Center for Cancer Research. He discusses his pioneering work on thymus development and T cell differentiation, including how T cells are selected to become CD4 helper or CD8 cytotoxic cells through MHC-restricted signaling. He shares the evolution of key concepts in the field, such as the “kinetic signaling” model of lineage commitment, and offers insights into T cell receptor signaling, regulatory T cell development, and the complexities of immune cell fate decisions. Featured Products and Resources: Receive a free 250 mL bottle of Lymphoprep plus a free SepMate tube to try in your own lab. Achieve simple, reliable EV isolation with EasySep kits from STEMCELL Technologies. The Immunology Science Round Up CEACAM6 Enables Viral Entry – Bat alphacoronavirus enters human cells via CEACAM6, revealing potential for zoonotic transmission. Cross-Dressing Drives T Cell Priming – mRNA vaccines activate CD8+ T cells through redundant dendritic cell pathways and cross-dressing mechanisms. Unlocking NK Antitumor Responses – Removing tumor Tregs unleashes NK cell responses to control cancers, including MHC I–deficient tumors. RUNX1 Controls Immune Aging – A single-cell immune aging clock identifies RUNX1 as a key regulator of T cell senescence and rejuvenation. Image courtesy of Dr. Alfred Singer Subscribe to our newsletter! Never miss updates about new episodes. Subscribe

In his weekly clinical update, Dr. Griffin and Vincent Racaniello note the uncertain future of the National Science Foundation amid shifting U.S. funding priorities and governance; the rise of China as a global research powerhouse; ongoing advances and controversies in vaccines shaped by the World Health Organization and the Centers for Disease Control and Prevention; vaccine policy battles in Florida; European approval of the moderna mCOMBRIAX, COVID-19 and influenza vaccine, the mounting evidence supporting preventive vaccination strategies including that for HPV and the HepB birth dose; the spread of drug-resistant infections and the resurgence of HIV in Zambia; and the enduring public trust in scientists despite political turbulence, before Dr. Griffin deep dives into the measles outbreak, recent statistics RSV, influenza and SARS-CoV-2 infections, the Wasterwater Scan dashboard, Johns Hopkins measles tracker, the efficacy of the influenza vaccine for children, PEMGARDA authorized use for certain immunocompromised individuals where to find PEMGARDA, how to access and pay for Paxlovid, use of remdesivir for RSV, how administration of Paxlovid did not affect hospitalization of high-risk vaccinated patients, where to go for answers about long COVID-19, if SARS-CoV-2 infection may facilitate EBV reactivation, exercise for treating long COVID and contacting your federal government representative to stop the assault on science and biomedical research. Subscribe (free): Apple Podcasts, RSS, email Become a patron of TWiV! Links for this episode Entire NSF science advisory board fired by Trump administration (Nature) United States v. Arthrex, Inc.(Harvard Law Review) United States v. Arthrex Inc. [SCOTUSbrief] (Federalist Society) China could be the world's biggest public funder of science within two years (Nature) The Vaccine Skeptic in Trump's New C.D.C. Leadership Team (NY Times) World Immunization week: Largest catch-up initiative delivers over 100 million childhood vaccinations (WHO) Pigs are flying!: Florida Republicans refuse to take up DeSantis bill loosening vaccine mandates (NY Times) Moderna Receives European Commission Marketing Authorization for mCOMBRIAX, Moderna's mRNA Combination Vaccine Against Influenza and COVID-19(moderna) America First! AIDS Creeps Back in Parts of Zambia, a Year After U.S. Cuts to H.I.V. Assistance (NY Times) Emergence of Extensively Drug-Resistant Shigellosis — United States, 2011–2023 (CDC: MMWR) Scientists Esteemed by Public, with Vaccine Scientists Seen as Similar to Scientists in General (Annenberg: Public Policy Center, University of Pennsylvania) RFK Jr. is holding up $600M in vaccines for poor countries (Politico) Trump Withdraws Nomination of Casey Means for Surgeon General (NY Times) What? Benefit of preventive strategies like vaccination? Incidence of human papillomavirus infections in women aged 27 years and older in the US: A federated data network study (International Journal of Infectious Diseases) Economic Impact of Delaying the Infant Hepatitis B Vaccination Schedule (JAMA Pediatrics) Impact of Removing the Universal Hepatitis B Birth-Dose Vaccination in the US (JAMA Pediatrics) Wastewater for measles (WasterWater Scan) Measles cases and outbreaks (CDC Rubeola) Measles Dashboard (South Carolina Department of Public Health) Utah measles outbreak response (Utah Department of Health and Human Services) Utah Measles Dashboard (Utah Department of Health and Human Services) Tracking Measles Cases in the U.S. (Johns Hopkins) Measles vaccine recommendations from NYP (jpg) Weekly measles and rubella monitoring (Government of Canada) Measles (WHO) Get the FACTS about measles (NY State Department of Health) Measles (CDC Measles (Rubeola)) Measles vaccine (CDC Measles (Rubeola)) Presumptive evidence of measles immunity (CDC) Contraindications and precautions to measles vaccination (CDC) Adverse events associated with childhood vaccines: evidence bearing on causality (NLM) Measles Vaccination: Know the Facts (ISDA: Infectious Diseases Society of America) Deaths following vaccination: what does the evidence show (Vaccine) Dangers of measles infection (NY Times) Influenza: Waste water scan for 11 pathogens (WastewaterSCan) US respiratory virus activity (CDC Respiratory Illnesses) Respiratory virus activity levels (CDC Respiratory Illnesses) Flu vaccine recommendations: Vaccines and Related Biological Products Advisory Committee March 12, 2026 Meeting Announcement (FDA) WHO updates all 3 viral strains to be included in fall flu shots (CIDRAP) FDA vaccine advisers recommend adding subclade K to fall shots (CIDRAP) Weekly surveillance report: cliff notes (CDC FluView) OPTION 2: XOFLUZA $50 Cash Pay Option (Xofluza) Influenza Vaccination Coverage Among Nursing Home Residents and Health Care Personnel — United States, 2024–25 Influenza Season (CDC: MMWR) Pediatric Vaccine Effectiveness Against Influenza Hospitalization And Outpatient Visits: 2021–2024 (Pediatrics) Influenza Vaccine Effectiveness in European Primary Care Pediatric Practices: 2022–2024 (Pediatrics) RSV: Waste water scan for 11 pathogens (WastewaterSCan) Respiratory Diseases (Yale School of Public Health) USrespiratory virus activity (CDC Respiratory Illnesses) RSV-Network (CDC Respiratory Syncytial virus Infection) Vaccines for Adults (CDC: Respiratory Syncytial Virus Infection (RSV)) Economic Analysis of Protein Subunit and mRNA RSV Vaccination in Adults aged 50-59 Years (CDC: ACIP) Respiratory Diseases (Yale School of Public Health) Impact of universal nirsevimab prophylaxis in infants on hospital and primary care outcomes across two respiratory syncytial virus seasons in Galicia, Spain (NIRSE-GAL): a population-based prospective observational study (LANCET: Infectious Diseases) First Report on Remdesivir Use for the Treatment of Respiratory Syncytial Virus in Five Allogeneic Hematopoietic Cell Transplant Recipients (JID) Waste water scan for 11 pathogens (WastewaterSCan) COVID-19 deaths (CDC) Respiratory Illnesses Data Channel (CDC: Respiratory Illnesses) COVID-19 national and regional trends (CDC) COVID-19 variant tracker (CDC) SARS-CoV-2 genomes galore (Nextstrain) Where to get pemgarda (Pemgarda) EUA for the pre-exposure prophylaxis of COVID-19 (INVIYD) Infusion center (Prime Fusions) CDC Quarantine guidelines (CDC) NIH COVID-19 treatment guidelines (NIH) Oral Nirmatrelvir–Ritonavir for Covid-19 in Higher-Risk Outpatients(NEJM) Same Pill, Different Impact — Reassessing the Efficacy of Nirmatrelvir–Ritonavir(NEJM) Paxlovid doesn't reduce hospitalization, death rates in vaccinated high-risk COVID outpatients, trial shows (CIDRAP) Drug interaction checker (University of Liverpool) Help your eligible patients access PAXLOVID with the PAXCESS Patient Support Program (Pfizer Pro) UnderstandingCoverage Options (PAXCESS) Infectious Disease Society guidelines for treatment and management (ID Society) Molnupiravir safety and efficacy (JMV) Convalescent plasma recommendation for immunocompromised (ID Society) What to do when sick with a respiratory virus (CDC) Managing healthcare staffing shortages (CDC) Anticoagulation guidelines (hematology.org) Daniel Griffin's evidence based medical practices for long COVID (OFID) Long COVID hotline (Columbia: Columbia University Irving Medical Center) The answers: Long COVID Acute COVID-19 is associated with altered CD8 T-cells indicative of impaired ability to control Epstein–Barr virus reactivation (Medical Microbiology and Immunology) Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial (Journal of Cachexia, Sarcopenia and Muscle) Reaching out to US house representative Letters read on TWiV 1318 Dr. Griffin's COVID treatment summary (pdf) Timestamps by Jolene Ramsey. Thanks! Intro music is by Ronald Jenkees Send your questions for Dr. Griffin to daniel@microbe.tv Content in this podcast should not be construed as medical advice.

Biomarkers of aging help researchers understand how diseases influence the body over time. However, most current biomarkers rely on measurements from mixed cell populations, making it difficult to distinguish between changes caused by shifts in cell types and aging processes occurring within individual cells. In this study, titled “Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV” and published in Volume 18 of Aging-US, researchers used single-cell RNA sequencing to analyze aging-related changes in human T cells. They developed Tictock, a single-cell transcriptomic clock that predicts both cellular age and T cell type across six human T cell subsets. Applying this tool, the researchers found that acute COVID-19 was associated with increased proportions of CD8⁺ cytotoxic T cells, while T cell composition remained relatively stable in individuals with HIV receiving antiretroviral therapy (HIV+ART). Despite these differences, both conditions showed signs of accelerated transcriptomic aging, particularly in naïve CD8⁺ T cells. Further analysis identified shared aging-related genes and biological pathways linked to ribosomal components and TNF receptor binding. These findings demonstrate how single-cell transcriptomic biomarkers can help separate systemic immune changes from cell-intrinsic aging processes, providing new tools to measure immune aging in disease. DOI - https://doi.org/10.18632/aging.206353 Corresponding author - Eric Verdin - EVerdin@buckinstitute.org Abstract video - https://www.youtube.com/watch?v=_r3AF7OrgKY Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206353 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, transcriptomic clock, aging biomarkers, systemic aging, intrinsic aging To learn more about the journal, please visit https://www.Aging-US.com​​ and connect with us on social media at: Bluesky - https://bsky.app/profile/aging-us.bsky.social ResearchGate - https://www.researchgate.net/journal/Aging-1945-4589 X - https://twitter.com/AgingJrnl Facebook - https://www.facebook.com/AgingUS/ Instagram - https://www.instagram.com/agingjrnl/ LinkedIn - https://www.linkedin.com/company/aging/ Reddit - https://www.reddit.com/user/AgingUS/ Pinterest - https://www.pinterest.com/AgingUS/ YouTube - https://www.youtube.com/@Aging-US Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Guest: Dr. Ido Amit is a Principal Investigator and the Eden and Steven Romick Professorial Chair at the Weizmann Institute of Science. His lab is at the forefront of developing and applying cutting-edge single-cell genomics technologies alongside advanced computational approaches. By integrating these innovative tools in both animal models and human studies, his team uncovers the immune regulatory mechanisms and pathways that shape health and disease. Featured Products and Resources: Stay up-to-date with the latest in human immunology news. Download a free wallchart on the production of CAR T cells. The Immunology Science Round Up Modified RNA Prevents Autoimmunity – Researchers show that modified RNA from our own cells naturally blocks TLR7 and TLR8, preventing harmful immune activation. Oncolytic Virus Boosts T Cells – In glioblastoma patients, a single virus treatment helped the immune system attack the tumor. Rewiring the Immune System During Food Scarcity – When food is scarce, stress hormones rebalance the immune system to fight infection while conserving glucose and preserving immune memory. Regulating Bystander T Cells – IL-4 can dial down how strongly memory CD8+ T cells respond to infection without direct antigen stimulation. Image courtesy of Dr. Ido Amit Subscribe to our newsletter! Never miss updates about new episodes. Subscribe

BUFFALO, NY — February 19, 2026 — A new #research paper was #published in Volume 18 of Aging-US on February 8, 2026, titled “Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV.” In this study, co-first authors Alan Tomusiak from the Buck Institute for Research on Aging and the University of Southern California, and Sierra Lore from the Buck Institute for Research on Aging and the University of Copenhagen, together with corresponding author Eric Verdin from the Buck Institute for Research on Aging, developed a new single-cell transcriptomic clock called T immune cell transcriptomic clock (Tictock) to measure aging in specific immune cells. Immune aging increases susceptibility to infection, cancer, and chronic inflammatory disease. Most aging clocks, used to measure it, rely on bulk measurements from mixed cell populations. As a result, they cannot determine whether age-related signals reflect shifts in cell proportions or true molecular aging within defined immune cells. To address this limitation, the research team used single-cell RNA sequencing, a method that measures gene expression in individual cells. They analyzed nearly two million immune cells from the blood of healthy adults to develop Tictock. This tool integrates automated classification of six canonical T cell subsets with cell-type specific age prediction models. This design enables the separation of systemic aging, reflected by changes in cell proportions, from intrinsic aging, which occurs within individual cells. When the team applied Tictock to patients with acute COVID-19, they found two clear effects. First, COVID-19 altered T cell composition, including significant reductions in naïve CD8 and naïve CD4 T cells. Second, the infection increased the biological age of naïve CD8 T cells. In people living with HIV who were receiving long-term antiretroviral therapy, T cell proportions remained largely stable. However, naïve CD8 T cells still showed signs of accelerated aging. The study also uncovered shared biological pathways linked to immune aging. Many of the genes that predicted age were involved in ribosomes, the structures that help cells produce proteins. The researchers also observed that older immune cells often had shorter average transcript lengths, a feature previously linked to aging. These findings suggest that changes in protein production and gene regulation play an important role in immune decline. “Gene Ontology enrichment of 209 genes shared across six clock models identified common pathways including the cytosolic small ribosomal subunit, TNF receptor binding, and cytosolic ribosome components.” Overall, Tictock was designed to measure relative aging within defined T cell populations rather than overall biological aging. By distinguishing systemic from cell-intrinsic immune aging, it provides a clearer understanding of how viral infections such as COVID-19 and HIV reshape immune function. This approach enables the study of immune aging at single-cell resolution and may support improved immune risk assessment in clinical and research settings. DOI - https://doi.org/10.18632/aging.206353 Corresponding author - Eric Verdin - EVerdin@buckinstitute.org Abstract video - https://www.youtube.com/watch?v=_r3AF7OrgKY Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts To learn more about the journal, please visit https://www.Aging-US.com​​. MEDIA@IMPACTJOURNALS.COM

In this episode of the Oncology Brothers podcast, we engaged in a thought-provoking discussion with Dr. Patrick Soon-Shiong, a pioneer in oncology and the innovator behind the approval of nab-paclitaxel (Abraxane). We delved into the exciting potential of Anktiva (N-803), an IL-15 receptor super agonist designed to expand and activate natural killer (NK) cells and CD8 T cells, with the hope of revolutionizing cancer treatment. Dr. Soon-Shiong shared insights into the mechanism of action of Anktiva, its current approvals in non-muscle invasive bladder cancer, and extended approval in non-small cell lung cancer in Saudi Arabia, and the promising clinical trial data that suggests a significant increase in overall survival for patients. The conversation also touched on the importance of restoring lymphocyte counts and the implications for treating various tumor types. Join us as we explore the future of immunotherapy, the challenges of regulatory approval, and the potential for Anktiva to change the landscape of cancer treatment. Key Topics: • Mechanism of action of Anktiva • Current approvals and clinical trial data • The role of lymphocyte counts in cancer treatment • Future directions for immunotherapy Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and hit the notification bell for more discussions on the latest in oncology! #Oncology #CancerTreatment #Immunotherapy #IL15Agonist #OncologyBrothers

HEALTH NEWS   Choline intake in pregnancy linked to lower inflammation Fatty acids found to influence immune defense during chronic infections Online shopping and social media use linked to higher stress levels Scientists Discover Natural Compounds With Unexpected Benefits for Skin, Anti-Aging, and Heart Health Discrimination damages the body—and makes victims age faster   Choline intake in pregnancy linked to lower inflammation Cornell University, February 5 2026 (Eurekalert)   A new Cornell University study suggests that choline, a nutrient many pregnant people consume too little of, may play an underappreciated role in keeping inflammation in check during pregnancy. Choline is an essential nutrient involved in many biological processes, including cell membrane structure, neurotransmitter production, methylation, immune cell receptor agonism, and fetal brain development, and some of these biochemical processes play a role in the regulation of inflammation. It is found primarily in eggs, meat, fish, dairy and some legumes and cruciferous vegetables. Researchers analyzed data from more than 1,300 pregnant participants enrolled in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort, one of the most detailed long-running pregnancy nutrition studies in North America. They found that higher recent dietary choline intake was associated with lower levels of inflammation in the third trimester. Most strikingly, participants with the highest choline intakes had dramatically lower odds of having clinically elevated inflammation than those with the lowest intakes.The current recommendation for choline during pregnancy is 450 mg, but there's some evidence that that may not be enough.     Fatty acids found to influence immune defense during chronic infections University of California at San Diego, February 5 2026 (Medical Xpress) Our immune system implements an array of strategies to combat threatening infections. White blood cells called cytotoxic T lymphocytes or "CD8 T cells" are soldiers of the immune system, serving as defensive agents that fight invading pathogens. When CD8 T cells reach the point of exhaustion, their protective capabilities decline and the immune system is much less effective. University of California San Diego immunologists have now studied the influences related to metabolism and the environment surrounding CD8 T cells. Their study led to intriguing new insights on the role of fatty acids in chronic infections and other persistent conditions, such as tumors. The research focused on metabolites, including small molecules such as amino acids, sugars, and lipids, in mice that play key roles in metabolism and its many functions and pathways. The study examined how such metabolites circulating in the blood change during short-lived or long-lasting viral infections. They discovered that an ongoing viral infection causes a brief but striking shift in the availability of nutrients in the early stages after infection. They saw levels of fatty acids increase during the first week after infection, associated with infection-induced changes in eating behavior and fat breakdown. At the same time, a special group of exhausted CD8 T cells with stem-like properties was found to absorb and store more fat than other T cells. These cells were able to use fatty acids as an energy source to power their mitochondria, the cell's energy producers. When fatty acids were provided later during chronic infection, the number of stem-like T cells expanded.   Online shopping and social media use linked to higher stress levels     Aalto University (Finland), January 9 2026 (News-Medical) Planning to save time by doing your shopping online? If so, it's possible you're not doing your well-being any favors. A study from Aalto University in Finland has found that online shopping is more strongly linked to stress than reading the news, checking your inbox or watching adult entertainment.  Previous studies have shown that social media and online shopping are often used to relieve stress. However, the new results show that a rise in social media use or online shopping is linked to an increase in self-reported stress across multiple user groups and across devices. The study found that users of YouTube and streaming services, as well as online gamers, also reported increased stress levels. For people experiencing high-stress, time spent on social media was twice more likely to be linked to stress as compared to time spent on gaming. Somewhat surprisingly, people who spent a lot of time on news sites reported less stress than others. On the other hand, those who already experienced a lot of stress didn't spend much time on news sites. Overall, the study found a strong connection between internet use, in general, and heightened stress, especially among those who already experienced a lot of stress in daily life. Women reported more stress than men, and the older and wealthier the participant, the less stress they experienced.   Scientists Discover Natural Compounds With Unexpected Benefits for Skin, Anti-Aging, and Heart Health Meijo University (Japan), February 5, 2026 (SciTech Daily) Scientists have found that certain natural compounds produced by algae and cyanobacteria may offer benefits beyond sun protection, including support for skin health and cardiovascular function. In lab experiments, two mycosporine-like amino acids were found to do more than soak up ultraviolet light. They also slowed down a major enzyme tied to blood pressure control, while showing antioxidant and anti-aging activity. One enzyme, Porphyra-334, is abundant in edible seaweed, which is already consumed widely in many countries. This raises the possibility that everyday foods may contain underappreciated bioactive compounds worthy of further health-related research.These compounds, called mycosporine-like amino acids (MAAs), are produced by seaweeds and other tiny organisms that spend their lives exposed to intense light. MAAs work like built in sun filters by absorbing ultraviolet (UV) radiation before it can harm cells. One of the most notable findings came from experiments on the inhibiting the angiotensin-converting enzyme ACE, a key regulator of blood pressure. Many widely prescribed hypertension drugs work by blocking ACE. Both compounds reduced the activity of this enzyme in laboratory tests, marking the first report of such an effect for MAAs. Although the observed effects were moderate and measured outside the human body, the discovery opens a new direction for future research.     Discrimination damages the body—and makes victims age faster University of Montreal, January 19 2026 (Medical Xpress) Has being discriminated against as an LGBTQ+ person been so bad, the stress so heavy, that the victim can literally feel it in their bones? Well, it turns out that's exactly what happens: discrimination damages the body and brain. That's the conclusion of a new study by researchers at Université de Montréal, who found that discrimination against sexually and gender-diverse people leaves measurable biological traces in the body—so much so, it should be considered a chronic health burden. Published in Psychoneuroendocrinology, the study was done on 357 Montreal adults aged 18 to 79: They included 129 cisgender sexual minority men and women, 96 transgender and non-binary people, and 72 cisgender heterosexual men and women. UdeM researchers measured the participants' allostatic load, the cumulative biological wear-and-tear associated with chronic stress. They looked at 16 biomarkers affecting the subjects' cardiovascular, metabolic, neuroendocrine and immune systems. Results show that major life experiences of discrimination and daily microaggressions were positively associated with allostatic load. This means that these two types of discriminatory events independently contribute to physiological dysregulation, creating a cumulative health burden and accelerated aging. The study revealed significant disparities: people on the male spectrum (cisgender and transgender men) had the highest levels of allostatic load, while sexual minority men (bisexual and gay) also showed high levels of biological stress.

Pre-Order The Forever Strong PLAYBOOK and receive exclusive bonuses: https://drgabriellelyon.com/playbook/Want ad-free episodes, exclusives and access to community Q&As? Subscribe to Forever Strong Insider: https://foreverstrong.supercast.comAre your immune cells aging faster than you are? In this episode, Dr. Gabrielle Lyon sits down with Dr. Anurag Singh, a leading physician-researcher and Chief Medical Officer at Timeline, to discuss a groundbreaking discovery: the gut-muscle-immune axis. While we often focus on muscle mass for longevity, new research published in Nature Aging reveals that our immune system undergoes a similar decline, with youthful sentinel cells (naive CD8 T-cells) dropping by 75% as we reach age 50. Dr. Singh explains how mitophagy —the targeted recycling of damaged mitochondria—is the key to "rewiring" an aging immune system to fight infection 20% more effectively. In this episode: Alzheimer's of the Muscle: Why sporadic inclusion body myositis (sIBM) is often misdiagnosed as simple aging. The Power of Urolithin A: How this postbiotic compound induces mitophagy to increase mitochondrial abundance by 20% in just 28 days. Immune Imprinting: Why children get 6-8 colds a year while adults only average 2-4. Repurposing Longevity Drugs: Dr. Singh's take on Metformin, Rapamycin, and GLP-1s for life extension. The 1:1 Exercise Rule:Why 150 minutes of moderate activity is the threshold for mitochondrial biogenesis. Thank you to our sponsors: BodyHealth - Use the code LYON 20 to get 20% off your first order https://www.bodyhealthaffiliates.com/73L4QL3/7XDN2/ Timeline - Get 35% off a Mitopure subscription at https://www.timeline.com/drlyon Manukora - Go to https://www.MANUKORA.com/DRLYON to save 31% plus $25 worth of free gifts. Chapters: 0:00 - Can You Tell If Your Immune System Is Healthy? 1:37 - Alzheimer's of the Muscle: Muscle-Immune Dysfunction 5:59 - The Thymus Design Flaw: Why Our Immune "Ammo" Disappears 8:44 - Naive CD8 T-Cells: The Elite Forces of Immunity 12:24 - The Axis of Aging: Mitochondria and Immune Cells in Muscle 16:15 - Mitophagy vs. Autophagy: Targeted Cellular Recycling 19:11 - Study Review: Rewiring the Immune System with Urolithin A 24:13 - Mitochondrial Remodeling: Switching from Glucose to Fatty Acids 27:45 - The Trifecta: Gut-Muscle-Immune Axis Connection 31:13 - Parkinson's and the PINK1/Parkin Mitophagy Pathway 35:04 - Clinical Results: Improving Leg Strength in 4 Months 38:51 - Joint Health: Can We Remodel Cartilage with Mitophagy? 43:34 - Targeted Mitophagy Inducers: Exercise vs. Postbiotics 46:44 - Precision Nutrition: The Ideal Muscle Longevity Supplement 53:33 - Why Alzheimer's is Now Considered an Inflammatory Disease 1:00:13 - The Placebo Effect: You Cannot Deceive the Immune System 1:03:13 - Lymphocyte Counts: The Clinical Marker for Immune Aging 1:08:14 - Rapamycin and Metformin: The Future of Longevity Drugs 1:11:42 - Optimal Dosing: Why 1,000mg of Urolithin A is the Standard 1:15:13 - Sports Medicine: Reducing Muscle Damage Markers (Creatine Kinase) 1:20:03 - The Final Frontier: Brain Aging and Selenium Repair Connect with Dr. Anurag Singh Instagram: @timeline_longevity Website: https://www.timeline.comFind Dr. Gabrielle Lyon at: Instagram:@drgabriellelyon TikTok: @drgabriellelyon

Send us a textWhat if cancer didn't have to be eradicated, but could be remembered, monitored, and controlled by the immune system itself?In this episode of Causes or Cures, Dr. Eeks speaks with Dr. Zachary Hartman, the lead researcher who revisited an extraordinary breast cancer vaccine trial conducted over 20 years ago. The trial involved a small group of women with advanced breast cancer. Women who, remarkably, are all still alive today.By analyzing their blood decades later, the research team discovered that these women still carried immune cells capable of recognizing their cancer, suggesting durable immune memory lasting more than two decades. (Study link here.)We discuss:The original breast cancer vaccine trial and what it was designed to do, in plain languageWhat it was like to discover that the women from the trial was still alive more than 20 years laterHow the immune systems of these women continued to recognize cancer cells long after the trialWhat CD27-positive immune cells are and why they matter, explained simplyWhy helper CD4 T cells may be just as important, or more important, than killer CD8 T cells when it comes to cancerWhat happened when researchers combined a CD27-boosting antibody with a cancer vaccine in miceWhat surprised the research team mostThe challenges of translating findings from mice to human trialsWhether cancer could someday be managed long-term by the immune systemHow generalizable this immune memory might be across different cancersWhat this research could mean for how we think about vaccines in a post-pandemic worldThe one key message the researcher hopes the public takes awayWhat's next in this line of researchThis episode offers a rare, hopeful (but scientifically grounded) look at how the immune system may be capable of remembering cancer for decades. Guest Bio: Dr. Zachary C. Hartman is an Associate Professor at Duke University in the Departments of Surgery, Pathology, and Integrative Immunobiology, where he also serves as Director of the Center for Applied Therapeutics and is a member of the Cellular and Molecular Biology and Genetics and Genomics programs. He earned his undergraduate degree from Northwestern University and completed his PhD at Duke University, followed by postdoctoral training in tumor immunology and breast oncology at Duke and the MD Anderson Cancer Center. In 2012, Dr. Hartman returned to Duke to establish a research program focused on tumor immunology and the development of cancer immunotherapies, including therapeutic vaccines, immune agonists, checkpoint inhibitors, antibody-based therapies, and strategies to stimulate anti-tumor immune responses.  Work with me? Perhaps we are a good match. You can contact Dr. Eeks at bloomingwellness.com.Follow Eeks on Instagram here.Follow Public Health is WeirdOr Facebook here.Or X.OnSupport the show

Most people are told: "If you have thyroid antibodies, you have Hashimoto's. If you don't, you don't." In this episode, Dr. Eric Balcavage, creator of the Adaptive Thyroid Model™, revisits that idea and shows why antibodies are only one piece of a much bigger picture. Discover how: ✅ Th1 and Th17 T-cells, CD8 T-cells, and low T-regs drive thyroid inflammation and tissue damage ✅ PAMPs (pathogen signals) and DAMPs (cell-danger signals) can bind to pattern-recognition receptors [PRRs] on thyroid cells, triggering cytokines and interferon activity ✅ Antibodies may confirm Hashimoto's, but their absence doesn't rule it out (seronegative Hashimoto's is real) ✅ Addressing the drivers of immune imbalance — gut permeability, sleep debt, oxidative stress, nutrient deficiencies — can help restore tolerance and thyroid function Dr. Balcavage breaks down the latest research on how inflammation starts inside the thyroid, why the body isn't "attacking" itself, and what a true recovery plan looks like.

Upgrade your biology in 10 minutes with this week's rundown from Dave Asprey. This episode breaks down the six biggest stories in biohacking and health tech, from sleep hormones to mitochondrial rejuvenation, giving you the data you need to live longer, think faster, and perform at your peak. This episode covers: • The Melatonin Heart Warning Everyone Missed A major new study from the American Heart Association reveals that long-term melatonin users face nearly twice the risk of heart failure and 3.5 times higher hospitalization rates. Once considered a harmless sleep aid, melatonin's hormonal effects may disrupt cardiovascular recovery, testosterone, and blood pressure regulation when used nightly. The takeaway: melatonin is a short-term circadian reset tool, not a forever supplement. Source: American Heart Association — newsroom.heart.org/news/long-term-use-of-melatonin-supplements-to-support-sleep-may-have-negative-health-effects • Bryan Johnson's Extreme Microplastics Detox Biohacker Bryan Johnson shared lab-verified results showing an 85% reduction in microplastics in his semen after one year of daily 200°F dry saunas followed by ice packs on the groin. It's not peer reviewed yet, but it'ssparking global discussion about environmental toxins, fertility, and detoxification. Whether or not you follow his protocol, this study highlights how widespread microplastics have become and how heat, sweat, and smarter exposure control may help fight back. Source: New York Post — nypost.com/2025/10/23/health/biohacker-bryan-johnson-got-rid-of-85-of-microplastics-from-his-semen • Urolithin A: The Mitochondrial Molecule That Strengthens Immunity A peer-reviewed human trial published in Nature Aging found that four weeks of daily Urolithin A (Mitopure®) supplementation improved immune function in adults aged 45–70, increasing youthful CD8 T-cells, natural killer cells, and mitochondrial performance inside immune cells. By triggering mitophagy, your body's cleanup process for old mitochondria, Urolithin A enhances energy, resilience, and immune strength. It's the clearest evidence yet that we can modulate immune aging through mitochondrial renewal. Head to timeline.com/dave to get 10% off your first order. Source: BioSpace — biospace.com/press-releases/timeline-continues-to-build-the-most-clinically-researched-longevity-products-targeting-immune-brain-and-muscle-aging • Google's New AI Model That “Talks” to Cells Google DeepMind and Yale launched Cell2Sentence-Scale, an open-source AI model that lets scientists query cellular pathways in natural language. The system can predict how cells transition from healthy to cancerous states and identify molecular switches that might reverse those changes. It's compressing years of biology into days and democratizing research for small labs and independent scientists alike. Isn't AI a beautiful thing? Source: Google DeepMind — blog.google/technology/ai/google-gemma-ai-cancer-therapy-discovery • Omega-3s Calm the Brain and the Temper A massive new meta-analysis of randomized controlled trials shows omega-3 fatty acids (EPA and DHA) reduce aggression by up to 28%. That includes both reactive anger and planned aggression. By lowering neuroinflammation and stabilizing cell membranes, omega-3s appear to balance dopamine and serotonin, proving that healthy fats aren't just heart food, they're emotional regulators too. Source: Science Alert — sciencealert.com/one-dietary-supplement-was-shown-to-reduce-aggression-by-up-to-28 • Chronic Fatigue Syndrome Finally Gets a Biomarker For the first time, researchers have developed a blood test that accurately identifies chronic fatigue syndrome (ME/CFS) using DNA methylation and micro-RNA expression patterns. This breakthrough distinguishes CFS from other autoimmune and viral conditions, marking a turning point for millions of patients long dismissed by traditional medicine. It's proof that data-driven diagnostics can transform how we understand mystery illnesses. Source: Science Daily — sciencedaily.com/releases/2025/11/251102205021.htm All source links provided for easy reference to the original reporting and research above. This is essential listening for fans of biohacking, hacking human performance, functional medicine, and longevity who want actionable tools from Host Dave Asprey and a guest who embodies what it means to age with energy, clarity, and vitality. Dave Asprey is a four-time New York Times bestselling author, founder of Bulletproof Coffee, and the father of biohacking. With over 1,000 interviews and 1 million monthly listeners, The Human Upgrade brings you the knowledge to take control of your biology, extend your longevity, and optimize every system in your body and mind. Each episode delivers cutting-edge insights in health, performance, neuroscience, supplements, nutrition, biohacking, emotional intelligence, and conscious living. New episodes are released every Tuesday, Thursday, Friday, and Sunday (BONUS). Dave asks the questions no one else will and gives you real tools to become stronger, smarter, and more resilient. Keywords: melatonin heart risk, sleep hormones, microplastics detox, Bryan Johnson, Urolithin A, mitophagy, mitochondrial health, immune aging, DeepMind AI, cellular modeling, omega-3 aggression, neuroinflammation, chronic fatigue biomarker, ME/CFS test, biohacking news, longevity research Thank you to our sponsors! -LYMA | Go to https://lyma.sjv.io/gOQ545 and use code DAVE10 for 10% off the LYMA Laser.-Vibrant Blue Oils | Grab a full-size bottle for over 50% off at https://vibrantblueoils.com/dave. Resources: • Danger Coffee: https://dangercoffee.com/discount/dave15 • My Daily Supplements: SuppGrade Labs (15% Off) • Favorite Blue Light Blocking Glasses: TrueDark (15% Off) • Dave Asprey's BEYOND Conference: https://beyondconference.com • Dave Asprey's New Book – Heavily Meditated: https://daveasprey.com/heavily-meditated • Upgrade Collective: https://www.ourupgradecollective.com • Upgrade Labs: https://upgradelabs.com • 40 Years of Zen: https://40yearsofzen.com Timestamps: 0:00 — Intro 0:18 — Story 1: Melatonin & Heart Health 1:58 — Story 2: Microplastics Detox 3:39 — Story 3: Urolithin A & Immune Function 5:19 — Story 4: AI Cell Model 6:57 — Story 5: Omega-3 & Aggression 8:43 — Story 6: CFS Blood Test 9:59 — Weekly Upgrade Protocol See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

In this solo episode of The Energy Code, Mike dives into two cutting-edge studies that expand the already impressive profile of Urolithin A, the postbiotic powerhouse derived from pomegranate. The first paper explores how Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and suppression of the NLRP3 inflammasome, while the second study—a randomized, placebo-controlled trial in humans—uncovers Urolithin A's ability to rejuvenate the immune system by increasing naive CD8+ T cells, boosting fatty acid oxidation, and reprogramming immune gene expression.   Key topics include: The dual role of Urolithin A in nerve repair: clearing damaged mitochondria & suppressing inflammation Why mitophagy is a linchpin in mitochondrial health, longevity, and disease prevention How TFEB acts as a master switch for cellular detox and mitochondrial renewal New clinical data showing Urolithin A's impact on immune cell function and inflammatory aging Why mitochondrial-targeted compounds (Urolithin A, methylene blue, PQQ, etc.) are foundational to healthspan   Plus, Mike teases the release of two new BioBlue formulations — BioBlue Lite and BioBlue Leuco Lite — featuring a simplified formula of just deuterium-depleted water and pharmaceutical-grade methylene blue or leucomethylene blue.  

تناولت حلقة بودكاست «تحت المجهر» دراسة أسترالية حديثة كشفت عن ارتباط وثيق بين الرضاعة الطبيعية وانخفاض خطر الإصابة بسرطان الثدي لدى الأمهات. أظهرت النتائج أن الرضاعة تسهم في تنشيط خلايا مناعية من نوع CD8+ T، تعمل على التعرف على الخلايا غير الطبيعية في أنسجة الثدي وتدميرها قبل تحولها إلى خلايا سرطانية. ركزت الدراسة بشكل خاص على سرطان الثدي الثلاثي السلبي، وهو من أكثر الأنواع عدوانية وصعوبة في العلاج، لتبيّن أن الرضاعة الطبيعية تفعّل استجابات مناعية قوية تمنح الأم وقاية طويلة الأمد. . تؤكد الحلقة أن الرضاعة الطبيعية تمثل علاقة فريدة تجمع بين الحماية والعطاء، فهي تغذي الطفل وتحمي الأم في آنٍ واحد. فماذا عن السيدات التي لم تنجبن ولم ترضعن؟ هل من حلول؟ الإجابة في حلقة تحت المجهر مع الدكتورة نسرين الشماس

运动可降低患癌风险、延长癌症患者生存期并提高癌症治疗效果已经成为共识。最新研究表明，运动通过诱导肠道微生物代谢产物甲酸盐，增强 CD8 T 细胞的抗肿瘤免疫，可以提高癌症免疫治疗效果。

Dr. Tamara Tilburgs is an Assistant Professor in the University of Cincinnati Department of Pediatrics, where her research focuses on immune tolerance during pregnancy. She talks about the immune paradox in trophoblast cells and how placental inflammation can lead to pregnancy complications. She also discusses CD8+ T cell responses at the maternal-fetal interface.

BUFFALO, NY - July 16, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on July 9, 2025, titled “A novel anti-human CD25 mAb with preferential reactivity to activated T regulatory cells depletes them from the tumor microenvironment.” In this study, researchers from the National Institute of Allergy and Infectious Diseases, led by first author Maja Buszko and corresponding author Ethan M. Shevach, discovered a new monoclonal antibody that selectively targets a subset of immune cells called regulatory T cells (Tregs). These cells, while normally important for preventing autoimmunity, also can block the body's ability to fight cancer by suppressing anti-tumor immune responses. This discovery could lead to novel cancer therapies that strengthen the immune system's capacity to attack tumors. The researchers identified an anti-CD25 monoclonal antibody with several atypical properties and named it 2B010. To evaluate its effects, they used humanized mice, laboratory mice that are engineered to carry human immune cells, to closely mimic how human immune systems respond to cancer. The treatment of these mouse models with 2B010 significantly decreased the number of Tregs in tumors and boosted the activity of CD8+ T cells, which are essential for killing cancer cells. Importantly, 2B010 worked without disrupting other key immune functions. Unlike traditional Anti-CD25 antibodies, it did not interfere with interleukin-2 (IL-2) signaling, which is essential for the growth and activity of effector T cells that fight cancer. “2B010 also had no effect on IL-2 induced STAT5 phosphorylation or CD4+ T cell proliferation in vitro while both were blocked by Clone D1 further supporting the view that 2B010 does not recognize the IL-2 binding site.” This finding is especially significant because high levels of Tregs in tumors are associated with poor outcomes in many cancers. By specifically removing these cells, 2B010 may help overcome one of the main barriers to current immunotherapy approaches. Its ability to preserve IL-2 signaling could also make it safer and more effective when used alone or in combination with existing therapies such as immune checkpoint inhibitors. While the 2B010 antibody showed strong effects in reducing Tregs and boosting immune cell activity, the study did not observe changes in tumor size in these models. Researchers suggest this may be due to limitations in the preclinical systems used, such as the lack of tumor-specific T cells in humanized mice. Nevertheless, these findings demonstrate that 2B010 has a unique mechanism of action that could complement other cancer immunotherapies in future clinical trials. In conclusion, the development of 2B010 is a promising step toward selectively disrupting the immune suppressive environment in tumors. As researchers continue to refine and test this antibody, it could become a powerful tool for enhancing the effectiveness of cancer treatments and improving outcomes for patients. DOI - https://doi.org/10.18632/oncotarget.28752 Correspondence to - Ethan M. Shevach - eshevach@Niaid.NIH.gov Video short - https://www.youtube.com/watch?v=2NJcGsI7WXA Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28752 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, Treg, CD25, TME, mAb, GVHD To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

BUFFALO, NY – June 20, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 10, 2025, titled “Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors.” In this paper, led by first author Helen Qian and corresponding author Crismita Dmello from Northwestern University Feinberg School of Medicine, researchers compiled growing evidence that the CHEK2 gene, long known for its role in repairing DNA damage, may also influence how tumors respond to immunotherapy. Their analysis suggests that problems in CHEK2 function might make cancer cells more vulnerable to immune system attacks, highlighting a new opportunity to improve treatment outcomes in solid tumors. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment; however, they are effective in only a subset of patients. This review suggests that tumors with reduced CHEK2 activity may accumulate more mutations that produce signals the immune system can recognize. These signals, known as neoantigens, help immune cells identify and destroy cancer cells more effectively. The review connects this process not only to CHEK2's established role in the DNA damage response but also to a newly proposed function in shaping the immune environment of tumors. CHEK2 normally helps maintain genomic stability by enabling precise DNA repair. When this function is lost, cells rely on more error-prone repair methods, leading to additional mutations. These mutations can increase tumor mutational burden, which has been linked to better outcomes with immunotherapy. Beyond DNA repair, the review highlights a second mechanism: activation of the cGAS-STING pathway. This pathway detects fragments of damaged DNA and triggers inflammation that attracts immune cells to the tumor. The authors highlight studies where CHEK2-deficient tumors responded better to PD-1 inhibitors, a common type of immune checkpoint inhibitor. In both lab models and early-stage clinical settings, CHEK2 loss was associated with increased infiltration of CD8+ T cells—immune cells essential for attacking cancer cells. In cancers such as glioblastoma and renal cell carcinoma, which are typically resistant to immunotherapy, reduced CHEK2 expression was linked with more favorable immune activity and higher expression of interferon-related genes. The compiled evidence points to CHEK2 as a potential biomarker for identifying patients likely to respond to immunotherapy. In addition, combining CHEK2 inhibitors with existing immunotherapies may enhance anti-tumor effects, particularly in cancers with limited treatment options. The review notes that some clinical trials using the CHEK1/2 inhibitor prexasertib alongside immune checkpoint therapies have already shown promising early results. “The initial results from this Phase I clinical trial support the immunomodulatory role of CHEK2 expression and even suggest CHEK2 potentiates immunosuppression.” Although more research is needed to confirm these mechanisms and improve treatment approaches, this review underscores the expanding role of DNA repair genes like CHEK2—not only in maintaining genome integrity but also in helping the immune system fight cancer. DOI - https://doi.org/10.18632/oncotarget.28740 Correspondence to - Crismita Dmello - stellacpak@outlook.com Video short - https://www.youtube.com/watch?v=C26pEBc0itk Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. John Sweetenham shares highlights from Day 5 of the 2025 ASCO Annual Meeting, including data from large trials in advanced malignant melanoma and mCSPC plus a new approach to first-line treatment for patients with multiple myeloma who are not transplant eligible. Transcript Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my takeaways on selected abstracts from Day 5 of the 2025 ASCO Annual Meeting. My disclosures are available in the transcript of this episode. The selected abstracts from this final day of ASCO25 include important new data from large, randomized trials in patients with advanced malignant melanoma and patients with metastatic castration-sensitive prostate cancer, as well as a new approach to the first-line treatment of patients with multiple myeloma who are not transplant eligible.  Starting with LBA9500, this study was conducted in patients with completely resected stage III or IV malignant melanoma and compared the combination of relatlimab plus nivolumab versus nivolumab alone in this population. The study, named the RELATIVITY-098 trial, was presented by Dr. Georgina Long from the University of Sydney, Australia. In her introduction to the study, Dr. Long explained that the current standard of care for adjuvant therapy of resected stage III/IV melanoma is with PD-1 monotherapy with nivolumab, but that about 50% of patients will suffer from a subsequent relapse. In the first-line setting in patients with advanced or unresectable melanoma, the combination of nivolumab with the LAG-3 inhibitor, relatlimab, has been previously shown to improve progression-free survival in the RELATIVITY-047 trial. The current study evaluated this same combination in the adjuvant setting. More than 1,000 patients from 24 countries were randomized to receive either nivolumab alone (546 patients) or the combination of nivolumab with relatlimab (547 patients). Both treatments were given for a maximum of 1 year or until progression of disease, unacceptable toxicity, withdrawal, or death. Various biomarker studies were also undertaken including LAG-3 and PD-1 expression on CD8-positive T cells. The primary endpoint of the study was relapse-free survival, and Dr. Long reported that this was the same in both arms of the study. For example, at 24 months, the relapse-free survival was 64% in the monotherapy arm compared with 62% in the combination arm. The hazard ratio was 1.01 and the P value was 0.928. Metastasis-free survival was also identical in both arms. No benefit was observed for the combination in any of the prespecified subgroups. No new toxicity signals emerged compared with the RELATIVITY-047 trial. Interestingly, the baseline surface expression of LAG-3 and co-expression of LAG-3 and PD-1 on CD8 T cells in the 098 adjuvant trial were lower than in the 047 advanced disease trial, perhaps explaining why the combination did not confer benefit over nivo alone in the adjuvant setting. This is an important result, demonstrating that results from one clinical setting cannot always be extrapolated to another. Although the combination has gained some use in the adjuvant setting, this study clearly demonstrates that more drug in this situation is no better and that monotherapy remains the current standard of care. Results from the AMPLITUDE trial for patients with metastatic castration-sensitive prostate cancer with alterations in homologous recombination repair (HRR) genes, in LBA5006, were presented today by Dr. Gerhardt Attard from University College London, UK. This international, multicenter study evaluated the combination of the selective PARP inhibitor, niraparib, in combination with abiraterone acetate and prednisone. The same combination has been previously shown to improve outcomes in castration-resistant metastatic prostate cancer harboring BRCA mutations in the MAGNITUDE study. The current trial included patients with castration-sensitive disease with HRR mutations including BRCA1/2. Six hundred and ninety-six patients were randomized between niraparib, abiraterone, and prednisone plus androgen deprivation therapy, or the same combination with placebo instead of niraparib. Permitted prior therapies included no more than 6 months of prior androgen deprivation therapy and the use of docetaxel, or prior palliative radiation therapy. The primary endpoint of the study was radiographic relapse-free survival. Dr. Attard reported that the risk for radiographic progression-free survival in the whole population was significantly reduced by 37% with niraparib and abiraterone acetate plus prednisone compared with the placebo arm. The radiographic progression-free survival risk reduction with niraparib in the prespecified BRCA1/2 subgroup was 48% and reached statistical significance compared with the placebo arm. The secondary endpoint of time to symptomatic progression was also improved with niraparib in the HRR population and the BRCA1/2 subgroup. There was a trend for overall survival favoring the niraparib combination. However, the overall survival data were immature at this first interim analysis and did not yet reach statistical significance. No new safety concerns emerged with the toxicity data consistent with the MAGNITUDE study. Less than 5% more of the patients on the experimental arm discontinued treatment in comparison to the control arm. The authors conclude that the AMPLITUDE study results support the use of niraparib, abiraterone, and prednisone as a new treatment option for patients with metastatic castration- sensitive prostate cancer and BRCA and homologous recombination repair gene alterations. The results certainly support this conclusion and are potentially practice-changing. Turning to hematologic malignancies, my final selection from today's presentations is Abstract 7504, presented by Dr. Hang Quach from St Vincent's Hospital, Melbourne, Australia, and describes a novel combination of elranatamab, daratumumab, and lenalidomide in patients with newly diagnosed multiple myeloma who are not transplant-eligible – the so-called MagnetisMM-6 trial part 1. Elranatamab is a novel bispecific T-cell engaging antibody directed against BCMA and CD3, which has previously been approved for certain patients with relapsed and refractory multiple myeloma. In the present study, this was combined with lenalidomide and daratumumab in newly diagnosed patients. The report today describes the dose-finding phase of this study, which was part 1, specifically addressing so-called dose level ‘G', comprising elranatamab 76mg subcutaneously every 4 weeks plus daratumumab 1800mg subcutaneously and lenalidomide 25mg given orally. Thirty-seven patients were entered at this dose level, of whom 32 were on treatment at the time of analysis. Early response data show an overall response rate of 97.3%. With median follow up of 7.9 months, the current CR rate is 27% with a VGPR rate of almost 68%. The most frequent toxicities were hematologic, with neutropenia observed in 75%. Some cytokine release syndrome was observed in about 60% of patients, but none was greater than grade 2. The authors conclude that this combination is active in untreated multiple myeloma, with manageable toxicity and evidence of responses which appear to deepen over time. The dose-finding component of this trial is continuing and will subsequently progress into a phase 3 trial based on the data from the current study. This will compare daratumumab plus lenalidomide with the same combination plus elranatamab in previously untreated patients. That concludes our special coverage from the 2025 ASCO Annual Meeting. Thanks for listening and we hope you have enjoyed listening to our top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts. Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speaker:    Dr. John Sweetenham    Follow ASCO on social media:     @ASCO on Twitter    @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn     Disclosures:   Dr. John Sweetenham:    No relationships to disclose

Broadcast from KSQD, Santa Cruz on 5-22-2025: Dr. Dawn explores groundbreaking cancer research using high-throughput "digital twin" analysis to reverse colon cancer cells back to normal states, identifying three master molecular switches that can induce normal cell differentiation without killing the cancer cells, thus avoiding traditional chemotherapy side effects. She discusses remarkable results from Memorial Sloan Kettering showing 80% of patients with mismatch repair deficient tumors, including all 49 rectal cancer patients, saw complete tumor disappearance after six months of dostarlimab immunotherapy, with no recurrence at five years and minimal side effects. The program covers innovative CRISPR applications, including targeting previously "undruggable" cancer mutations like KRAS and BRAF by selectively degrading mutant RNA messages while preserving healthy genes, offering unprecedented precision in cancer treatment. Dr. Dawn explains a clever immunotherapy approach that disguises tumors as pig organs using Newcastle disease virus carrying alpha-gal enzyme, tricking the immune system into mounting fierce attacks against cancer cells, showing promising results in both monkey and human trials. She describes fascinating research using cryoshocked tumor cells as Trojan horses, where liquid nitrogen-treated cancer cells carrying CRISPR gene editing tools directly seek out tumors, offering superior targeting compared to injecting CRISPR. The show reveals how cancers create protective acid walls around themselves to repel immune cells, with individual cancer cells pumping lactic acid away from the tumor center to form pH 5.3 barriers that kill attacking CD8 T cells within hours. Dr. Dawn discusses breakthrough mRNA cancer vaccines for glioblastoma using patients' own tumor cells, showing rapid immune system activation within 48 hours and extending survival in both dogs and humans with this aggressive brain cancer. She explores the "flower code" mechanism where cancer cells gaslight healthy cells through epigenetic manipulation, expressing dominant "flower win" codes to overpower normal cells expressing "flower lose" codes in biological turf wars. The program addresses systemic problems in cancer classification, explaining how organ-based categorization delays access to effective treatments, with patients waiting years for drugs that could help based on molecular profiles rather than tumor location. Dr. Dawn concludes by highlighting medical discrimination against people with Duffy null phenotype, primarily affecting African Americans, whose naturally lower neutrophil counts lead to reduced chemotherapy doses and excluded clinical trial participation despite no increased infection risk.

Broadcast from KSQD, Santa Cruz on 5-22-2025: Dr. Dawn explores groundbreaking cancer research using high-throughput "digital twin" analysis to reverse colon cancer cells back to normal states, identifying three master molecular switches that can induce normal cell differentiation without killing the cancer cells, thus avoiding traditional chemotherapy side effects. She discusses remarkable results from Memorial Sloan Kettering showing 80% of patients with mismatch repair deficient tumors, including all 49 rectal cancer patients, saw complete tumor disappearance after six months of dostarlimab immunotherapy, with no recurrence at five years and minimal side effects. The program covers innovative CRISPR applications, including targeting previously "undruggable" cancer mutations like KRAS and BRAF by selectively degrading mutant RNA messages while preserving healthy genes, offering unprecedented precision in cancer treatment. Dr. Dawn explains a clever immunotherapy approach that disguises tumors as pig organs using Newcastle disease virus carrying alpha-gal enzyme, tricking the immune system into mounting fierce attacks against cancer cells, showing promising results in both monkey and human trials. She describes fascinating research using cryoshocked tumor cells as Trojan horses, where liquid nitrogen-treated cancer cells carrying CRISPR gene editing tools directly seek out tumors, offering superior targeting compared to injecting CRISPR. The show reveals how cancers create protective acid walls around themselves to repel immune cells, with individual cancer cells pumping lactic acid away from the tumor center to form pH 5.3 barriers that kill attacking CD8 T cells within hours. Dr. Dawn discusses breakthrough mRNA cancer vaccines for glioblastoma using patients' own tumor cells, showing rapid immune system activation within 48 hours and extending survival in both dogs and humans with this aggressive brain cancer. She explores the "flower code" mechanism where cancer cells gaslight healthy cells through epigenetic manipulation, expressing dominant "flower win" codes to overpower normal cells expressing "flower lose" codes in biological turf wars. The program addresses systemic problems in cancer classification, explaining how organ-based categorization delays access to effective treatments, with patients waiting years for drugs that could help based on molecular profiles rather than tumor location. Dr. Dawn concludes by highlighting medical discrimination against people with Duffy null phenotype, primarily affecting African Americans, whose naturally lower neutrophil counts lead to reduced chemotherapy doses and excluded clinical trial participation despite no increased infection risk.

Host Roz is joined by Timucin Taner, MD, PhD and Dami Ko, PhD to discuss the key articles of the May issue of the American Journal of Transplantation. Dr. Timucin Taner is a professor of surgery at Mayo Clinic, Rochester, MN. Dr. Dami Ko is an assistant professor at the School of Nursing at Northeastern University. [02:51] Development and validation of the Neuro-Score: a specific scale to detect and monitor cognitive impairment in kidney or liver transplant recipients Editorial: Cognitive impairment after liver and kidney transplant: An easy way to check [14:16] Randomized trial investigating the utility of a liver tissue transcriptional biomarker in identifying adult liver transplant recipients not requiring maintenance immunosuppression [20:46] Donor-specific immune senescence as a candidate biomarker of operational tolerance following liver transplantation in adults: Results of a prospective, multicenter cohort study Editorial: Acquired immune tolerance 2.0 [29:10] Major histocompatibility complex and peptide specificity underpin CD8+ T cell direct alloresponse Editorial: Direct and indirect allorecognition—not so different after all?

Description: Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. Melanie Ruffner, an Attending Physician with the Division of Allergy and Immunology and the Center for Pediatric Eosinophilic Disorders at Children's Hospital of Philadelphia. Dr. Ruffner describes her work in clinic and the paper she co-authored about pediatric and adult eosinophilic esophagitis (EoE). She covers the questions they considered in the paper and the conclusions they reached. Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.   Key Takeaways: [:49] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda. Ryan introduces co-host Holly Knotowicz.   [1:17] Holly introduces today's topic, pediatric and adult eosinophilic esophagitis (EoE), and introduces today's guest, Dr. Melanie Ruffner.   [1:23] Dr. Melanie Ruffner is an attending physician with the Division of Allergy and Immunology in the Center for Pediatric Eosinophilic Disorders at Children's Hospital of Philadelphia. Holly welcomes Dr. Ruffner to Real Talk.   [1:50] As an attending physician in the Center for Pediatric Eosinophilic Disorders at Children's Hospital of Philadelphia, Dr. Ruffner sees patients who have eosinophilic esophagitis and other eosinophilic disorders, including eosinophilic GI tract disorders.   [2:09] Dr. Ruffner also leads a research group that studies how the immune system causes inflammation in response to certain foods, leading to EoE.   [2:20] Inflammation in the esophagus is tied to other diseases like epithelial barrier dysfunction and fibrosis.   [2:28] Our bodies use many different proteins that allow cells to communicate with one another. One type of signaling protein that causes inflammation is called cytokines.   [2:41] Dr. Ruffner's group is interested in how these signaling proteins called cytokines interact with epithelial cells and how that impacts the oral function of the esophagus in patients with EoE.   [3:02] In training, Dr. Ruffner became interested in eosinophilic esophagitis and other non-IgE-mediated food allergies because we don't have a lot of clear treatments or clear mechanisms that cause them.   [3:21] Dr. Ruffner felt there was a lot of work to be done in that area. It was rewarding to be in clinical encounters with those patients. Often, patients had spent a long time trying to find out what was happening and to find a treatment plan that worked for them.   [4:31] Dr. Ruffner's group sees some patients who have eosinophilic gastroenteritis and patients who are referred for hypereosinophilia with impacts of inflammation in other organ systems.   [5:06] Dr. Ruffner co-authored a paper about pediatric and adult EoE published in the Journal of Allergy and Clinical Immunology. It explored if EoE in pediatric patients and adult patients is a spectrum or distinct diseases.   [5:29] EoE is a chronic allergic condition that affects the esophagus. The esophagus carries food from the mouth to the stomach. In people with EoE, the immune system overreacts to foods and causes inflammation in the esophagus.   [5:47] Eosinophils are a type of white blood cell. Eosinophils infiltrate the tissue in the esophagus of people with EoE. Doctors look for eosinophils in the tissue of the esophagus as a sign that inflammation in the esophagus is EoE.   [6:04] The symptoms of EoE can vary in children and adults. That was one of the things the doctors were interested in when they were thinking about this paper. There are no blood or allergy tests that make it easy to diagnose EoE, which requires an endoscopy.   [6:31] An endoscopy is performed by a gastroenterologist. The gastroenterologists look at the appearance of the esophagus and take biopsies.   [6:49] A pathologist counts the eosinophils in the tissue to determine if there are eosinophils present. If there are more than 15 eosinophils in the high-powered field of the microscope and symptoms and clinical conditions are present, EoE is diagnosed.   [7:25] One of the variables Dr. Ruffner considers is that symptoms can be different in children versus adults. In older adolescents and adults, the classic symptom is difficulty swallowing or dysphagia. That is often caused by fibrosis in the esophagus.   [7:54] In younger children this is often not how EoE presents. They may vomit or refuse food. They may experience more weight loss. Symptoms vary over the lifespan. Pediatric EoE symptoms of nausea and abdominal pain can also show up in adults.   [9:54] Atopy refers to allergic conditions. In the paper, a history of atopy means a history of allergic conditions, like atopic dermatitis, IgE-mediated food allergy, allergic rhinitis, or asthma.   [10:37] These disorders tend to cluster together, over time, because they share many common genetic risks. They cluster in families because some of the genetic risks are the same. Not every family member will have the same atopic or allergic conditions.   [11:07] In families, perhaps one person will have atopic dermatitis and allergic rhinitis while another will have atopic dermatitis, allergic rhinitis, asthma, and EoE. They may have inherited different genetics or had different environmental exposures.   [11:50] Ryan says that describes his family. They each have different atopic conditions. Ryan got them all! Dr. Ruffner says it describes her family, as well.   [12:26] Dr. Ruffner says it's understandable for families to stress about atopic conditions. Unfortunately, right now, there's no way to predict who will develop which atopic conditions. It's on the minds of the medical and research communities.   [13:10] IgE is an antibody that binds to food allergens and mediates anaphylaxis, usually within 30 minutes, with hives, vomiting, and difficulty breathing. Not everyone with a diagnosed food allergy will be given an epinephrine auto-injector.   [13:44] IgE-mediated food allergies are influenced by type 2 cytokines. Cytokines are immune system signaling proteins that have been labeled as groups. The group that is involved in allergy most heavily is under the label type 2.   [14:15] These type 2 cytokines are responsible for influencing B cells to make IgE. In the tissue in EoE, we find that there is a large amount of these type 2 cytokines present.   [14:37] This is quite relevant because dupilumab, the monoclonal antibody that has been approved to treat EoE, targets type 2 inflammation by blocking type 2 cytokines.   [16:04] Dr. Ruffner says one of the biggest challenges in the field of EoE is we don't have a way to stratify who should get which treatment for EoE. Patients have to choose between diet and pharmacologic therapy.   [16:48] We don't know enough about the inflammatory profiles to give any patient the specific guided information that one therapy would be better than another.   [17:11] Pediatric and adult patients are given the same treatment options. Some dosing, such as proton pump inhibitors and dupilumab, is weight-based so different doses are needed.   [17:36] Over time, people's needs change. From early school age to when people leave home, they may have very different needs. They may do well on diet therapy when their diet is controlled by parents, but, on their own, that may not be the best option for them.   [18:20] Therapy may change over time to support each patient's individual goals. It can be challenging because therapies are imperfect. Each therapy has a percentage probability of success. Not every therapy is guaranteed to work for every individual.   [19:01] There is some flexibility and possibility of switching between therapies to support people. Ryan shares one of his experiences in changing treatments.   [20:03] Some patients are stable on a therapy for a time but then see symptoms creep back up. Dr. Ruffner strongly suggests they talk to their care team for an endoscopy and biopsy to see if they need to switch therapy and if their diet has changed.   [21:31] In young children, Dr. Ruffner sees a much higher incidence of feeding refusal. The child may have a preferred food or a preferred texture like puree, long past when that would be appropriate for the age.   [22:41] It can be very difficult to move past this learned behavior even if remission is achieved through therapy. The child may need feeding therapy to help with that. [22:59] Feeding behaviors in older individuals may be much more subtle. Talk about them with your care team. Needing water to eat, cutting food very small, and fearing to eat around people are common eating behaviors to discuss in older patients.   [23:53] These eating behaviors affect people's well-being deeply because they affect how social they feel when they are around people. Ideally, you want to be around people and share in social times.   [24:16] Holly has used these eating behaviors herself and notices them in other people. When adults come to her for therapy, she asks how many times they refill their water when they eat, and if food ever gets stuck. They are surprised that those are symptoms.   [26:01] Dr. Ruffner says it's important to recognize the difference in symptoms in diagnosing EoE. The main risk factor of EoE is fibrosis, over time. The thought is that early in EoE there is an inflammatory phenotype, but later, there is a fibrotic phenotype.   [26:51] The phenotype refers to the presentation or characteristic of disease. What is the appearance at endoscopy? What do we see in the biopsied tissue? Is there fibrosis or not?   [27:15] This is the crux of the paper: Is this on a spectrum, that the inflammation is driving the fibrosis, or are these two different things altogether? There is some evidence to suggest that the inflammation contributes to this fibrosis over time.   [27:40] One thing that is missing is following a group of patients from the start and having that evidence. There is mechanistic evidence from studies to show that inflammation can contribute to fibrosis. That was one of the discussions in the paper.   [28:29] In endoscopies, something that can be seen with fibrosis or fibrostenotic features is more of an appearance of rings and narrowing of the esophagus. A proportion of patients with strictures or narrowing need to have them dilated.   [29:11] For patients who have dilation, it can help with symptoms significantly. When pathologists look at the tissue with fibrosis, they can see changes in the protein structure. There is more collagen and other changes in the tissue, causing fibrosis.   [30:03] Some patients use adaptive eating behaviors to adapt to significant changes in their esophagus and go for many years without being diagnosed until they present with an impaction when food becomes stuck in their esophagus.   [30:46] This makes EoE a challenging disorder for many because it can be very difficult to diagnose. The journey to a diagnosis is very individual. As a group, adults are much more likely to have fibrosis, leading to dysphagia, strictures, or impaction.   [31:25] Statistically, across all patients, you see fibrosis more in adults than in children.   [32:42] In the paper, Th1 cells are mentioned. Th1 is an immune system term referring to a cell that produces interferon-gamma. Studies show there may be differences in interferon signaling in different age groups but it needs to be studied further.   [33:57] Dr. Ruffner's team had looked at a small group and saw that interferon signaling seemed to be relatively similar between children and adults. Both CD4 and CD8 T cells (types of immune system cells) are potentially producing interferon in the esophagus.   [34:32] More study needs to be done around those immune system cells and their potential significance in EoE, if any.   [35:33] The paper suggests that EoE in children and adults is essentially a spectrum of the same disorder rather than distinct diseases.   [35:42] Aspects of immunology, responses to different treatments across children and adults, the similar responses to diet and different medications, and over time in the same individuals, indicate these are changes and complications over time.   [36:41] Dr. Ruffner suggests that medical researchers need to understand which patients are at the highest risk of complications and work to identify the best treatments to prevent those.   [37:14] Dr. Ruffner is thinking about the response to proton pump inhibitor therapy. One of the things she is looking at is whether or not proton pump inhibitors affect how eosinophils migrate into the tissue.   [37:33] They are finding that it seems that PPIs can decrease the degree of migration of eosinophils into the tissue. They are very interested in looking at that. Ryan says when Dr. Ruffner gets that paper published, she'll have to come back on the show!   [38:06] Ryan thanks Dr. Ruffner. For our listeners who would like to learn more about eosinophilic disorders, including EoE, please visit APFED.org and check out the links in the show notes.   [38:15] If you're looking to find a specialist who treats eosinophilic disorders, we encourage you to use APFED's Specialist Finder at APFED.org/specialist.   [38:24] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at APFED.org/connections.   [38:33] Ryan thanks Dr. Ruffner for participating in the podcast episode. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda for supporting this episode.   Mentioned in This Episode: Dr. Melanie Ruffner, MD, PhD, Attending Physician with the Division of Allergy and Immunology and the Center for Pediatric Eosinophilic Disorders at Children's Hospital of Philadelphia “Pediatric and adult EoE: A spectrum or distinct diseases?” by Stanislaw J. Gabryszewski, Melanie A. Ruffner, and Jonathan M. Spergel   APFED on YouTube, Twitter, Facebook, Pinterest, Instagram Real Talk: Eosinophilic Diseases Podcast apfed.org/specialist apfed.org/connections   Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, Regeneron, and Takeda.   Tweetables:   “EoE is a chronic allergic condition that affects the esophagus. The esophagus carries food from the mouth to the stomach. In people with EoE, the immune system overreacts to food allergens and causes inflammation in the esophagus.” — Dr. Melanie Ruffner   “In EoE, there are no blood or allergy tests that make it easy to diagnose EoE without an endoscopy.” — Dr. Melanie Ruffner   “Is EoE on a spectrum, that the inflammation is driving the fibrosis, or are these two different things altogether? There is some evidence to suggest that the inflammation contributes to fibrosis over time.” — Dr. Melanie Ruffner   “When pathologists look at the tissue with fibrosis, they can see the changes in the protein structure.” — Dr. Melanie Ruffner   “There are some folks who have adapted their eating behavior quite significantly and may have quite a number of chronic changes in their esophagus that they have adapted around, and they go for many years without being diagnosed.” — Dr. Melanie Ruffner

An unexpected link between KLRG1 and PD-1, two key immune system proteins, was revealed in a study recently published in Oncotarget. This discovery could help explain why some cancer immunotherapy treatments are less effective for certain patients and lead to new therapeutic strategies. How the Immune System Fights Cancer The immune system is a powerful defense mechanism against cancer, with CD8 T cells acting as the primary soldiers. These specialized immune cells identify and destroy tumor cells. However, cancer can cleverly evade this attack by manipulating immune checkpoints—natural “breaks” on the immune system that prevent it from overreacting and damaging healthy tissue. One of the most studied checkpoints is PD-1 (Programmed Death-1), a receptor on T cells that acts as an “off switch” when activated by tumor cells. This mechanism suppresses the immune response, allowing cancer to grow without control. In response, researchers have developed treatments called PD-1 inhibitors, which block this “off switch” and keep T cells active. The Study: Investigating KLRG1 and PD-1 in Tumor-Fighting T Cells In the study titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells,” Dr. Steven A. Greenberg from Harvard Medical School analyzed publicly available gene expression data from various cancer types, including lung cancer, melanoma, and colorectal cancer. His goal was to identify immune-related proteins that could complement existing therapies, such as PD-1 inhibitors. Full blog - https://www.oncotarget.org/2025/01/28/a-new-approach-for-cancer-treatment-the-surprising-relationship-between-klrg1-and-pd-1/ Paper DOI - https://doi.org/10.18632/oncotarget.28679 Correspondence to - Steven A. Greenberg - sagreenberg@bwh.harvard.edu Video short - https://www.youtube.com/watch?v=PME2xfyYN18 Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28679 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, immunotherapy, KLRG1 About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - January 21, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 20, 2025, titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells." The study, authored by Dr. Steven A. Greenberg from Harvard Medical School, has discovered a potential new way to improve cancer treatment by studying two key molecules found in immune cells: KLRG1 and PD-1. Analysis of data from cancer patients and healthy individuals revealed that these molecules work in opposite ways in cancer-fighting cells, suggesting that targeting both at the same time could enhance the effectiveness of cancer immunotherapy. “Much effort in the field of immuno-oncology has involved the study of combination therapies, including combinations involving blockade of more than one T cell inhibitory receptor.” The immune system helps fight cancer through specialized cells called T cells. Treatments known as checkpoint inhibitors, which block proteins like PD-1, have been successful in helping these cells attack cancer. However, combining different checkpoint inhibitors has not always provided the expected improvements. This new research focuses on KLRG1, a lesser-known protein, and its relationship with PD-1. The findings suggest that targeting both markers simultaneously could create a stronger and more effective immune response against cancer. Most existing immunotherapy treatments focus only on blocking PD-1, which is commonly found in “exhausted” T cells that struggle to fight cancer. In contrast, KLRG1 is linked to more active, mature T cells that are better at attacking tumors. By blocking both PD-1 and KLRG1, new treatment strategies could help patients with hard-to-treat cancers, such as lung cancer, melanoma, and colorectal cancer. KLRG1 has not been widely studied in cancer immunotherapy, but this research highlights its potential to revolutionize treatment strategies. While current combinations of checkpoint inhibitors have shown only limited improvements, using therapies that target both PD-1 and KLRG1 could lead to more significant and long-lasting benefits. “Whereas much of the T cell inhibitory drug development efforts over the last decade have been focused on combinations of expression-correlated inhibitory receptor targets, the targeting of anti-correlated inhibitory receptors has greater potential to produce supra-additive benefit, and KLRG1 has this distinct property.” Further studies and clinical trials are needed to explore how combining PD-1 and KLRG1 treatments could benefit different types of cancer. If successful, this strategy could open the door for the creation of new combined immunotherapies. DOI - https://doi.org/10.18632/oncotarget.28679 Correspondence to - Steven A. Greenberg - sagreenberg@bwh.harvard.edu Video short - https://www.youtube.com/watch?v=PME2xfyYN18 About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Professor Nancy Klimas is interviewed about the mechanisms behind how a nebulised medication caused a remarkable recovery from symptoms of ME/CFS and Long COVID in a small group of individuals and her objective to gain the ability to extend this research into a larger population of people with the hope of finding a viable treatment for these diseases.REFERENCES1 Gil A, Hoag GE, Salerno JP, Hornig M, Klimas N, Selin LK. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent a restropective case series.2 Long COVID the Answers Episode 6:“PEM, Long COVID & It's Management featuring Professor Todd Davenport”3 Appelman B, Charlton BT, Goulding RP, Kerkhoff TJ, Breedveld EA, Noort W, Offringa C,Bloemers FW, van Weeghel M, Schomakers BV, Coelho P., Wüst Rob.C Muscle abnormalitiesworsen after post-exertional malaise in long COVID. Nature communications. 2024Jan 4;15(1):1-54 Oldham WM, Lewis GD, Opotowsky AR, Waxman AB, Systrom DM. Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing. Pulm Circ. 2016 Mar;6(1):55-62. 5 Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Aug;160(2):642-651. 6 Singh I, Joseph P, Heerdt PM, Cullinan M, Lutchmansingh DD, Gulati M, Possick JD, Systrom DM, Waxman AB. Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing. Chest. 2022 Jan;161(1):54-63. 7 Joseph P, Pari R, Miller S, Warren A, Stovall MC, Squires J, Chang CJ, Xiao W, Waxman AB, Systrom DM. Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest. 2022 Nov;162(5):1116-1126. 8 Open Medicine Foundation: Dr. David Systrom Discusses OMF's LIFT Clinical Trial

JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.”  Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us.  Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off.  Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance.  Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes?  Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations.  Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study?  Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort?  Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil?  Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in.  Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial.  Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees.  Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology.   And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr Philip Smith, Digital and Education Editor of Gut and Honorary Consultant Gastroenterologist at the Royal Liverpool Hospital, Liverpool, UK, interviews Professor Jihui Hao from the Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China, on the paper "CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells" published in paper copy in Gut in December 2024. A close transcript of this podcast is available at this link: https://bit.ly/3Ox8Io2 Please subscribe to the Gut podcast on your favourite platform to get the latest podcast every month. If you enjoy our podcast, you can leave us a review or a comment on Apple Podcasts (https://apple.co/3UOTwqS) or Spotify (https://spoti.fi/3Ifxq9p).

In this week's episode we'll discuss how CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia; learn more about the effect of ATM germline pathogenic variants on the outcomes in children with ataxia-telangiectasia and hematological malignancies; and discuss the preclinical efficacy of a potent, selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias.Featured Articles:CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemiaATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematologicalmalignanciesPreclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) inKMT2A- and NPM1-altered leukemias

A video snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Shane Crotty: A Landmark Study on Upper Airway Mucosal ImmunityTranscriptThis is the first time a Ground Truths podcast is being posted simultaneous with a new publication, this one in Nature, by Professor Shane Crotty and his colleagues at La Jolla Institute for Immunology. Shane is one of the leading immunologists and virologists in the country; he and his group published in 2020 the first detailed analysis for how our immune system responds to SARS-CoV-2. Shane also, among many other notable contributions during COVID, illuminated the role of hybrid immunity vs COVID, the differences between and additivity of vaccination and infection.Today's paper in Nature is indeed a landmark contribution doing something that hasn't been done before—to understand the underpinnings of mucosal immunity of the upper airway. 100 participants had monthly nasal and nasopharyngeal swabs throughout the pandemic. With a median of >100,000 cells per swab recovered, they undertook single-cell sequencing and full characterization of the cells (tissue-resident memory B cells, CD4+ and CD8+ T cells, germinal center follicular helper T cells and B cells, etc.) to determine optimal immune protection of the upper airway, the effect of infections by different variants, breakthrough infections, vaccination, and age.Here is the transcript of our conversation about the new report with links to the audio:Eric Topol (00:06):Hello, it's Eric Topol with Ground Truths, and with me today is Professor Shane Crotty from the La Jolla Institute of Immunology (LJI), not too far away from where I work at Scripps. And Shane has been a go-to immunologist colleague here in the Mesa, and he and his colleagues were the ones that really first published the response to SARS-CoV-2 as far as the immunologic response. And today we're doing something very unique. We're going to go over for the first time in the two year plus history of Ground Truths, going to have a publication with at least simultaneous or near simultaneous podcast. Shane, welcome and congratulations on this really important paper in Nature.Shane Crotty (00:57):Thanks, Eric. Thanks for having me. Yeah, somebody asked if I was going to go over to Scripps for the podcast and I was like, yeah, we could.Eric Topol (01:06):You could. You could. But no, it's good. And it's nice having the logo of this great institute you work at right in the right corner. And you've done so many contributions with your colleagues at La Jolla Institute. It's really a privilege to have a chance to learn from you and particularly about what we're going to talk about today, which is mucosal immunity to upper airway infections, which is especially germane to COVID. And we're actually in the middle of a significant wave of COVID right now. And I guess it would maybe be fair to say, Shane, that we've never truly understood the underpinnings, the real details of upper airway mucosal immunity. Is that a fair statement?Shane Crotty (01:53):Yeah, it is a fair statement.Eric Topol (01:56):Okay. So today we're going to crack the case. This paper from you and your colleagues, of course, you're the senior author and first author, Sydney Ramirez did a remarkable study. I mean, just extraordinary. This is why we're doing a special podcast about it. Maybe you could just kind of give us the overview of the design because you were doing things that haven't been done before.Shane Crotty (02:24):Sure. And, I would say the genesis even of it goes back to what you were introducing. I mean, during the pandemic, we like a lot of scientists spent a lot of time and energy trying to help understanding immune responses to this virus, and immune memory to this virus, and what was involved in protective immunity. And we're certainly proud of the work that we did. And it was hard work. And after a while we were exhausted and we stopped.Shane Crotty (02:59):And then we came back to it after a while and said, well, the virus is still here. And so many people have contributed so much to better understanding the virus and creating vaccines. But there are clearly still things we don't understand. What are those biggest knowledge gaps and where might we be able to contribute? And really to me the biggest one was location, location, location. This is a virus that infects your nose, infects your upper airway—your nose, and throat, and oral cavity. And then obviously if you get severe disease, the severe disease and death are from the lungs. And it's just been a big knowledge gap in terms of understanding what actually occurs in those tissues immunologically and what is associated with protective immunity or what could be associated with protective immunity. And sort of looking forward what might be helpful for mucosal vaccine development from things that we could learn.Shane Crotty (04:12):So we started from what we would call the basics, and what does immune memory look like in the upper airways in normal people? And that hasn't been available really even in, and we started this two years ago, even in the biggest atlases published of the human body. There was no upper airway tissue representation at all. And that's because technically it's just tough to access and difficult to reproducibly get at. And so, we recruited people to a group of 20 to 30 people to come to LJI once a month, and just started testing out, published and unpublished sampling techniques to see were there ways where we could reproducibly sample immune cells in the upper airways from people. And once we got things, so the keys for us were you got to have enough cells that you can collect to learn something from. And luckily with modern techniques of flow cytometry and single cell sequencing, you don't need that many cells. And so, we could get a hundred thousand cells on a swab and that's enough to do a lot with. And second, how reproducible was it? So we showed, we had people come in every month for a year and we could reproducibly find the same things in their swab; same cell types in their swabs. And the third thing was that people would come back.Shane Crotty (06:05):We found that if you have good nurses doing the techniques, we could find ways that this would be a sampling approach that was tolerable and people would come back for repeat measures, which is really valuable to see what's happening in people over time. So that was what we started from in the study and built from.Eric Topol (06:27):And if I am correct, you sampled two places with the swabs, one in the nose and one of the throat. Or, I think one which you have in the paper as the MT for something about the median nasal turbinate and the other adenoid in the back of the throat. Is that right?Shane Crotty (06:50):So all the sampling is a swab into your nose. And when we were doing that, we were really excited to see the diversity of immune cells, particularly T cells and B cells, memory T cells and B cells that we isolated. They're like, wow, there's actually a lot of interesting immune memory up in there. And the lab said, oh, by the way, we're seeing T follicular helper cells (TFH). Now that happens to be my favorite cell type.Eric Topol (07:22):Why is that, Shane? Of all the cells, why do you say that's your favorite? I know you publish a lot on it.Shane Crotty (07:31):Because those are the T cells that are required for basically all neutralizing antibody responses. All high-quality antibody responses depend on—almost all high-quality antibody responses depend on—T cell help. That T cell help comes from T follicular helper cells. Antibody evolution is certainly one of the coolest processes of the immune system. And all of that depends on T follicular helper cells. So the fact that for example, you could get Omicron neutralizing antibodies even after only being vaccinated with ancestral vaccine, that's the immune system making guesses of what variants would look like. And those guesses come about through this antibody evolution that's driven by T follicular helper cells. So, it's really one of the most brilliant things the immune system does, and that's a cell type that's really key, but those processes happen in lymphoid tissue. That's what happens in lymph nodes and spleen. And here we were sampling epithelium, your nasal epithelium, so the cells didn't really belong there.Shane Crotty (08:37):And so, that's what turned the study in another direction. And we said, okay, let's figure out why is it that these cells are present in these swabs? And we had a couple of possibilities. One possibility was that the swab was going all the way back to the posterior wall of your nasopharynx, your top of your throat and sampling adenoid tissue. So adenoid tonsils and adenoids are a true lymphoid tissue and they're a mucosal lymphoid tissue. And so, we came up with multiple ways to validate that that's what we were testing. And in fact, it was the Sydney Ramirez, a clinician, and the ENTs involved who said, well, let's just look. And so, they actually did endoscopies with the swab to actually see where the swab went. We've got videos of the swabs going into the adenoid crypt in the back, and then we've got measurements of here are the cells that you find on those swabs.Shane Crotty (09:58):And what's cool about it is that, yes, so we did studies with two sets. We then shifted to doing studies with two sets of swabs. One where we essentially went “halfway back” where we were detecting that epithelium of your nasal passages and then one where it was all the way back and detecting the adenoid lymphoid tissue. So here we've got two different sites in your upper airways that are about an inch apart, and we're detecting essentially completely different cells of the immune system at those two places. And we tend to think of the cells present in that epithelial tissue as probably the sentinels, the cells that are sitting there that can potentially immediately react and try and protect you against a viral or bacterial infection. Whereas the lymphoid tissue, the adenoids, is really about generating the immune responses in the first place and priming immune responses. And that's where these germinal centers can occur, which are where the TFH are where you can get antibody evolution. And so, we found in the course of the study that with this non-invasive technique that we can.Eric Topol (11:14):By the way, I don't want to be signing up for the one way up there because I mean just a mid-nose enough for me. So wow, I got to give credit to your study participants for coming back every month for a year to have that. Some people call it a brain biopsy.Video of swab of nasopharyngeal tissueShane Crotty (11:33):Right. So I will tell you, it is a different experience than the COVID nasopharyngeal swab might've gotten through your car window. If you're actually sitting down in a comfortable space and there's a nurse doing it with these particular goals. We really found, we had a hundred people in the study and a total of 300 swabs, and the vast majority of people came back if we asked them to.Eric Topol (12:06):That's great.Shane Crotty (12:07):And we're certainly very thankful for the volunteers. Obviously they were volunteering in the first place to participate. So I'm a little hesitant about the video because I've told people to not show it to potential volunteers because it definitely doesn't encourage you to volunteer. You're like, wait, that's what's happening? But actually, I've had it done on me.Video of the swab to the nasopharynx for adenoid (lymphoid tissue) access.Eric Topol (12:37):Not that bad.Shane Crotty (12:39):It's really pretty compelling. And by doing these repeated samples, we actually now have the capacity to look at ongoing immune responses like after an infection or vaccination in people and see how that results in the immune system changing and what might be the source of the protective immunity that comes up. So we've actually got data in the paper looking at this antibody evolution in real time. So we've got affinity maturation of B cells occurring in just normal healthy adults of mucosal B cells against COVID. And so, that's really helping us learn what's possible, basically to figure out, okay, if you're going to try and make a vaccine, what types of immune cells are even possible to generate in this tissue? And where might you try and generate them? Or if you're trying to study some disease state, what are types of cells that might be problematic?Eric Topol (13:45):Yeah, I mean, I think the idea that so many of us have been pushing for a nasal vaccine to induce mucosal immunity because, as you know very well, the current shots are not very good at any durable or substantial protection from upper airway infections of COVID or SARS-CoV-2 and other infections. So I think one of the most important parts of this report is that it lends itself well to helping towards artificially, if you will, make a vaccine to get the protective features that you were able to identify. Maybe you could just [speculate], if you had the ideal nasal airway, what would the cellular profile look like?Shane Crotty (14:44):Ah, I see. Yeah, great question. So, first of all, antibodies are great. So most of my career has been dedicated to most licensed vaccines. The correlate of protection is antibodies. Antibodies clearly can be protective, and if you can get them that's excellent, so certainly I would want, in terms of the non-cellular component, I would want antibodies present, neutralizing antibodies present in it.Eric Topol (15:26):Are these IgA or IgG?Shane Crotty (15:31):Yeah, in an ideal situation, what would I want? I'd want a mix of both, basically. The IgAs look like they have a little more protective efficacy, but the IgGs, just at a molecular level have a longer half-life, stick around a little. So yeah, I'd want both. And then really the premise for most of what we do is saying, in situations where antibody isn't enough or the antibodies don't stay around long enough, or you've got a variant that now obviates the protective efficacy of that particular antibody, are there other types of protective immunity you can have? And the immune system has other stuff besides antibodies for a reason. Of the lymphocytes in your blood, most of them aren't antibody producing cells. Most of them are other things. And so, well sticking with adjacent to antibodies, those antibodies in the mucosa, I'd want them to be made by cells that were literally right there. So plasma cells living in that site so that you've got basically the highest concentration of antibodies you can get because they're not having to diffuse through the whole body. They're just already at their highest concentration right there. Now antibodies come from B cells, that's what encodes the antibodies.Shane Crotty (17:03):And so, the B cells can make neutralizing antibodies if it turns out that you haven't made enough neutralizing antibodies, or if there's a variant that escapes those, maybe there are other B cells that could make, once you get infected, more B cells that could make more antibody rapidly infection, or B cells that recognize this variant that is mismatched to the current antibodies you have. But memory B cells are basically a library of different antibody specificities representing different guesses about what viral variants or structures might look like. And so, I would want memory B cells in that upper airway tissue that could reactivate quickly. There are memory B cells in your blood and we don't know how long it takes. And that's one of the reasons we're hoping we and others build upon this study. But it might take, let's say five days for memory B cells to go from your blood into your upper airway.Eric Topol (18:06):Oh, right.Shane Crotty (18:08):That's right, you were already quite sick by that point. Instead, if memory B cells are right there, as soon as virus showed up, they got activated. Now maybe after (we're not sure yet), but maybe after 48 hours those cells are now activated and doing something useful. That would be optimal. So then we can pivot to the T cell side. So there's a fantastic recognition that T cells being physically present in tissues, tissue resident memory cells, as they're most often called, can really have fantastic protective capacities. From a lot of mouse model systems where you can see T cells are in the skin or the liver, or whatever [tissue] are already there, they're more protective than if the cells are in the blood. So if you could also have T cells essentially permanently parked in the epithelium of your nasal passages and in the adenoid, hopefully those could essentially be sentinels for protective immunity, and as soon as you get infected, those T cells would reactivate and start killing off infected cells. 'That's the mix that I would want to see. And I think there's at least some reasonable evidence in the context of COVID that people who have T cells in their upper airways maybe manage to control the virus so quickly that it's a subclinical infection; they never notice when they get infected. And so, building on those types of observations, that's what I would want.Eric Topol (19:56):That sounds good. I like that. I'd like to have that in my nasal airway. Now, just to make sure I've got this, what you found, of course, the memory B cells, the T cell memory, CD8+, that is the cell-killing T cells that you mentioned, the resident T cells. One clarification on that, they are not really going to do much until there's been some cells that have been infected with the virus, right? Then they come alive and kill those cells. So they're not immediate, but they can work pretty quickly still though, right? If they're resident T cells?Shane Crotty (20:45):Yeah, in theory it might take as little as 12 hours for a virus to infect a cell, and then you get some antigen presentation on that cell that could activate the T cell.Eric Topol (20:58):And that's all happening perhaps within the incubation phase of the virus, right?Shane Crotty (21:07):Correct. That's a tough thing to study, but conceptually that's the way people tend to sketch it out.Eric Topol (21:13):Right. Now the other part of the story is, and you alluded to it earlier, is the lymphoid tissue up there, higher up where there are these germinal centers; is there anything different you want in these germinal centers? Do they contribute to mucosal immunity that you haven't already mentioned?Shane Crotty (21:36):So they really contribute in this forward looking sense or really in the classroom kind of sense. The germinal centers are where you're basically teaching the B cells in advance of seeing the infection either with your vaccine or with your previous infection, evolving better B cells and better antibodies and hopefully instructing them where to go reside to then be ready for the next infection. If you get really great protection that next time, hopefully then you don't need to start.Eric Topol (22:14):Right. So it's like the training grounds for this coordinated response, I guess. Now you also noted this, I mean this is a rich paper, which is we're illuminating something that's never been done before in human beings. I mean it's pretty damn important and impressive. But you also found that you had an age relationship. Can you tell us about that?Shane Crotty (22:39):Sure. This is one of our favorite parts of the study. I'd say in particular for several of the clinicians who were involved, because the general conversations people have about upper airway lymphoid tissue, like your tonsils and including your adenoids, is that adults don't really have functional lymphoid tissue in the upper airway that your tonsils atrophy by the time maybe you're 20 or something. So, immunologically, functionally, what that means is if you have let's say an intranasal vaccine or you get infected with a new [virus] like SARS-CoV-2, if those would normally be the sites that start your immune response, where does it now happen? And instead what we saw was, we had such a diverse group of people in our studies—we realized we had people from age 18 to 68—and so we could directly ask, in normal healthy individuals across a large age span of adulthood is there functional mucosal lymphoid tissue? And the answer was yes, it was there. But it definitely declines over time, and it's declining on a log scale. Our simplest statement was that 75% of everybody we sampled still had functional tissue, but the younger the people were, the more functional it was, and the more germinal centers actually we saw; again these training grounds.Eric Topol (24:35):So this is really important because we know for COVID and obviously for influenza and other respiratory infections that people of advanced age are much more susceptible. And here you are finding something that supports that ,and it's almost like, the thymus, it involutes. After that, what age 20, and our lymphoid tissue [involutes]. We're just set up to fail. Old codgers, like me we're defenseless, I guess, right?Shane Crotty (25:12):So what I've liked about that in a positive sense is that it's not that all of these things go to zero. Like for example, naive T cells are definitely less abundant in people over the age of 60 than under, but they're not zero. And the mucosal lymphoid tissue is definitely less abundant in people over the age of 60, but in most people it still wasn't zero. And I always think about these things from a vaccine immunology perspective, and fundamentally the difference between getting vaccinated and infected frequently is that the whole point of the vaccine is you get to generate the immune response on your own time. And so, even if you're starting with five times fewer T cells or five times fewer germinal centers, if you're getting to do all that training ground in advance, you can end up with just as many bispecific T cells as a 20-year-old or just as many memory B cells as a 20-year-old because these things occur on an exponential scale because of the cell divisions. And so, it might take you three extra days, for example, to get to the same level, which again, if you're racing a virus, can be the difference between life and death. But if it's not a race and if you're doing it in the context of a vaccine, it's a much smaller factor. And that's some of what we've been trying to learn.Eric Topol (26:42):Now we only have started to scratch the surface of your findings. One of the things that drives me nutty in reading papers, especially from great immunologists like you, is that in each figure there's like 20 different panels. We get to one of the figures, figure three is all the way to panel W. I mean that starts with A. That gives you a little impression of the data. It's rich, another one goes to N or R. I mean we're talking about a lot of data. So I've only started to really deconvolute what you've done here, which is just an amazing study. But what are some other things that we should touch on before wrapping up?Shane Crotty (27:35):A lot of the goal in this study was to establish baselines of what is normal in humans in the upper airways. And that's one reason why in this case there actually are a lot of figure panels because we could work out a bunch of individual parts of the immune system that really hadn't been characterized in this way before. And something we really cared about was durability of immune memory. It's often talked about, well, mucosal responses are inherently short-lived. And we're like, well, what does that mean? Does that mean there's just no memory? Is it different kinds of memory? And so, this is the first measurement of memory B cells in this tissue in an antigen specific way. And we were doing it in people who had had recent COVID breakthrough infections. And we saw really the mucosal memory was stable for six months. And so, to me that's quite encouraging that it's not one month and it's gone, at least with an infection, it's at least six months and it looks like it'll project out for substantially longer.Shane Crotty (28:53):Amongst those cells, many of them are IgA. IgA is this antibody isotype that's particularly mucosal associated. And only 5% of the memory B cells circulating in blood were IgA. Whereas many of the memory B cells in the local tissue were IgA, which we think is also telling us that there's a lot of immune memory and the immune system in this tissue that we're probably not sampling in the blood. And so, sampling blood's great, right? It's accessible and we can learn a lot from it, but it does look like there is some tissue compartmentalization.Eric Topol (29:37):Oh, not a question. And the findings you had of the resident T cell is so indicative of that. And what's really striking, of course Shane, is that as we assess the immune system in people at large, we look at a lymphocyte neutrophil ratio [in the blood], we get almost nothing. And then in the course of the pandemic, you and your colleagues there provided such granular data on B and T cells, CD4 and CD8 T cells, and that you illuminated things that are not done ever clinically. These are research, high tier research labs like yours. The only question I have on before I just wrap up with the nasal vaccine story, interferon wasn't really part of this. As we know SARS-CoV-2 can shut down the interferon response, it's considered a frontline part of the defense. Where does that fit into the mucosal immunity of the upper airway?Shane Crotty (30:46):Yeah, it's really important. And that's in this basic divide we do in the immune system, the innate immune system and the adaptive immune system. So everything I was talking about is the B cells, the T cells, and antibodies. That's all the adaptive immune system. That's all virus specific. And then the innate immune system is the generalists, and really sort of the fire alarm, just sensing some danger. And definitely in COVID interferon is very important. I'm quite intrigued to see if using these techniques. I'm curious to see if some of these other aspects of the immune system can compensate somewhat for the fact that this virus. To me, if this virus has one superpower, it's its incredible ability to evade triggering interferon for as long as it does. And that has this massive cascading effect to almost everything about the pandemic essentially. And so, I'm intrigued by whether in people who have immunity are there ways that these other cells of the immune system or even antibodies can do things when a viral infection occurs, that helps trigger the overall immune system to recognize that something's there, even in the absence of type 1 interferons. That's where I think for now it fits in.Eric Topol (32:14):Well. I think you've so aptly described, not surprisingly, the superpower of SARS-CoV-2, which I think a lot of people haven't realized that it's so good at shutting down that defense system. Now on the basis of you having really gotten this understanding of the mucosal immunity in the upper airway, does this make you think that the nasal vaccine that we aspire to have is more of a reality? Do you kind of know what the ideal profile might look like to keep people healthy and resist infections? Do you think this is achievable in any durable sense at high level success with a nasal spray vaccine?Shane Crotty (33:04):I'm optimistic for several reasons. One is we really saw a lot of different immune memory cell types that were present, that was encouraging and seeing the B cell memory durability for at least six months—pretty flat line for that six months—was encouraging. It looks like the immune system knows how to keep these cells around if it wants to for a significant period of time. We'll have to do more in follow up. But again, it was encouraging. Third, we had some people who were vaccinated only and some people who had breakthrough infections. And really in the vaccinated only, we didn't see T cell memory in the upper airways. And I actually consider that encouraging because it suggests local exposure does give you the memory and exposure in your arm really doesn't. So I think there is something to improve upon. It can be improved upon. And lastly, I get asked all the time, I'm sure you get asked all the time: Why aren't there more intranasal vaccines or inhaled vaccines, more mucosal vaccines in some way?Shane Crotty (34:25):And I think there's more than one reason, but I tend to be very practical, and I think one practical reason is there's very little to measure, to guide you in your vaccine development. If you have six ideas or six constructs that you think might work in humans as a nasal vaccine, you basically just have to pick one, try something, and hoping there's not much you can measure it clinical trials for what might be the type of response even. So for example, the FluMist vaccine, it's the only licensed inhaled vaccine, intranasal vaccine. In adults it doesn't have a clear correlate of protection. If you get vaccinated with that, your circulating antibody responses don't increase, but also increases in nasal antibody didn't correlate with protection well. So, what does that mean? That probably means there's other things going on up there that could be indicative of protection but weren't being measured before. So I'm hopeful with these types of approaches. Now, if you're an intranasal vaccine developer, you maybe have 4, 5, 6, 7, 8 ideas or constructs. If you can try those in a few people and make these different measurements and you've got your favorite immune profile that you might, now you have something to, it's more of an engineering problem. It's not a throwing a dart problem. You're like, yeah, this has given me the type of response that I like and I'm going to try and push this into clinical trials. So those are the things that I'm optimistic about moving forward.Eric Topol (36:04):Well, I love it because we really need it. And if anybody's optimistic that means a lot; it's yours. What you've done here has been quite extraordinary because you defined for the first time really the underpinnings of the mucosal immune response, the upper airway, you did it by age, you did it by variant, you did it by vaccine and infection. And most importantly, perhaps for longer term is you established what are the desirable features to have, which didn't exist before. It seemed like whatever I read for nasal vaccines, they were measuring some IgA or IgG, and they didn't get down to the memory B cells and the tissue resident T cells, memory cells, and all these other things that you found. You did all this single cell sequencing and flow cytometry. The work is just really fantastic. So Shane, just in closing, I just want to congratulate you.Eric Topol (37:05):You made seminal findings along the pandemic. You were the one that really illuminated hybrid immunity, the advantage of if you don't want to have an infection of COVID, but if you did have that and a vaccine, you kind of had some extra synergy, if you will. But here you've done something, you and your team. Unique. Congratulations on that. No surprise that it's in Nature this week. I'm sure a lot of people will share your optimism that we will have something beyond just shots in the future because COVID isn't going away. There's other respiratory pathogens. And finally, somebody did the right study, who knows immunology inside and out. So Shane, thanks very much.Shane Crotty (37:52):Thanks Eric. Very much appreciated particularly coming from you.*****************************************Thanks for listening, reading or watching!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 for 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

On this episode of JHLT: The Podcast, the JHLT Digital Media Editors explore two studies from the July issue of The Journal of Heart and Lung Transplantation. Digital Media Editor Marty Tam, MD, a transplant cardiologist from the University of Michigan in Ann Arbor, hosts this episode.   First, Dr. Tam and Digital Media Editor Erika Lease, MD, FCCP, interview their first guest, Daniel Calabrese, MD, first author on the study “Macrophage and CD8 T cell discordance are associated with acute lung allograft dysfunction progression.” The study's authors sought to tackle challenges behind early detection of chronic lung allograft dysfunction (CLAD) by identifying biomarkers associated with acute lung allograft dysfunction (ALAD) progression to CLAD.   To do this, they collected bronchoalveolar lavage (BAL) cells at the time of ALAD diagnosis and performed single cell RNA sequencing to identify significant differences in 26 unique cell populations across groups, with discordant CD8 T cells and macrophages providing the best discrimination between ALAD with decline from ALAD with recovery and controls.   Dr. Calabrese discusses how his team identified the diagnostic criteria, why the biomarkers might lead ALAD to progress to CLAD, and how the findings might lead to early targeted therapies.   Next, Dr. Tam joins and Digital Media Editor Khue Ton, MD and David Schibilsky, MD, to interview their next guest, David D'Alessandro, MD, the Surgical Director of Cardiac Transplantation and MCS at Massachusetts General Hospital in Boston. Dr. D'Alessandro was the first author on the study “Impact of controlled hypothermic preservation on outcomes following heart transplantation,” which sought to assess the impact of the Paragonix SherpaPak Cardiac Transport System, a device allowing controlled hypothermic  preservation, on rates of primary graft dysfunction (PGD) and post-transplant mortality.   The key finding was that controlled hypothermic preservation was associated with a lower incidence of severe PGD – 6.6% compared to ice storage at 10.4%. In the conversation, Dr. D'Alessandro answers questions about the need for innovation over traditional ice cold storage, the greatest advantages of controlled hypothermic approaches, and the next steps in this research.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt.   Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.

Host Roz is joined by AJT Associate Editor Orla Morrissey, MD (Monash University) and AJT Editorial Fellow Elena-Bianca Barbir, MD (Mayo Clinic-Rochester). [3:16] The respiratory syncytial virus vaccines are here: Implications for solid organ transplantation [19:14] Association between cytomegalovirus viremia and long-term outcomes in lung transplant recipients [35:40] Genetic versus self-reported African ancestry of the recipient and neighborhood predictors of kidney transplantation outcomes in 2 multiethnic urban cohorts [EDITORIAL] Untangling genetic and environmental risks in kidney transplant outcomes: The interplay of self-identified race, genetic ancestry, monogenic risk alleles, and socioeconomic factors [45:15] Low-affinity CD8+ T cells provide interclonal help to high-affinity CD8+ T cells to augment alloimmunity [53:44] Outcomes in solid organ transplant recipients with a pretransplant diagnosis of melanoma

Host Roz is joined by AJT Executive Guest Editor Nadim Mahmud, MD, MPH (University of Pennsylvania) and AJT Editorial Fellow Tina Marinelli, MBBS, MPH&TM,  FRACP (Royal Prince Alfred Hospital).   [03:10] Semidirected Living Donors in Israel: Sociodemographic Profile, Religiosity, and Social Tolerance   [11:54] TCRseq Reveals Selected Donor-reactive CD8+ T cell Clones Resist Anti-Thymocyte Globulin Depletion after Kidney Transplantation   [18:47] Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation   [26:36] Surgical site infections after kidney transplantation are independently associated with graft loss   [38:26] Introduction to Virtual Special Issue, Insights into ACLF: From Pathogenesis to Interventions   [39:21] Immunopathogenesis of acute on chronic liver failure   [43:43] Geographic disparities in access to liver transplant for advanced cirrhosis: Time to ring the alarm!

TWiV reviews a fatal Alaskapox case, MERS in Kenya, diagnostic tests for Nipah and Lassa diseases, HPV vaccination rates in the US, cases of measles in Arizona and Minnesota, hepatitis C virus-derived RNA circles in infected cells, and prevention of respiratory virus transmission by resident memory CD8+ T cells. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Brianne Barker Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode MicrobeTV Discord Server MicrobeTV store at Cafepress Become a member of ASV (asv.org) Research assistant position in Rosenfeld Lab CBER/FDA (pdf) The New City by Dickson Despommier Viruses of Microbes 2024 Fatal case of Alaskapox (AK Beacon) MERS in Kenya (Emerg Inf Dis) Diagnostic tests for Nipah and Lassa (CEPI) Measles in Arizona and Minnesota HCV-derived circular RNAs (PNAS) Resident memory CD8 T cells prevent respiratory virus transmission (Nature) Letters read on TWiV 1087 1:24:33 Timestamps by Jolene. Thanks! Weekly Picks Dickson – Visualizing Science: Illustration and Beyond Brianne – Vaccination from the Misinformation Virus and Invisible Corps Alan – Preventing needlephobia in kids Vincent – Two new Djs I discovered Rosana Nun and Sunset Cartel Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv

Arnold Han, MD PhD, of Columbia University, was awarded the 2022 Beyond Celiac and SSCD Early Career Investigator Grant to investigate the role of CD8 T-cells in celiac disease. Thus far, Dr. Han's innovative research has found more precise ways that gluten sets off damage to the intestine in those who have celiac disease, which he believes could help in the development of innovative approaches to finding a treatment. In our discussion, Han reveals what he's discovered so far through this research and where he hopes it leads in the future. Special thanks to our friends at Crunchmaster Crackers for sponsoring this event! To hear more episodes of Celiac Straight Talk, visit https://www.beyondceliac.org/news-events/podcast-series/. 

Today, you'll learn about the hunt for the elusive sixth taste, a new discovery showing how HIV keeps fighting the immune system even with effective treatment, and the altruism of bees. Sixth Taste “And then there were 6 - kinds of taste, that is.” by Darrin S. Joy. 2023. “How does our sense of taste work?” NIH. 2020. “Researchers Say Ammonium Is the Sixth Basic Taste: Here's What to Know.” by Julia Ries. 2023. HIV Immunity Battle “‘Dormant' HIV has ongoing skirmishes with the body's immune system.” by John Carey. 2023. “10 Things to Know About HIV Suppression.” NIH. 2020. “Spontaneous HIV expression during suppressive ART is associated with the magnitude of function of HIV-specific CD4 and CD8 T cells.” by Mathieu Dube, et al. 2023. Altruistic Bees “Honey bees may inherit altruistic behavior from their mothers.” by Katie Bohn. 2023. “Beyond conflict: Kinship theory of intragenomic conflict predicts individual variation in altruistic behaviour.” by Sean T. Bresnahan, et al. 2023. Follow Curiosity Daily on your favorite podcast app to get smarter with Calli and Nate — for free! Still curious? Get exclusive science shows, nature documentaries, and more real-life entertainment on discovery+! Go to https://discoveryplus.com/curiosity to start your 7-day free trial. discovery+ is currently only available for US subscribers. Hosted on Acast. See acast.com/privacy for more information.

Klaus Früh visits the Incubator to discuss his career and his work on cytomegalovirus-vectored vaccines which are unique in their ability to persistently maintain an immune shield of effector memory T cells, including highly unconventional MHC-II and MHC-E restricted CD8+ T cells. Host: Vincent Racaniello, Rich Condit, and Brianne Barker Guest: Klaus Früh Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode MicrobeTV Discord Server MicrobeTV store at Cafepress Spike shirts at vaccinated.us (promo code Microbetv) Research assistant position in Rosenfeld Lab CBER/FDA (pdf) HCMV-based attenuated vaccine platform (Sci Rep) HLA-E-restricted, Gag-specific CD8+ T cells suppress HIV-1 infection (Sci Immunol) RhCMV/SIV vaccine shows long-term efficacy against SIV challenge (Sci Transl Med) Timestamps by Jolene. Thanks! Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv

In this Buddisode, we sit down with Dr. Nataliya Prokhnevska to discuss her work on the fate and role of non-cytotoxic CD8+ T cells found in the tumor-draining lymph nodes of cancer patients.

4.07 Polymyositis and Dermatomyositis MSK/Rheum review for the USMLE Step 1 Exam Polymyositis and dermatomyositis are autoimmune inflammatory myopathies. They are caused by abnormal activation of T cells that attack skeletal muscle and both cause proximal muscle weakness, especially of the shoulders and pelvic girdle muscles. Polymyositis develops when there is abnormal activation of CD8 T cells, while dermatomyositis is primarily attacked by CD4 T cells. Both are diagnosed through a muscle biopsy and the presence of elevated CK levels and several different autoantibodies. Dermatomyositis includes dermatologic manifestations, such as gottron papules, heliotrope rash, and shawl rash. Both are associated with MI, interstitial lung disease, and various types of cancer (dermatomyositis more so). Both diseases require prompt treatment with steroids and immunosuppressive agents.

Videos: 1.  World Economic Forum – Hackable Humans – Yuval Noah Harari, 2.  Introducing The Reset: The Great Reset Docuseries (start @ 11:00) 3. Lara Logan Rapid Fires Truth Bombs On Ukraine Propaganda & The Democrat Narratives Of The Day (2:57) 4 .Kissinger: China, US Should Work Together to Understand, Respect Each Other's Core Interests (3:14) 5. Tipping Point – The Risks of Pfizer's Vaccine to Unborn Babies – with Naomi Wolf (start at 1.48) 6.  Good news! WHO Pandemic ‘Treaty' voted down (6:09) 7. Gravitas: Is climate activism becoming a nuisance to society? (4:32) 8. Why Asia Pacific Chose China (You Won't Believe What America Did) – Cyrus Janssen (10:37) Study confirms benefit of supplements for slowing age-related macular degeneration National Eye Institute, June 2 The Age-Related Eye Disease Studies (AREDS and AREDS2) established that dietary supplements can slow progression of age-related macular degeneration (AMD), the most common cause of blindness in older Americans. In a new report, scientists analyzed 10 years of AREDS2 data. They show that the AREDS2 formula, which substituted antioxidants lutein and zeaxanthin for beta-carotene, not only reduces risk of lung cancer due to beta-carotene, but is also more effective at reducing risk of AMD progression, compared to the original formula. “Because beta-carotene increased the risk of lung cancer for current smokers in two NIH-supported studies, our goal with AREDS2 was to create an equally effective supplement formula that could be used by anyone, whether or not they smoke,” said Emily Chew, M.D., at the National Eye Institute (NEI).” In AREDS2, begun in 2006, Chew and colleagues compared the beta-carotene formulation to one with 10 mg lutein and 2 mg zeaxanthin instead. Like beta-carotene, lutein and zeaxanthin are antioxidants with activity in the retina. The beta-carotene-containing formation was only given to participants who had never smoked or who had quit smoking. At the end of the five-year AREDS2 study period, the researchers concluded that lutein and zeaxanthin did not increase risk for lung cancer, and that the new formation could reduce the risk of AMD progression by about 26%. (NEXT) Exercise amplifies immune attack on pancreatic cancer New York University Langone Health, June 2 Aerobic exercise reprograms the immune system to reduce pancreatic tumor growth and amplify the effects of immunotherapy, a new study finds. Published online in Cancer Cell, the study provides new insight into how the mammalian immune system, designed to attack foreign invaders like bacteria, can also recognize cancer cells as abnormal. Exercise-induced increases in levels of the hormone adrenalin cause changes to the immune system, say the study authors, including in the activity of cells that respond to signaling protein interleukin-15 (IL-15). The current study found that exercise promotes the survival of CD8 T cells sensitive to IL-15, and doubles the number of them homing to pancreatic ductal adenocarcinoma (PDAC) tumors in mice. Such “effector” T cells have been shown by other studies to be capable of killing cancer cells. Other tests found that aerobic exercise for 30 minutes five times a week reduced the rate of cancer formation by 50 percent in one mouse model of PDAC, and reduced tumor weight by 25 percent in another model, in which mice ran on treadmills for three weeks. Our findings show, for the first time, how aerobic exercise affects the immune microenvironment within pancreatic tumors,” says first author Emma Kurz, MD, Ph.D., at NYU Grossman School of Medicine's Vilcek Institute of Graduate Biomedical Sciences. (NEXT) Antibiotics wreak havoc on athletic performance University of California at Riverside, June 1 New research demonstrates that by killing essential gut bacteria, antibiotics ravage athletes' motivation and endurance. The UC Riverside-led mouse study suggests the microbiome is a big factor separating athletes from couch potatoes. Other studies have examined the way that exercise affects the microbiome, but this study is one of few to examine the reverse — how gut bacteria also impact voluntary exercise behaviors. Voluntary exercise involves both motivation and athletic ability. Researchers confirmed through fecal samples that after 10 days of antibiotics, gut bacteria were reduced in two groups of mice: some bred for high levels of running, and some that were not. So, when wheel running in the athletic mice was reduced by 21 percent, researchers were certain the microbiome damage was responsible. In addition, the high runner mice did not recover their running behavior even 12 days after the antibiotic treatment stopped. (NEXT) Study: Trans Fat Hides in at Least a Quarter of Supermarket Foods Environmental Working Group, May 22 A new analysis  by Environmental Working Group has found that harmful artificial trans fatty acids lurk in more than 27 percent of more than 84,000 processed foods common in American supermarkets.  Another 10 percent contain ingredients likely to contain trans fat. EWG analysts used information from EWG's Food Scores database and mobile app  to determine which foods contained partially hydrogenated oils and other trans fat containing-ingredients. The interactive, searchable tool rates more than 84,000 foods and 5,000 ingredients based on nutrition, ingredient and processing concerns. In most cases, the products' trans fat content on the nutrition label doesn't add up. The reason: an obscure loophole in federal food labeling regulations that allows food processors to round off less than half a gram of trans fat per serving to zero. A single serving of more than 400 foods in the Food Scores database contained enough trans fat to exceed the World Health Organization's recommended limit of less than 2 grams per day for an adult who consumed a 2,000 calorie diet, the analysis said. (NEXT) Coffee drinking again linked with longer life Jinan University (China), June 1 2022.  Yet another study has found an association between coffee drinking and a lower risk of premature mortality. The research was reported n the Annals of Internal Medicine. The investigation included 171,616 men and women who did not have cancer or heart disease upon enrollment between 2006 to 2010 in the UK Biobank prospective cohort study. Participants were 37 to 73 years old at recruitment. During a 7-year median follow-up period, participants who consumed unsweetened coffee had up to a 29% lower risk of death (which was associated with drinking 2.5 to 4.5 cups per day) compared to those who did not drink coffee. Participants who drank sugar-sweetened coffee had up to a 31% lower risk, associated with consuming 1.5 to 2.5 cups per day. The association between artificially sweetened coffee and mortality risk was inconclusive. “This prospective analysis found that moderate consumption of unsweetened coffee and that of sugar-sweetened coffee were associated with similar reductions in risk for all-cause, cancer-related, and cardiovascular disease-related mortality,” authors Dan Liu, MD, of Jinan University and colleagues concluded.