Podcasts about CD8

Can Victor Marx conduct exorcisms over the phone? The ordained minister and front-runner in the GOP primary for governor says so, and made national news when HBO's Last Week Tonight with John Oliver picked up 9News' debate between Marx, State Sen. Barbara Kirkmeyer, and State Rep. Scott Bottoms. Journalist Kyle Clark joins host Bree Davies and politics contributor Adrian Felix to dig into that unhinged Republican rodeo Kyle and colleague Marshall Zelinger moderated, plus discuss CD8 primary candidate Manny Rutinel's sudden switch on fracking and veganism, and of course our wins and fails of the week.  Plus, if you're a City Cast Denver Neighbor, you get a special bonus segment where the trio discusses Bow Mar's dystopian dream of building a wall around the tiny town and what it says about humanity. Come see us at Denver Bike Fest, this Saturday, June 13, from 3-9 p.m. at York Street Yards! Bree mentioned her interview with reporter Logan Davis about Advance Colorado, scooter accidents and kids, and DIY venue, The D.M.V. Kyle talked about the tornado false alarm and Tina Peters' appearance at “Freedom Fest.” Adrian discussed DPD's proposal to replace discipline with training, the return of City Park Jazz, and Kyle's Word of Thanks fundraising for the City Park Bandstand.  For even more news from around the city, subscribe to our morning newsletter at denver.citycast.fm. Follow us on Instagram: @citycastdenver Chat with other listeners on Reddit: r/CityCastDenver Support City Cast Denver by becoming a member: membership.citycast.fm What do you think? Text or leave us a voicemail with your name and neighborhood, and you might hear it on the show: 720-500-5418 Learn more about the sponsors of this episode: Denver Bike Fest Energy Outreach Colorado Vail Wine Classic Regional Air Quality Council Looking to advertise on City Cast Denver? Check out our options for podcast and newsletter ads at citycast.fm/advertise

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

In a conversation with CancerNetwork®, Nathan Goodyear, MD, spoke about the role that exercise and lifestyle intervention can play in the treatment of patients with cancer. He described how prescribed exercise may serve as a biologically interventional therapy that can help prolong longevity, reduce the risk of recurrence; and supplement the efficacy of standard therapeutic approaches like chemotherapy, immunotherapy, and surgery.Goodyear, an integrative medicine physician at the Williams Cancer Institute, pointed to literature indicating the potential benefits of structured exercise programs across different cancer populations. For example, data from the phase 3 CHALLENGE trial (NCT00819208) highlighted a lower risk of death and reduced recurrence following a 3-year structured program among patients with stage II and III colorectal cancer. Furthermore, the OPTIMUS trial (NCT02950324) demonstrated that a short-term exercise program that takes place before surgery or alongside chemotherapy can increase CD8-positive T-cell infiltration while decreasing immunosuppressive cells, effectively turning “cold” tumors “hot.”Additionally, Goodyear addressed some preconceptions surrounding the potential role of exercise in oncologic care, defending it as a prescribable therapy that necessitates a deliberate, properly applied approach to achieve success among patients. He discussed the importance of structuring individualized exercise-based regimens by considering performance status and other physical patient characteristics. He also noted how exercise intervention may mitigate immunosenescence and accelerated aging may be associated with one's disease and anti-cancer therapy. “Surgery, chemotherapy, and radiation…have efficacy; there's no question about that. They also promote senescence and accelerated aging. What if we're able to bring in these therapies that can work to break those cycles, like exercise?” Goodyear stated. “If it improves the outcome, helps the patient heal better, empowers their immune system in intended [and] direct ways that are reproducible in the research, and if it helps to block that accelerated aging, we reengage the immune system, countering the immunosenescence that is accelerating that process called inflammation.”References Courneya KS, Vardy JL, O'Callaghan CJ, et al. Structured exercise after adjuvant chemotherapy for colon cancer. N Engl J Med. 2025;393(1):13-25. doi:10.1056/NEJMoa2502760 Rayner CJ, Bartlett DB, Allen SK, et al. Prehabilitation during neoadjuvant chemotherapy results in an enhanced immune response in esophageal adenocarcinoma tumors: a randomized controlled trial. J Sport Health Sci. 2025;14:101063. doi:10.1016/j.jshs.2025.101063

Join the Conversation at 303-477-5600 or text to 307-200-8222 Monday - Friday from 3 pm - 6 pm MT. https://RushToReason.com HOUR 1 Global Conflict, Economic Anxiety, And America's Energy Future Collide. Hour 1 of Rush To Reason features John Rush, Andy Peth, and financial expert Jordan Goodman in a rapid-fire discussion of global war threats, economic uncertainty, energy policy, and political power. They examine how rising tensions with Iran could impact oil prices, inflation, airline travel, and global stability. The conversation asks if the world is edging toward wider conflict and how much America's economic future hinges on events in the Strait of Hormuz. The hour also sharply critiques the Federal Reserve and Jerome Powell, debating interest rates, housing, inflation, and the political forces shaping economic decisions. Other topics include Spirit Airlines' collapse, blocked mergers, LNG exports, Colorado's natural gas, Cuba's ongoing crisis, and the political fallout from rising utility bills. From energy independence and airline bankruptcies to inflation and geopolitics, Hour 1 highlights how deeply interconnected today's major systems are. HOUR 2 Colorado Republicans Face A Political Identity Crisis. Hour 2 delivers a candid look at Colorado's Republican Party and its candidates, spotlighting the divide between ideology, strategy, and electability. John Rush and Andy Peth assess Greg Lopez, Victor Marks, Scott Bottoms, and Barb Kirkmeyer, raising the tough question: who can win statewide in today's Colorado? They cover campaign charisma, debate strategy, abortion politics, voter psychology, caucus influence, and whether splitting the conservative vote unintentionally helps Democrats. John and Andy discuss how unaffiliated voters influence elections, why emotional political movements struggle to expand beyond their base, and how internal Republican divisions could affect congressional races. They also examine the decline of Colorado Republican leadership, criticizing infighting, failed strategy, and divisive figures. The hour ends with a warning about political reality, messaging, and whether Colorado Republicans will adapt or keep losing statewide influence. HOUR 3 Candidate Vetting, Party Chaos, And The Fight Over Colorado's Republican Future. Hour 3 dives into candidate vetting, political credibility, and the growing feud within Colorado's Republican Party. John Rush, Andy Peth, and Eli Bremer discuss the controversy surrounding former CD8 candidate Adam DeRito and what his story reveals about the party leadership and candidate screening in Colorado. They explore allegations about DeRito's military history, dishonesty, and fabricated stories, showing how flawed candidates can still rise inside activist circles. The discussion then broadens: Colorado Republicans are accused of empowering emotional factions and unelectable candidates while alienating the unaffiliated voters needed to win statewide. They also discuss Ron Hanks, Dave Williams, caucus politics, donor fatigue, lawsuits, and party cronyism, highlighting frustration with a system that rewards activism over electability. The hour ends with a warning about political incentives, failed leadership, and whether Colorado Republicans can rebuild credibility before losing statewide relevance for good.

Join the Conversation at 303-477-5600 or text to 307-200-8222 Monday - Friday from 3 pm - 6 pm MT. https://RushToReason.com HOUR 1 Global Conflict, Economic Anxiety, And America's Energy Future Collide. Hour 1 of Rush To Reason features John Rush, Andy Peth, and financial expert Jordan Goodman in a rapid-fire discussion of global war threats, economic uncertainty, energy policy, and political power. They examine how rising tensions with Iran could impact oil prices, inflation, airline travel, and global stability. The conversation asks if the world is edging toward wider conflict and how much America's economic future hinges on events in the Strait of Hormuz. The hour also sharply critiques the Federal Reserve and Jerome Powell, debating interest rates, housing, inflation, and the political forces shaping economic decisions. Other topics include Spirit Airlines' collapse, blocked mergers, LNG exports, Colorado's natural gas, Cuba's ongoing crisis, and the political fallout from rising utility bills. From energy independence and airline bankruptcies to inflation and geopolitics, Hour 1 highlights how deeply interconnected today's major systems are. HOUR 2 Colorado Republicans Face A Political Identity Crisis. Hour 2 delivers a candid look at Colorado's Republican Party and its candidates, spotlighting the divide between ideology, strategy, and electability. John Rush and Andy Peth assess Greg Lopez, Victor Marks, Scott Bottoms, and Barb Kirkmeyer, raising the tough question: who can win statewide in today's Colorado? They cover campaign charisma, debate strategy, abortion politics, voter psychology, caucus influence, and whether splitting the conservative vote unintentionally helps Democrats. John and Andy discuss how unaffiliated voters influence elections, why emotional political movements struggle to expand beyond their base, and how internal Republican divisions could affect congressional races. They also examine the decline of Colorado Republican leadership, criticizing infighting, failed strategy, and divisive figures. The hour ends with a warning about political reality, messaging, and whether Colorado Republicans will adapt or keep losing statewide influence. HOUR 3 Candidate Vetting, Party Chaos, And The Fight Over Colorado's Republican Future. Hour 3 dives into candidate vetting, political credibility, and the growing feud within Colorado's Republican Party. John Rush, Andy Peth, and Eli Bremer discuss the controversy surrounding former CD8 candidate Adam DeRito and what his story reveals about the party leadership and candidate screening in Colorado. They explore allegations about DeRito's military history, dishonesty, and fabricated stories, showing how flawed candidates can still rise inside activist circles. The discussion then broadens: Colorado Republicans are accused of empowering emotional factions and unelectable candidates while alienating the unaffiliated voters needed to win statewide. They also discuss Ron Hanks, Dave Williams, caucus politics, donor fatigue, lawsuits, and party cronyism, highlighting frustration with a system that rewards activism over electability. The hour ends with a warning about political incentives, failed leadership, and whether Colorado Republicans can rebuild credibility before losing statewide relevance for good.

Join the Conversation at 303-477-5600 or text to 307-200-8222 Monday - Friday from 3 pm - 6 pm MT. https://RushToReason.com HOUR 1 Global Conflict, Economic Anxiety, And America's Energy Future Collide. Hour 1 of Rush To Reason features John Rush, Andy Peth, and financial expert Jordan Goodman in a rapid-fire discussion of global war threats, economic uncertainty, energy policy, and political power. They examine how rising tensions with Iran could impact oil prices, inflation, airline travel, and global stability. The conversation asks if the world is edging toward wider conflict and how much America's economic future hinges on events in the Strait of Hormuz. The hour also sharply critiques the Federal Reserve and Jerome Powell, debating interest rates, housing, inflation, and the political forces shaping economic decisions. Other topics include Spirit Airlines' collapse, blocked mergers, LNG exports, Colorado's natural gas, Cuba's ongoing crisis, and the political fallout from rising utility bills. From energy independence and airline bankruptcies to inflation and geopolitics, Hour 1 highlights how deeply interconnected today's major systems are. HOUR 2 Colorado Republicans Face A Political Identity Crisis. Hour 2 delivers a candid look at Colorado's Republican Party and its candidates, spotlighting the divide between ideology, strategy, and electability. John Rush and Andy Peth assess Greg Lopez, Victor Marks, Scott Bottoms, and Barb Kirkmeyer, raising the tough question: who can win statewide in today's Colorado? They cover campaign charisma, debate strategy, abortion politics, voter psychology, caucus influence, and whether splitting the conservative vote unintentionally helps Democrats. John and Andy discuss how unaffiliated voters influence elections, why emotional political movements struggle to expand beyond their base, and how internal Republican divisions could affect congressional races. They also examine the decline of Colorado Republican leadership, criticizing infighting, failed strategy, and divisive figures. The hour ends with a warning about political reality, messaging, and whether Colorado Republicans will adapt or keep losing statewide influence. HOUR 3 Candidate Vetting, Party Chaos, And The Fight Over Colorado's Republican Future. Hour 3 dives into candidate vetting, political credibility, and the growing feud within Colorado's Republican Party. John Rush, Andy Peth, and Eli Bremer discuss the controversy surrounding former CD8 candidate Adam DeRito and what his story reveals about the party leadership and candidate screening in Colorado. They explore allegations about DeRito's military history, dishonesty, and fabricated stories, showing how flawed candidates can still rise inside activist circles. The discussion then broadens: Colorado Republicans are accused of empowering emotional factions and unelectable candidates while alienating the unaffiliated voters needed to win statewide. They also discuss Ron Hanks, Dave Williams, caucus politics, donor fatigue, lawsuits, and party cronyism, highlighting frustration with a system that rewards activism over electability. The hour ends with a warning about political incentives, failed leadership, and whether Colorado Republicans can rebuild credibility before losing statewide relevance for good.

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

"They are small, powerful little nuggets. They are actually small signaling proteins that our immune cells use to communicate. They really help regulate immune activation or inflammation and even the growth and survival of immune cells. When cytokines are used therapeutically in oncology, they help to stimulate immune cells such as T cells or natural killer cells to better recognize and attack cancer cells," Maribel Pereiras, PharmD, BCPS, BCOP, clinical pharmacy specialist at the John Theurer Cancer Center of Hackensack University Medical Center in New Jersey, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about the cytokine drug class. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours (including 30 minutes of pharmacotherapeutic content) of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by April 24, 2027. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Nurses caring for people with cancer require knowledge of cytokines to provide appropriate education and to safely administer related therapies. Episode Notes  Complete this evaluation for free NCPD.  ONS Podcast™ episodes: Pharmacology 101 series Episode 256: Cancer Symptom Management Basics: Hematologic Complications Episode 196: Oncologic Emergencies 101: Bleeding and Thrombosis ONS Voice articles: FDA Approves Nogapendekin Alfa Inbakicept-Pmln for BCG-Unresponsive Non–Muscle Invasive Bladder Cancer Manage Cancer-Associated Anemia With Erythropoietin-Stimulating Agents Oncology Drug Reference Sheet: Motixafortide ONS books: Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) and 2024 Drug Supplement Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (fourth edition) Guide to Cancer Immunotherapy (second edition) Clinical Journal of Oncology Nursing article: Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Nursing Considerations What's Old Is New Again, Unfortunately ONS Symptom Interventions Colony-Stimulating Factors Including Biosimilars for At-Risk Patients for Prevention of Infection: General Platelet Growth Factors for Prevention of Bleeding National Comprehensive Cancer Network To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode "Cytokines are actually among some of the earliest forms of immunotherapy used in the treatment of cancer, and it really goes back to the 1980s and the 1990s. We're talking therapies like interferon [alpha] or interleukin-2 that were used to stimulate the immune system, with the idea that they would recognize and attack cancer cells, particularly in diseases like metastatic melanoma and renal cell carcinoma. What made these therapies unique was that although the overall response rates were relatively modest, when patients did respond, those responses could be very durable and sometimes long lasting. And that observation was really important for the field of oncology, because it was part of the process that demonstrated that the immune system could potentially control cancer in really meaningful ways." TS 1:49 "One nice new example of an engineered cytokine is nogapendekin alfa inbakicept, which is quite the tongue twister to say. … This agent is really interesting because it's an engineered interleukin-15 receptor agonist that works on stimulating natural killer cells and CD8-positive T cells. And what makes this so interesting is that it's used in combination with a medication that probably some of us are familiar with—good old BCG—for patients specifically with invasive bladder cancer. The other really interesting thing about this new therapy is the fact that it is one of our first ones to be engineered in a combination fashion. So the nogapendekin alfa is combined with a receptor component that is called inbakicept. And what happens is it forms a complex to enhance signaling and prolong the activity of the cytokine." TS 7:50 "When you're looking at our therapeutic cytokines, those tend to produce larger-scale systemic inflammatory effects leading to much more global side effect reactions, while your supportive care cytokines are more commonly associated with either bone marrow stimulation effects or hematologic changes." TS 14:01 "Regardless of what type of cytokine therapy may you be using, across the board, early recognition of the symptoms and proactive supportive care are really important. And this is where many of our oncology nurses play such a critical role in identifying changes that are happening in real time to the patient's condition and helping to coordinate, relay information to the rest of the providing team so that timely interventions can occur for the best care of the patient." TS 18:01 "The other fascinating thing about these cytokines is that they're not being used as monotherapy anymore. They're now being looked at in combination with other therapies or even other immunotherapies like our checkpoint inhibitors. They're being looked at in the sense that they may be able to help expand and further activate immune cells that our current therapies rely on. And so it's really interesting that while cytokines were some of the earliest forms of cancer immunotherapy, they're now being reimagined as part of modern combination strategies designed to really further help enhance the immune responses against cancer." TS 29:08

The fight for Congressional District 8 is heating up – known to swing both ways, the race is anyone's game. In a party with a growing divide, democratic centrist Shannon Bird and progressive Manny Rutinel are both vying for the seat, so how will things shake out for the dems? Green chile correspondent Justine Sandoval joins producer Paul Karolyi and host Bree Davies to discuss the CD8 tossup, plus talk about ⁠new over-the-top snacks⁠ coming to Coors Field, Westword editor-in-chief Patty Calhoun's ⁠big retirement announcement⁠, and of course, our wins and fails of the week.  Paul talked about Welton Street Café winning its $1 million case ⁠against a shoddy contractor⁠, and the ⁠GoFundMe for Eduardo Morales⁠, a TSA agent who was killed in a hit and run accident. Justine talked about the panaderia saving Jim's Burger Haven from a ⁠big bun shortage⁠. Bree mentioned the Denver Post's reporting on ⁠Bruce Brown's mustache⁠.   For even more news from around the city, subscribe to our morning newsletter at⁠ denver.citycast.fm⁠. Follow us on Instagram:⁠ @citycastdenver⁠ Chat with other listeners on reddit:⁠ r/CityCastDenver⁠ Support City Cast Denver by becoming a member:⁠ membership.citycast.fm⁠ What do you think? Text or leave us a voicemail with your name and neighborhood, and you might hear it on the show: 720-500-5418 Learn more about the sponsors of this March 27th episode: ⁠Arvada Center⁠ Looking to advertise on City Cast Denver? Check out our options for podcast and newsletter ads at⁠ citycast.fm/advertise⁠

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

Immune discusses how tattoo ink accumulates in lymph nodes, promotes inflammation and influences response to two different vaccines. Hosts: Vincent Racaniello, Cindy Leifer, Stephanie Langel, and Brianne Barker Subscribe (free): Apple Podcasts, RSS, email Become a patron of Immune! Links for this episode MicrobeTV Discord Server IL-9, CAR T cells and anti-tumor CD8 cells Tattoo ink, inflammation and vaccines Time stamps by Jolene Ramsey. Thanks! Music by Tatami. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv Information on this podcast should not be construed as medical advice.  

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

On https://rushtoreason.com, guest host Andy Peth fills in for John Rush and is joined by Tanner Coleman. Together, they deliver a fast-paced, unapologetic Hour 1. The pair set the tone for a no-nonsense conversation about culture, leadership, and values. As the year winds down, the discussion starts with humor and reflection. Then, they focus on California's political direction—new laws, wildfire mismanagement, and what critics call a growing gap between common sense and governance. The hour then sharpens its focus on border security, patriotism, and race. The hosts push back against claims from Los Angeles leadership about Hispanic Border Patrol agents. Are these men and women motivated by money, or by love of country and respect for the rule of law? Using real quotes, vivid analogies, and pointed questions, Andy and Tanner challenge listeners. They urge the audience to reconsider media narratives and the real-world consequences of mass illegal immigration. The conversation shifts again. This time, it moves to culture and morality. Humor explores a serious question: do we still teach why things are wrong, or just warn of consequences? That thread sets up the next topics: wealth, taxes, voting, and whether “fairness” quietly replaced personal responsibility. HOUR 2 Andy returns for a hard-hitting Hour 2 alongside Tanner, opening with an intense deep dive into the massive Minnesota fraud scandal tied to COVID-era programs. How did billions in taxpayer dollars allegedly vanish—and why were whistleblowers ignored or silenced? Andy and Tanner argue this wasn't just a bureaucratic failure, but a political one, repeatedly questioning the role of Tim Walz and asking how accountability might look if a different political movement were involved. Mid-hour, the tone shifts as Richard Rush joins the show, bringing weekly NFL picks, playoff implications, and late-season drama. Which teams are collapsing at the worst possible time—and which quarterbacks are carrying franchises on their backs? From draft positioning to coaching courage, the sports conversation mirrors the political theme: leadership matters, mindset matters, and excuses only go so far. Blending sharp analysis, dark humor, and rapid-fire debate, Hour 2 challenges listeners to question media narratives, political double standards, and even how success—or failure—is measured, whether in government or on the field. HOUR 3 Andy Peth and Tanner return for a politically charged Hour 3 with special guest Eli Bremer, taking a hard look at the future of Republican politics in Colorado and beyond. What happens when party unity breaks down—and who pays the price when candidates prioritize personal brand over winning elections? The hour opens with a candid discussion about internal GOP fractures, performative politics, and the fallout surrounding Marjorie Taylor Greene, raising tough questions about loyalty, teamwork, and governing with slim majorities. The conversation then shifts to Colorado, where Eli walks through the importance of vetting candidates in competitive districts like CD8 and CD3, highlighting incumbents Gabe Evans and Jeff Hurd—and warning how fringe challengers can jeopardize winnable seats. The hour crescendos with a blunt assessment of Joe Altman's newly announced gubernatorial run, exploring how extreme rhetoric and unchecked behavior can turn a difficult race into a political disaster. The message is clear: in a purple state, credibility, discipline, and strategy matter—or the consequences will be severe.

On https://rushtoreason.com, guest host Andy Peth fills in for John Rush and is joined by Tanner Coleman. Together, they deliver a fast-paced, unapologetic Hour 1. The pair set the tone for a no-nonsense conversation about culture, leadership, and values. As the year winds down, the discussion starts with humor and reflection. Then, they focus on California's political direction—new laws, wildfire mismanagement, and what critics call a growing gap between common sense and governance. The hour then sharpens its focus on border security, patriotism, and race. The hosts push back against claims from Los Angeles leadership about Hispanic Border Patrol agents. Are these men and women motivated by money, or by love of country and respect for the rule of law? Using real quotes, vivid analogies, and pointed questions, Andy and Tanner challenge listeners. They urge the audience to reconsider media narratives and the real-world consequences of mass illegal immigration. The conversation shifts again. This time, it moves to culture and morality. Humor explores a serious question: do we still teach why things are wrong, or just warn of consequences? That thread sets up the next topics: wealth, taxes, voting, and whether “fairness” quietly replaced personal responsibility. HOUR 2 Andy returns for a hard-hitting Hour 2 alongside Tanner, opening with an intense deep dive into the massive Minnesota fraud scandal tied to COVID-era programs. How did billions in taxpayer dollars allegedly vanish—and why were whistleblowers ignored or silenced? Andy and Tanner argue this wasn't just a bureaucratic failure, but a political one, repeatedly questioning the role of Tim Walz and asking how accountability might look if a different political movement were involved. Mid-hour, the tone shifts as Richard Rush joins the show, bringing weekly NFL picks, playoff implications, and late-season drama. Which teams are collapsing at the worst possible time—and which quarterbacks are carrying franchises on their backs? From draft positioning to coaching courage, the sports conversation mirrors the political theme: leadership matters, mindset matters, and excuses only go so far. Blending sharp analysis, dark humor, and rapid-fire debate, Hour 2 challenges listeners to question media narratives, political double standards, and even how success—or failure—is measured, whether in government or on the field. HOUR 3 Andy Peth and Tanner return for a politically charged Hour 3 with special guest Eli Bremer, taking a hard look at the future of Republican politics in Colorado and beyond. What happens when party unity breaks down—and who pays the price when candidates prioritize personal brand over winning elections? The hour opens with a candid discussion about internal GOP fractures, performative politics, and the fallout surrounding Marjorie Taylor Greene, raising tough questions about loyalty, teamwork, and governing with slim majorities. The conversation then shifts to Colorado, where Eli walks through the importance of vetting candidates in competitive districts like CD8 and CD3, highlighting incumbents Gabe Evans and Jeff Hurd—and warning how fringe challengers can jeopardize winnable seats. The hour crescendos with a blunt assessment of Joe Altman's newly announced gubernatorial run, exploring how extreme rhetoric and unchecked behavior can turn a difficult race into a political disaster. The message is clear: in a purple state, credibility, discipline, and strategy matter—or the consequences will be severe.

On https://rushtoreason.com, guest host Andy Peth fills in for John Rush and is joined by Tanner Coleman. Together, they deliver a fast-paced, unapologetic Hour 1. The pair set the tone for a no-nonsense conversation about culture, leadership, and values. As the year winds down, the discussion starts with humor and reflection. Then, they focus on California's political direction—new laws, wildfire mismanagement, and what critics call a growing gap between common sense and governance. The hour then sharpens its focus on border security, patriotism, and race. The hosts push back against claims from Los Angeles leadership about Hispanic Border Patrol agents. Are these men and women motivated by money, or by love of country and respect for the rule of law? Using real quotes, vivid analogies, and pointed questions, Andy and Tanner challenge listeners. They urge the audience to reconsider media narratives and the real-world consequences of mass illegal immigration. The conversation shifts again. This time, it moves to culture and morality. Humor explores a serious question: do we still teach why things are wrong, or just warn of consequences? That thread sets up the next topics: wealth, taxes, voting, and whether “fairness” quietly replaced personal responsibility. HOUR 2 Andy returns for a hard-hitting Hour 2 alongside Tanner, opening with an intense deep dive into the massive Minnesota fraud scandal tied to COVID-era programs. How did billions in taxpayer dollars allegedly vanish—and why were whistleblowers ignored or silenced? Andy and Tanner argue this wasn't just a bureaucratic failure, but a political one, repeatedly questioning the role of Tim Walz and asking how accountability might look if a different political movement were involved. Mid-hour, the tone shifts as Richard Rush joins the show, bringing weekly NFL picks, playoff implications, and late-season drama. Which teams are collapsing at the worst possible time—and which quarterbacks are carrying franchises on their backs? From draft positioning to coaching courage, the sports conversation mirrors the political theme: leadership matters, mindset matters, and excuses only go so far. Blending sharp analysis, dark humor, and rapid-fire debate, Hour 2 challenges listeners to question media narratives, political double standards, and even how success—or failure—is measured, whether in government or on the field. HOUR 3 Andy Peth and Tanner return for a politically charged Hour 3 with special guest Eli Bremer, taking a hard look at the future of Republican politics in Colorado and beyond. What happens when party unity breaks down—and who pays the price when candidates prioritize personal brand over winning elections? The hour opens with a candid discussion about internal GOP fractures, performative politics, and the fallout surrounding Marjorie Taylor Greene, raising tough questions about loyalty, teamwork, and governing with slim majorities. The conversation then shifts to Colorado, where Eli walks through the importance of vetting candidates in competitive districts like CD8 and CD3, highlighting incumbents Gabe Evans and Jeff Hurd—and warning how fringe challengers can jeopardize winnable seats. The hour crescendos with a blunt assessment of Joe Altman's newly announced gubernatorial run, exploring how extreme rhetoric and unchecked behavior can turn a difficult race into a political disaster. The message is clear: in a purple state, credibility, discipline, and strategy matter—or the consequences will be severe.

I sit down with L.A. City Council President Marqueece Harris-Dawson to discuss everything L.A. from the Crenshaw District to the Civic Center. Now in his third term representing CD8, Harris-Dawson is stewarding growth and development in one of the most crucial districts in Los Angeles, but also spearheading ambitious projects such as the $2.6 billion overhaul of the Convention Center. A highly engaging conversation with a dynamic personality, it's easy to see why MHD was unanimously elected President of the City Council.

Dr. Ari Vojdani, Chief Scientific Officer at Cyrex Labs, describes the two primary components of the immune system--humoral and cell-mediated immunity and how the Cyrex diagnostics are designed to measure both. The Cyrex food immune reactivity testing measures antibodies against raw, cooked, modified, and processed food proteins as the structure of these proteins can change and affect immune responses. Cyrex is also developing tests to measure antibodies against various gut bacteria, fungi, and toxins, and how these relate to autoimmune conditions. Ari explains, "Cyrex performs lots of tests, but we can divide them based on the immune system. As you know, the immune system has two major components, the humoral and cell-mediated immunity. The humoral components of the immune system deal with measurements of antibodies. So when we get exposed to certain antigens, proteins of pathogens, food, or toxic chemicals, when they bind to human tissue, our body reacts to them, and the end result of that is specific antibody production against that specific protein or antigen." "The second component of the immune system is cell-mediated immunity, which looks at different lymphocytes, their markers, such as whether it is a T-cell, B-cell, CD4, CD8, T helper 1, T helper 2, regulatory T cells, or natural killer cells. So that also could be abnormal in certain inflammatory and autoimmune disorders. That's why at Cyrex, the tests that they are performing are classified based on humoral and cell-mediated immunity."   "In 1986 and 1987, I developed the ELISA method for measuring antibodies against different food antigens. Then I did not have the knowledge about the importance of raw versus cooked or raw versus modified foods. I established the methodologies, and many others came to visit my laboratories. Years later, they started their own laboratories. So they continue using the same raw food for measuring antibodies in their own laboratories." #CyrexLabs #FunctionalImmunology #FunctionalMedicine #immuneHealth #FoodSensitivity #FoodAllergies cyrexlabs.com Download the transcript here

Dr. Ari Vojdani, Chief Scientific Officer at Cyrex Labs, describes the two primary components of the immune system--humoral and cell-mediated immunity and how the Cyrex diagnostics are designed to measure both. The Cyrex food immune reactivity testing measures antibodies against raw, cooked, modified, and processed food proteins as the structure of these proteins can change and affect immune responses. Cyrex is also developing tests to measure antibodies against various gut bacteria, fungi, and toxins, and how these relate to autoimmune conditions. Ari explains, "Cyrex performs lots of tests, but we can divide them based on the immune system. As you know, the immune system has two major components, the humoral and cell-mediated immunity. The humoral components of the immune system deal with measurements of antibodies. So when we get exposed to certain antigens, proteins of pathogens, food, or toxic chemicals, when they bind to human tissue, our body reacts to them, and the end result of that is specific antibody production against that specific protein or antigen." "The second component of the immune system is cell-mediated immunity, which looks at different lymphocytes, their markers, such as whether it is a T-cell, B-cell, CD4, CD8, T helper 1, T helper 2, regulatory T cells, or natural killer cells. So that also could be abnormal in certain inflammatory and autoimmune disorders. That's why at Cyrex, the tests that they are performing are classified based on humoral and cell-mediated immunity."   "In 1986 and 1987, I developed the ELISA method for measuring antibodies against different food antigens. Then I did not have the knowledge about the importance of raw versus cooked or raw versus modified foods. I established the methodologies, and many others came to visit my laboratories. Years later, they started their own laboratories. So they continue using the same raw food for measuring antibodies in their own laboratories." #CyrexLabs #FunctionalImmunology #FunctionalMedicine #immuneHealth #FoodSensitivity #FoodAllergies cyrexlabs.com Listen to the podcast here

Ever since the election in November, Democrats across the country have been scrambling to figure out what went wrong, so they can rally and try to take back control of Congress in 2026. One candidate who has emerged, at least in terms of his impressive early fundraising numbers, is Commerce City's own Manny Rutinel, a fresh face even in the Colorado Capitol, where he has served only two sessions as a state representative. So, as Rutinel and the rest of the legislature return to Denver today for a special legislative session, he joins producer Paul Karolyi to talk about the state's budget priorities, possible tweaks to his controversial AI law, immigration, food trucks, veganism, and his campaign to win back Congressional District 8 from Republican Gabe Evans.  Rutinel has reportedly raised $1.6 million for his campaign so far, as of the second quarter of this year. For more on Evans' and the other Democrats' fundraising, Axios Denver has the details.  What do you think about Manny Rutinel's chances in CD8? Would you like to hear from the other candidates hoping to unseat Republican Gabe Evans? We want to hear from you! Text or leave us a voicemail with your name and neighborhood, and you might hear it on the show: 720-500-5418 For even more news from around the city, subscribe to our morning newsletter Hey Denver at denver.citycast.fm. Follow us on Instagram: @citycastdenver Chat with other listeners on reddit: r/CityCastDenver Support City Cast Denver by becoming a member: membership.citycast.fm If you enjoyed the sponsored interview with Dr. Jessica Apted, Medical Director of Sploot, learn more here. Learn more about the other sponsors of this August 21st episode: Arvada Center Denver Health Looking to advertise on City Cast Denver? Check out our options for podcast and newsletter ads at citycast.fm/advertise

Schau dir das Video zu dieser Folge an: Keto bei KREBS: Mythos oder Wahrheit? | Die ECHTE Wissenschaft der ketogenen Ernährung gegen KrebsYouTube Kanal gleich abonnieren und keine neue Folge mehr verpassenZusammenfassungIn dieser Episode räumt Julia Tulipan mit den Mythen rund um die ketogene Ernährung bei Krebs auf. Anstatt polarisierender Social-Media-Debatten liefert sie eine wissenschaftlich fundierte Analyse der Studienlage. Du erfährst, dass es nicht darum geht, den Tumor "auszuhungern", sondern um die komplexen Wirkmechanismen von Ketonen: Sie senken Blutzucker und Insulin, reduzieren Entzündungen, modulieren das Immunsystem und können gesunde Zellen schützen, während sie Tumorzellen für Therapien verwundbarer machen. Julia klärt die Fakten zum Warburg-Effekt (nicht widerlegt!) und zur metabolischen Flexibilität von Krebszellen. Sie entkräftet die Behauptung, Ketone würden Tumore füttern, und zeigt stattdessen die antitumorale Wirkung, die in vielen Studien beobachtet wird. Wir beleuchten vielversprechende klinische Studien zu Bauchspeicheldrüsen- und Brustkrebs, die zeigen, wie Keto in Kombination mit Standardtherapien die Krankheitsstabilität und Lebensqualität verbessern kann. Julias Fazit: Keto ist kein Allheilmittel, aber eine wissenschaftlich gut begründete, ergänzende Strategie, die die Wirksamkeit konventioneller Therapien unterstützen und Nebenwirkungen reduzieren kann. Eine professionelle Begleitung ist dabei unerlässlich.Was du in dieser Episode lernst

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

 | Artist  | Title  | Album Name  | Album Copyright  | Alger "Texas" Alexander  | Bantam Rooster Blues (1927)  | Complete Recorded Works, Vol. 1 (1927 - 1928)  | Roy Bookbinder  | Travelin' Man  |   |   | Jake Leg Jug Band  | Kitchen Man  | LIve At The Audley Theatre   | Tight Like That  | How You Want Your Rolling Done  | Shake That Thing [The Blues In Britain 1963-1973]  | Snooks Eaglin  | Mailman Passed  | That's Alright  |   | Chris Kramer & Paddy Boy Zimmermann  | The Duck Yas Yas Yas  | Tales of Tampa  |   | Blind Willie Johnson  | Dark Was The Night (Cold Was The Ground)  | Satan's Blues  |   | Big Bill Broonzy  | Border Blues  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Johan 'Bottleneck John' Eliasson  | Broken  | Road Worn  |   | Geiger von Muller  | Cosmic Cruiser  | Slide Sonatas II  | Lightnin' Hopkins  | Whiskey Headed Woman  | Blues Master Works: Lightnin' Hopkins  | Robert Lockwood Jr.  | Take A Little Walk With Me  | I Got To Find Me A Woman  | Scott Low  | Gamblin' Man  | Appalachian Blues  |   | Etta Baker  | Talks About The Banjo  | Sisters Of The South (Cd2)  | Blind Blake  | West Coast Blues  | All the Published Sides  | Son House  | Special Rider Blues  | The Delta Blues Of Son House  | Bessie Jones & with the Georgia Sea Island Singers  | There Was An Old Lady from Brewster  | Get In Union  | Alan Lomax Archives/Association For Cultural Equity

 | Artist  | Title  | Album Name  | Album Copyright  | Rory Block  | Death Don't Have No Mercy  | I Belong To The Band  | Tom Doughty  | Girl from the North Country  | You Can't Teach An Old Dog  | Charles -Cow Cow- Davenport  | Back in the Alley  | Complete Recorded Works, Vol. 1  | Big Bill Broonzy  | I'll Start Cutting On You  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Mike Ross  | Don't Say A Word  | Tennessee Transition  | The Jake Leg Jug Band  | Your Feet's Too Big  | Fifth Avenue  |   | Adam Franklin  | Falling Rain Blues  | England's Newest Hit Maker - The Best Of Adam Franklin  | Hans Theessink  | Early This Morning Blues [WISHING WELL]  | Wishing Well  |   | Michael Messer  | The Rising Sun  | Rhythm Oil 1993  |   | The Curse of K.K. Hammond  | Death Roll Blues  | Death Roll Blues  |   | Half Deaf Clatch  | A Road Less Travelled  | A Road Less Travelled  | Seasick Steve  | Happy (To Have A Job)  | Man From Another Time  | Stompin' Dave  | Supposed To Do  | Acoustic Blues  |   | Gary Grainger  | Nobody's Fault But Mine  | Mistakes and Out-takes  | Jimmy Womack  | Talking Blues  | Playing for the Man at the Door Disc 3  | Furry Lewis  | Cannonball Blues  | In His Prime 1927-1928

Dr. Tara Reid from the University of Washington Division of Allergy & Infectious Diseases and Dr. Meena Ramchandani discuss Dr. Reid's recent study to identify key T. pallidum proteins which stimulate CD4 T cell response to syphilis. View episode transcript and reference at www.std.uw.edu.This podcast is dedicated to an STD [sexually transmitted disease] review for health care professionals who are interested in remaining up-to-date on the diagnosis, management, and prevention of STDs. Editor and host Dr. Meena Ramchandani is an Assistant Professor of Medicine at the University of Washington (UW) and Program Director of the UW Infectious Diseases Fellowship Program. 

The body's immune response to syphilis and how the response impacts the development of a vaccine is complex. Dr. Tara Reid from the University of Washington Division of Allergy & Infectious Diseases delves into the various responses and the difficulties of vaccine development with Dr. Meena Ramchandani. View episode transcript at www.std.uw.edu.This podcast is dedicated to an STD [sexually transmitted disease] review for health care professionals who are interested in remaining up-to-date on the diagnosis, management, and prevention of STDs. Editor and host Dr. Meena Ramchandani is an Assistant Professor of Medicine at the University of Washington (UW) and Program Director of the UW Infectious Diseases Fellowship Program. 

Featuring an interview with Dr Steven Horwitz, including the following topics: Overview of peripheral T-cell lymphomas (PTCLs) (0:00) Efficacy and safety of brentuximab vedotin in the management of treatment-naïve and relapsed PTCLs (9:57) Emerging therapeutic strategies for PTCLs (19:48) Case: A man in his early 50s with CD30-positive anaplastic large cell lymphoma who experienced complete response (CR) to BV-CHP and continued remission after consolidation with autologous stem cell transplant (ASCT) (25:53) Management of ALK-positive anaplastic large cell lymphoma (32:14) Case: A man in his late 50s with CD8-positive PTCL not otherwise specified who achieved CR with CHOEP and experienced relapse after ASCT (34:33) Case: A woman in her early 70s with chemorefractory CD30-positive angioimmunoblastic T-cell lymphoma (38:26) Ongoing first-line studies for T-cell lymphomas; association of CAR T-cell therapy with T-cell malignancies (42:18) CME information and select publications  

Matt was joined by Jen Schultz, who is the DFL nominee in the 8th Congressional district against Republican incumbent Pete Stauber. CD8 includes Duluth, the Iron Range and other areas in northeast Minnesota.

0:00 Republicans and Democrats agree with Prop 140 groundswell opposition. Angela breaks down the dishonest “end the ban” campaign pro abortion prop 139'ers are running. Every time she talks, Kamala Harris is massively annoying the male demo and they're running away to Trump!  24:24 PROP 487, BBB tax discussion with Heidi Hansen, Director of the Economic Vitality Department of the City of Flagstaff. 38:30 HOW to CHECK the status of your ballot! www.My.Arizona.Vote  43:00 Abe Hamadeh talks about the border and the drug cartels and the need to “go to war against these barbarians”. We also hit on the election system and what the country looks like after November 5th.  Abe is a candidate for CD8. https://www.abeforaz.com 63:00 NAZ and its TWO Seasons.  67:00 I answer listener questions (talkwithjeff@icloud.com) mostly asking me to answer specific election issues.  83:20 Is there a new danger on NAZ roads? Olivia sheds light on it!     https://talkwithjeff.podbean.com/e/abe-hamadeh-is-a-cartel-war-coming-ep-1996/   —————————————— Please FOLLOW or SUBSCRIBE to the Jeff Oravits Show! RUMBLE   YouTube   ApplePodCasts   AmazonMusic   Spotify        Also on Twitter and www.TalkWithJeff.com   Disclaimer: The information provided on the Jeff Oravits Show does not constitute legal, medical, financial or tax advice.  All information is the opinions of the host's and his guests.  You should always seek the advice of a professional regarding any of these complex issues to make sure all circumstances of your situation are properly considered.   ——————————————

 | Artist  | Title  | Album Name  | Album Copyright  |  | Seasick Steve  | Just Because I Can  | Man From Another Time  |   | Amedie Ardoin & Dennis McGee  | Two Step De La Prairie Soileau  | The Stuff that Dreams are Made Of (disc 1)  | Pink Anderson  | In The Jailhouse Now  | Blues Legend  |   |   | Charles -Cow Cow- Davenport  | Alabama Strut  | Complete Recorded Works, Vol. 1  | Guy Davis  | Ramblin' All Over  | The Adventures Of Fishy Waters In Bed With The Blues (2012)  -   | Ma Rainey  | Little Low Mama Blues  | Classic Blues Artwork From  the 1920's  | Gary Fletcher.  | It's Just Feel.  | River Keeps Flowing'  |   |   | Seasick Steve & The Level Devils  | Cheap  | Cheap  |   |   |   | Big Bill Broonzy  | Why Do You Do That To Me  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | The Jake Leg Jug Band  | Your Feet's Too Big  | Fifth Avenue  |   |   | Arthur Montana Taylor  | Five O' Clocks (NYC 28/6/47)  | Montana Taylor  |   |   | Bukka White  | The Promise True And Grand  | The Vintage Recordings 1930 -1940  | Gladys Bentley  | Ground Hog Blues (1928)  | Broadcasting the Blues, volume 2  | Merle Travis  | Louisiana Boogie  |   |   |   | Blind Willie McTell  | That Will Never Happen No More (Remastered 2018)  | Last Session - Remastered  | Prestige/Bluesville Records  | J.B. Lenoir  | If I Get Lucky  | American Folk Blues Festival 1962-1965  CD5  |  

Dr. John Lewis earned his BS in Business Administration from University of Tennessee, his MS in Exercise Physiology also from the University of Tennessee and then his PhD in Education and Psychological Studies from University of Miami in Coral Gables, Florida. In the 90's and early 2000's he grew in rank at the University of Miami Miller School of Medicine in various areas of research. I tracked him down in 2014 to find out more about his study titled “The Effect of an Aloe Polymannose Multinutrient Complex on Cognitive and Immune Functioning in Alzheimer's Disease”.RESOURCES:Get Daily Brain Care:https://drlewisnutrition.com/Visit the Show Blog Page:https://drhaley.com/reversing-alzheimers-diseaseSubscribe to Dr. Lewis on YouTube:https://www.youtube.com/channel/UC5xvuUBaSGsAuSo4ZxhNR0AGet Aloe from Haley Nutrition:https://haleynutrition.com/Who is Dr. Reg McDaniel:https://www.drreg.net/about/TIMESTAMPS:00:00 Intro Snip00:41 Introduce Dr. John Lewis01:40 How is it possible "Sugar Is Good For You"?04:07 What was the study "The effect of an aloe poly mannose multi nutrient complex on cognitive and immune functioning in Alzheimer's disease" about?04:25 Why aren't studies of this nature typically financed through organizations like NIH and Alzheimer's Association?10:33 Why a couple was willing to donate so much money to study nutrition for a disease process when even positive results would only amount to dietary recommendations11:25 A psychiatrists perspective that food could never help - only drugs work. (He was wrong!)12:10 Why doctors are so blind to the fact that nutrition plays such a large role in the allowance of and recovery from disease.13:00 Dr. Reg McDaniel's ("Reg") story about realizing how nutrition plays a role in disease and may even make the HIV viral load undetectable.16:50 How Dr. Wesley Calvin, a naturopath, had patients with HIV that became "HIV undetectable" by consuming aloe vera.20:30 How the psychiatrist that was part of the aloe multi-nutrient study came to realize that nutrition could make a difference.22:19 What was the product used in the study on cognitive health and Alzheimer's disease?23:37 how positive were the results of this study?23:56 What is the "ADAS-Cog"?24:55 What is the difference between clinically and statistically significant?28:41 What is the amount of product people had to have to get these positive results and is more better?29:53 Can you consumer more than is recommended?30:27 What is your theory on how the mechanism of the benefit was?31:07 What is the CD4 to CD8 ratio and how was it affected by the multi-nutrient complex used in your study?33:20 How did the polymannose multi-nutrient product affect stem cell production?35:10 What is neuroplasticity?37:10 What is the summary of benefits shown by this study?39:40 Product Reveal "Daily Brain Care" in the canister and capsules44:49 What are the special sugar molecules found in the "Daily Brain Care" products?52:00 The study done in the 30's showing mannose when given to rats that were in ketosis53:27 Dr. Robert LoPinto who mentioned Dr. John Lewis and his lecture at the FCA55:08 What is the principle investigator?55:43 What does "peer reviewed" mean?

Jen Schultz, Congressional candidate for CD8 joins the show; Matt discusses her opponent Pete Stauber; more fallout from Trump campaign violations at Arlington National Cemetery; Republican racism in money allocations; right-wing media goes after Democratic-donating State Fair donut stand; Bloomington Kennedy will drop hockey; disappointing test results; Michael Brodkorb makes a visit.

Kari Lake advances to face far left Democrat, who now plays the part of centrist, Rubin Gallego. No surprise! But what were the surprises Tuesday night in the Arizona Primary? Rob Wilson joins me to break down the BIG results in LD1 between Ken Bennett & Mark Finchem, LD7 and the controversial race for the AZ House as well as the slugfest between Wendy Rogers and David Cook in the LD7 senate race. We'll also hit on the CD2 and CD8 congressional races and several mayoral elections. We'll also analyze and guess as to what this all means going into the general election in November.    Rob and I also discuss an attempt to block uranium ore transport in NAZ, another grilling of the Secret Service by Congress, the Middle East flaring up even more and a windmill story.    —————————————— Please FOLLOW or SUBSCRIBE to the Jeff Oravits Show! RUMBLE   YouTube   ApplePodCasts   AmazonMusic   Spotify        Also on Twitter and www.TalkWithJeff.com   Disclaimer: The information provided on the Jeff Oravits Show does not constitute legal, medical, financial or tax advice.  All information is the opinions of the host's and his guests.  You should always seek the advice of a professional regarding any of these complex issues to make sure all circumstances of your situation are properly considered.   ——————————————

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

In this episode, we sit down with Dr. John Lewis, a leading expert in nutritional research and the therapeutic potential of Aloe polysaccharides. Dr. Lewis shares insights from his groundbreaking studies on Alzheimer's disease, multiple sclerosis (MS), and the broader impacts of Aloe polysaccharides on immune function and brain health. Key Topics Discussed Understanding Aloe Polysaccharides What are Aloe polysaccharides? How are they extracted and formulated for nutritional supplements? Research on Alzheimer's Disease and Multiple Sclerosis Overview of Dr. Lewis's studies on Alzheimer's disease and MS. Impact of Aloe polysaccharides on cognitive function and disease progression. Immune System Modulation Effects of Aloe polysaccharides on CD4 to CD8 ratios. Regulation of key cytokines: TNF-alpha, VEGF, and BDNF. Balancing TH1 and TH2 responses. Brain Care Formulation Detailed discussion on the Brain Care formulation developed by Dr. Lewis. Clinical results and patient outcomes. Challenges in Nutritional Research Funding difficulties for nutritional and supplement research. Issues with the pharmacological model of placebo-controlled randomized double-blind trials. Why this model is challenging for evaluating supplements and nutritional interventions. Future Directions and Innovations Potential future applications of Aloe polysaccharides in other health conditions. Innovations in nutritional research methodologies. Key Takeaways Aloe Polysaccharides: Naturally occurring compounds with significant therapeutic potential, particularly in modulating immune function and supporting brain health. Clinical Research: Dr. Lewis's studies highlight the positive effects of Aloe polysaccharides on Alzheimer's disease, MS, and overall immune health. Nutritional Research Challenges: The current pharmacological model of clinical trials poses challenges for the study of supplements, necessitating new research approaches. Research References Studies on Alzheimer's disease and Aloe polysaccharides: Positive impacts on cognitive function and disease markers. Research on MS: Aloe polysaccharides and their role in managing symptoms and progression. Immune modulation: Detailed findings on CD4/CD8 ratios, cytokines (TNF-alpha, VEGF, BDNF), and TH1/TH2 balance. Dr. John Lewis provides compelling evidence on the health benefits of Aloe polysaccharides and underscores the need for innovative research methodologies in nutritional science. This episode offers valuable insights for anyone interested in the intersection of nutrition, immune function, and brain health.Connect with Dr. John Lewis Website: Dr. John Lewis Nutrition If you want to get Daily Brain Care visit our online curated range of cutting edge longevity and anti-aging supplements at  BIO John E. Lewis, Ph.D. is the Founder and President of Dr Lewis Nutrition™. Dr. John E. Lewis has spent most of his career developing a unique approach as someone who "walks the walk" through all of his combined professional and personal experiences to attaining optimal health through nutrition, dietary supplements, and exercise. Throughout his research career, he has evaluated many different nutritional approaches to enhancing well-being, particularly for brain health, immune function, and counteracting aging. He can separate fact from fiction regarding how to utilize nutrition and dietary supplements to help you achieve and maintain optimal health. If you need a trusted source of information, products, and services, then look no further than Dr. Lewis and how he can help you achieve your health-related goals. Professional Career Dr. Lewis is past full-time Associate Professor in the Department of Psychiatry and Behavioral Sciences at the University of Miami Miller School of Medicine and the Founder and President of Dr Lewis Nutrition™. He is a Diplomate, Faculty Member, and Advisor of the Medical Wellness Association. He has been the principal investigator of over 30 different studies on human health in his research career. During that time, he either directly raised or indirectly supported raising over $23 million in grants, gifts, and contracts for research studies and clinical trials and educational programs for medical students. In addition to his research, Dr. Lewis has been an invited national and international lecturer and guest speaker at conferences and as a guest on television shows. He is a well-known author with over 180 peer-reviewed publications in some of the world's leading scientific journals. He has also mentored many different students, from undergraduates to post-doctoral trainees, in not only how to conduct clinical research but to apply the principles of health promotion into daily practice. Research Interests Much of Dr. Lewis's research has focused on evaluating the effects of nutrition, dietary supplements, and exercise on various aspects of human health. He and his colleagues have been continually searching for ways to help people achieve and maintain health through natural treatments that align with our physiology. A primary stimulus for the origin of Dr Lewis Nutrition™ occurred after Dr. Lewis ran his landmark study on how an aloe polysaccharide multi-nutrient complex improved cognitive and immune functioning after 12 months in persons with moderate to severe Alzheimer's disease, leading to the creation of the dietary supplement, Daily Brain Care. Daily Brain Care showed clinically and statistically significant improvements in cognition according to the ADAS-cog cognition score and statistically significant improvements in inflammation (according to TNFα and VEGF), immune function (according to the CD4/CD8 ratio), and adult stem cells (according to CD14+ cells). His seminal publication from the study in the Journal of Alzheimer's Disease not only spurred him to leave academics and pursue a science-based business career, but also enabled him to be selected for a widely-acclaimed TEDxMiami talk. Founding Dr Lewis Nutrition™ While Dr. Lewis still maintains an academic affiliation, he chose to leave a full-time research career to pursue his true passion of helping people achieve health through nutrition, dietary supplements, and exercise. His research in brain health and immune function was key in the creation of Daily Brain Care, but afterward he chose to shift into business where the opportunity to reach a larger audience is greater. Dr Lewis Nutrition™ is the vehicle through which Dr. Lewis leverages his many years of personal and professional work to spread a message of health that is so desperately needed, particularly for those who are afflicted with an all-too-common chronic disease, e.g., neurodegeneration, immune dysfunction, or cardiac and metabolic disorder. Dr. Lewis will continue to be a thought leader to help people utilize the power of nutrition and dietary supplements and learn how to take control of and optimize their health.         Personalised Health Optimisation Consulting with Lisa Tamati Lisa offers solution focused coaching sessions to help you find the right answers to your challenges. Topics Lisa can help with:  Lisa is a Genetics Practitioner, Health Optimisation Coach, High Performance and Mindset Coach. She is a qualified Ph360 Epigenetics coach and a clinician with The DNA Company and has done years of research into brain rehabilitation, neurodegenerative diseases and biohacking. She has extensive knowledge on such therapies as hyperbaric oxygen,  intravenous vitamin C, sports performance, functional genomics, Thyroid, Hormones, Cancer and much more. She can assist with all functional medicine testing. Testing Options Comprehensive Thyroid testing DUTCH Hormone testing Adrenal Testing Organic Acid Testing Microbiome Testing Cell Blueprint Testing Epigenetics Testing DNA testing Basic Blood Test analysis Heavy Metals  Nutristat Omega 3 to 6 status and more  Lisa and her functional medicine colleagues in the practice can help you navigate the confusing world of health and medicine . She can also advise on the latest research and where to get help if mainstream medicine hasn't got the answers you are searching for whatever the  challenge you are facing from cancer to gut issues, from depression and anxiety, weight loss issues, from head injuries to burn out to hormone optimisation to the latest in longevity science. Book your consultation with Lisa    Join our Patron program and support the show Pushing the Limits' has been free to air for over 8 years. Providing leading edge information to anyone who needs it. 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Lisa is constantly researching and interviewing the top scientists and researchers in the world to get you the best cutting edge supplements to optimize your life.   Subscribe to our popular Youtube channel  with over 600 videos, millions of views, a number of full length documentaries, and much more. You don't want to miss out on all the great content on our Lisa's youtube channel. Youtube   Order Lisa's Books Lisa has published 5 books: Running Hot, Running to Extremes, Relentless, What your oncologist isn't telling you and her latest "Thriving on the Edge"  Check them all out at  https://shop.lisatamati.com/collections/books   Perfect Amino Supplement by Dr David Minkoff Introducing PerfectAmino PerfectAmino is an amino acid supplement that is 99% utilized by the body to make protein. PerfectAmino is 3-6x the protein of other sources with almost no calories. 100% vegan and non-GMO. The coated PerfectAmino tablets are a slightly different shape and have a natural, non-GMO, certified organic vegan coating on them so they will glide down your throat easily. Fully absorbed within 20-30 minutes! No other form of protein comes close to PerfectAminos Listen to the episode with Dr Minkoff here:    Use code "tamati" at checkout to get a 10% discount on any of their devices.   Red Light Therapy: Lisa is a huge fan of Red Light Therapy and runs a Hyperbaric and Red Light Therapy clinic. If you are wanting to get the best products try Flexbeam: A wearable Red Light Device https://recharge.health/product/flexbeam-aff/?ref=A9svb6YLz79r38   Or Try Vielights' advanced Photobiomodulation Devices Vielight brain photobiomodulation devices combine electrical engineering and neuroscience. To find out more about photobiomodulation, current studies underway and already completed and for the devices mentioned in this video go to www.vielight.com and use code “tamati” to get 10% off     Enjoyed This Podcast? If you did, subscribe and share it with your friends! If you enjoyed tuning in, then leave us a review and share this with your family and friends. Have any questions? You can contact my team through email (support@lisatamati.com) or find me on Facebook, Twitter, Instagram and YouTube. For more episode updates, visit my website. You may also tune in on Apple Podcasts.  To pushing the limits, Lisa and team

 | Artist  | Title  | Album Name  | Album Copyright  |  | J.D. Harris  | The Grey Eagle  | The Stuff that Dreams are Made Of (disc 1)  | Lonnie Johnson  | Lonesome Road  | Lonnie Johnson Tomorrow Night 1970  | Tampa Red  | Through Train Blues  | Tampa Red Vol. 1 (1928-1929)  |   | Lightnin' Hopkins  | Mean Old Frisco  | The Blues of Lightnin' Hopkins (1967)  | Big Bill Broonzy  | Sad Letter Blues  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Leecan and Cooksey  | Dirty Guitar Blues  | A Richer Tradition - Country Blues & String Band Music, 1923-1928  | Corey Harris  | Jack O' Diamonds  | Fish Ain't Bitin'  |   |   | Half Deaf Clatch  | Storm Brewin  | The Blues Continuum  |   | Sonny Terry and Brownie McGhee  | Worried Life Blues (Recorded Live At The Free Trade Hall, Manchester  | Chris Barber Presents The Blues Legacy Lost & Found Series  | Jake Leg Jug Band  | I Love Me  | Break A leg  |   |   | Dik Banovich  | Pay Day  | Run to You  |   |   | Blind Blake  | Fancy Tricks  | All The Recorded Sides  |   | Tom Doughty  | Come Back Baby  | You Can't Teach An Old Dog  |   | Bluesblabber  | The Ballad of Mr. Wright  | Like It Raw  |   |   | Bessie Jones & with the Georgia Sea Island Singers  | That Suits Me  | Get In Union  | Alan Lomax Archives/Association For Cultural Equity  | Peg Leg Howell  | Coal Man Blues  | Country Southern Blues  | 

RINOs slapped down in bid to oust CO GOP Chair Dave Williams.  Grassroots conservative Tim Leonard says they suffer from "Dave derangement syndrome".   With Rep. Brandi Bradley and CD8 candidate Dr. Janak Joshi.

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. 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The Chuck & Julie Show with Chuck Bonniwell and Julie Hayden With Guests, Dr. Janak Joshi, Wes Imer and Laurel Imer A great grassroots candidate has just entered the CD8 race, DFr. Janak Joshi joins the show. Plus Wes Imer and Laurel Imer have been at a contentious RNC Winter Meeting and report in. Lots to talk about regarding RNC Chair Ronna McDaniel's scandalous spending.

Questions and concerns about RNC spending.  Laurel Imer and Wes Imer report in from the RNC Winter Meeting.  Plus Dr. Janak Joshi jumps in the CD8 race.

Onita Davis, Wreathes Across America; David Muskowitz, Author/Lawyer; Blake Masters, GOP Candidate, U.S. House, CD8

Drive in with The Morning Ritual weekday mornings on KNST AM790 Blake Masters is officially in the CD8 race, which is in the west valley. He talks about moving to the district, having a primary battle with Abe Hamadeh, thoughts on Israel, Biden bringing us into WW3, the border and more.

Drs. Diwakar Davar and Ben Boursi discuss the role of the gut microbiome in the outcome of cancer immunotherapy and the prevention of immunotherapy-related adverse events, as well as compelling research on nutritional interventions to improve response to immune checkpoint inhibitors. TRANSCRIPT   Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. 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.   Researchers have shown that microorganisms in the gut can impact the effectiveness of immunogenic chemotherapy for patients with cancer. Although microbial therapies for cancer are still at a very early stage of clinical development, compelling research in recent years has shown that changing the gut microbiome can help improve outcomes in patients receiving treatments for cancer enduring immune checkpoint inhibition.  My guest today is Dr. Ben Boursi, a GI medical oncologist at the Sheba Medical Center at Tel Aviv University in Israel. Dr. Boursi is also an adjunct professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He joins me today to discuss his pivotal research on the role of the gut microbiome in mediating its effects on immunotherapy. And again, I want to highlight that we're recording this on October 9th, and as you may well know, many recent events over the last couple of days have happened in Israel, and so Dr. Boursi has joined us at a very difficult time. So, we're very grateful for him taking time out of his suddenly very busy schedule to join us at a time that is fraught for all. You'll find our disclosures in the transcript of this episode. You'll also find the disclosures of all guests on the podcast at asco.org/DNpod. Ben, it's great to have you on the podcast today. Thank you for being here at such a difficult time, sharing what will, I think, be a great episode.  Dr. Ben Boursi: Thanks for having me, Diwakar. Dr. Diwakar Davar: Ben, the gut microbiome and its role in terms of mediating effects and side effects of cancer immunotherapy has gotten a lot of interest recently. You've done some fundamental work in this space. Why don't you briefly summarize for the audience, firstly, what is the gut microbiome and what are the major themes in relation to cancer immunotherapy?  Dr. Ben Boursi: Well, the microbiome is the ecosystem of microorganisms, bacteria, phages, fungi, that are crucial for immunologic, metabolic and hormonal homeostasis of the host. In the last decade, we began to understand the central role of the gut and tumor microbiome in tumorigenesis, metastasis, treatment efficacy and toxicities, and in 2022, polymorphic microbiomes became one of the hallmarks of cancer, in addition to previous hallmarks that focused mainly at the cellular/genetic levels. The initial studies in mice models showed that therapeutic efficacy of immunotherapy depends on both the presence and composition of the microbiota (In germ-free or antibiotic treated mice, immunotherapy is ineffective), and following these studies, three observational studies in human patients showed that the gut microbiome can predict response to immunotherapy and that response to immunotherapy could be transferred to germ-free mice by fecal microbiota transplantation (FMT) from responding patients.  These studies helped us to define three main research questions regarding the possible role of microbial modulation in cancer treatment. First, can microbial modulation overcome resistance to immunotherapy, both primary and secondary resistance? And this question was the focus of the initial proof of concept studies. Second, can microbial modulation improve response to immunotherapy in treatment-naive patients? And third, can microbial modulation prevent or treat immune related adverse events? The initial positive results of clinical trials also led to additional questions. For example, can microbial modulation induce anti-tumor immune response even in non-immunogenic tumors? And it is important to note that there are many ways to modulate the microbiota, but so far, the only reliable way that showed positive results is fecal microbiota transplantation that allows the transfer of the entire microbiota both in terms of composition and relative abundance. Dr. Diwakar Davar: That's great. Essentially with the trials that I think the data sets that you're referencing of course, are papers by Jennifer Wargo, Thomas Gajewski, and Lawrence Zitvogel, looking at the role of gut microbiota in several different cancers, primarily immune checkpoint sensitive tumors such as melanoma, non-small cell lung cancer and kidney cancer. And then the work from several different groups showing that essentially proof of concept experiments can be done to try to change this, certainly preclinically, and now we know that that can be done clinically.   So, I guess the failure rates of immunotherapy in some patients are quite high. And we know that the microbial composition can change the likelihood to respond to immunotherapy based on all these trials. And actually, even going back to 2015, we had two seminal papers that looked at the role of CTLA-4 blockade as well. But subsequently, many years after that, 7 years after 2015, and certainly 3 years after 2018, when the three observational PD-1 papers were published, there were 2 pivotal trials in PD-1 advanced or refractory melanoma. They demonstrated that changing the gut microbiome can reprogram the immune system to attack tumors. So, there were 2 separate trials, both published the same issue of Science. One trial was led by your group at Sheba, and another one's led by us, the University of Pittsburgh. Why don't you summarize both studies for our audience. Dr. Ben Boursi: So, both studies were Phase I clinical trials of FMT in metastatic melanoma patients who failed immunotherapy. Recipients were metastatic melanoma patients that progressed on at least one line of anti PD-1 and in BRAF mutated patients, BRAF inhibitors as well. Donors in the Sheba study were metastatic melanoma patients with durable complete responses to immunotherapy for at least one year, and in the Pittsburgh study, you also included patients with durable partial responses of more than two years as donors. It is important to note that each fecal transplant in both studies was composed of a single donor. Prior to transplantation, we performed a microbiome depletion phase using a combination of two antibiotics, vancomycin and neomycin. The goal of this phase was to assist in engraftment (by avoiding colonization-resistance by recipient bacteria) and to “reset” the immune system, which may remind some people of the logic behind bone marrow transplantation. In the Pittsburgh study, there was no bacterial eradication with antibiotics, mainly because of studies showing that response to immunotherapy is lower following antibiotic treatment.  Both studies performed FMT through colonoscopy. At Sheba, we also performed maintenance FMT using capsules in order to keep the donor's microbial composition. After the initial FMT, both studies reintroduced the same immunotherapy in which the patient progressed in the past. Clinically, we have seen a 30% response rate with durable, complete and partial responses, and in the Pittsburgh study, there was a 20% response rate and 40% disease control rate. Both studies showed following FMT, immune response in the gut and in the tumor, and tumors that were immune deserts prior to FMT became infiltrated with lymphocytes. Interestingly, in our study, there were no moderate to severe immune related adverse events following FMT and reintroduction of immunotherapy. And this is despite the fact that five of the patients had significant side effects during previous rounds of the same immunotherapy.  Dr. Diwakar Davar: So essentially, in these very early proof of concept studies, what I think is pretty remarkable is that obviously the sample sizes were very small, but remarkably, patients that appeared to respond, responded in a setting in which they were not expected to respond. So, the probability of a patient responding to attempt at giving PD-1 in patients who were PD-1 relapse refractory is on the order of about 7%, based on an FDA analysis by Viva et al. And here, two separate studies, two independent studies, investigators had not known that each paper was being published, remarkably similar results clearly demonstrating that this is perhaps one of the best pieces of evidence to suggest that microbiome modulation may actually truly be effective in reversing PD-1 refractoriness.  More recently, our colleague Dr. Bertrand Routy at University of Montreal has done a proof of concept trial in evaluating the use of healthy donor fecal microbiota transplant in addition to anti PD-1 monotherapy in PD-1 naive metastatic melanoma. In this study, published in Nature Medicine a few weeks ago, his group reported an objective response rate of 65%. What are your thoughts about this study? And specifically, what are your thoughts about some of the pharmacodynamic and translational results that were demonstrated?  Dr. Ben Boursi: This is a very interesting question, because in both the Sheba and the University of Pittsburgh studies we chose responding patients as donors. We thought that by using these patients, we provide beneficial bacteria that enhance responses to immunotherapy through several mechanisms (molecular mimicry, immunomodulatory bacterial metabolites, modulation of immune checkpoint expression, and much more), and here in the Routy paper, the researchers used FMT from healthy donors without any selection for specific beneficial bacteria, and they demonstrated a similar effect on overall response rate. So maybe FMT works actually through reducing colonization by deleterious bacteria? Another question that we should ask is whether we need to choose donors differently when we use microbial modulation in treatment resistant patients compared to treatment-naive patients? Moreover, a previous meta-analysis of FMT studies across indications that was conducted by the group of Dr. Nicola Segata, demonstrated that recipients with better engraftment were more likely to experience clinical benefit, and that increased engraftment was mainly observed in individuals receiving FMTs through multiple routes, colonoscopy and capsules, as well as recipients that received antibiotics prior to FMT. But in Routy's trial, they not only used healthy donors, they performed bacterial cleansing only prior to FMT instead of bacterial eradication with antibiotics, and used FMTs through colonoscopy only, and they didn't give maintenance FMT. Of course, such an approach is much more feasible in the clinical setting and is relevant for designing future clinical trials.  Dr. Diwakar Davar: So, many differences, relatively few similarities, but I guess one interesting point is that of engraftment, which is that in your paper, our paper, and certainly in Bertrand's paper, it is very interesting that engraftment appears to be a key pharmacodynamic biomarker of microbiome modulation. And certainly, the analogy that you used earlier, which is that it's very similar to what happens in a stem cell transplant, which is that if there's no take, there's probably not going to be any effect. So that's very interesting that engraftment is emerging as a key PD biomarker of essentially the success of any kind of microbiome modulation across multiple different settings.  Now, we've heard of certainly defined microbial consortia, of cultivated species, as an alternative gut microbiome modulation strategy that balances the benefits of the ecological complexity of FMT with the scalability and practicality of probiotics. Do you think we are ready to design consortia?  Dr. Ben Boursi: So to date there are several probiotics that use a single bacteria and several microbial consortia that were evaluated in clinical trials, and as you mentioned, they may offer more tractable solutions for widespread clinical use. If we begin with the single bacteria probiotics, two phase 2 clinical trials found that administration of the butyrate producing probiotic clostridium butyricum 588 (CBM588) to immunotherapy naive patients with metastatic renal cell carcinoma led to markedly better immunotherapy responses, although the probiotic had a minimal effect on the composition of the microbiota, and the control arm of the trial responded worse than expected. In addition, in preclinical studies, probiotic strains of lactobacillus and bifidobacterium have been shown to enhance immune control of transplanted tumors and to augment anti PD-1 activity. However, a clinical trial in patients with metastatic melanoma found that the use of lactobacillus or bifidobacterium probiotics was associated with reduced microbiota diversity and worse responses to anti PD-1.  So here the conclusion is that when we try to design probiotics, we should not focus only on the composition since other factors, such as the relative abundance also matter. Too much of a beneficial bacterial species may potentially be worse than having a balanced and diverse microbiota. For example, a recent study of patients with non-small cell lung cancer receiving immunotherapy found that patients with a detectable Akkermansia muciniphila in their gut microbiota (this is a beneficial bacteria) responded well to treatment, but those with relative abundance of Akkermansia muciniphila greater than 5% responded worse than patients lacking Akkermansia, and this is due to the mucolytic effect of the bacteria. So, the use of rationally designed consortia may be better than a single probiotic strain.  And there are currently 3 main microbial consortia that are being evaluated: the SER-401, a bacterial consortium enriched with clostridium, led in a randomized controlled trial to reduced response to immunotherapy compared to placebo control in first line metastatic melanoma patients, potentially due to a confounding effect of a vancomycin pretreatment; MET4 is a 30 bacteria consortium that was shown to be safe and to alter the gut microbiota and serum metabolome of immunotherapy naive patients. Here, the initial study was underpowered to determine the effect on treatment efficacy; And finally, VE800 is an immunotherapy enhancing 11-bacterial consortium that is currently being evaluated in phase 1 and 2 clinical trials, and we are looking forward to see the results with this agent. Dr. Diwakar Davar: So I guess where we are right now is that social design is clearly difficult because of all the reasons you've mentioned. The SER-401 data and the MET4-IO trials certainly give us pause for thought. Certainly, no pharmacodynamic changes that were seen with SER-401, MET4-IO did result in pharmacodynamic shifts metagenomically, but neither trial was positive. And certainly, the VE800 trial, which has been ongoing now for several years, and the lack of publicly reported data certainly doesn't suggest that there's a huge efficacy signal. So consortias, at least at this point, certainly do not appear to be having a significant effect, though we don't know what might happen in the future. Data from multiple groups has shown that gut microbial composition influences the development of immune related adverse events (irAEs) in both PD-1 and combination PD-1 and CTLA-4 treated patients. Unsurprisingly, as a result, there have been attempts made at evaluating the role of fecal microbiota transplants to treat refractory immune related adverse events and very specifically immune checkpoint associated colitis or IMC. So, Dr. Yinghong Wang, who is the chair of the Immunotherapy Toxicity Working Group at the University of Texas MD Anderson Cancer Center has been very prominent in this space, and in a recent paper published in Science Translational Medicine, which is a follow up paper to her early work in Nature Medicine, she reported that HDFMT, healthy donor fecal transplantation, was very efficacious in feeding early refractory immune checkpoint colitis. So, what are your thoughts on this approach and how important is this space and where else might it be efficacious?  Dr. Ben Boursi: When I talked about the Sheba clinical study, I mentioned the possible role for microbiota modulation in the prevention of immunotherapy related adverse events in general, not only colitis. But the study by Dr. Yinghong showed that FMT can actually treat immune-related colitis refractory to steroids and anti-TNF. Now, this approach is probably relevant not only for immune related colitis, but also to other immune related adverse events. We can define certain bacterial species that may be associated with different immune related events. For example, streptococci can be associated with immune related arthritis. And maybe in the future we won't need to use FMT, but we will rather be able to target these specific immunogenic strains by narrow spectrum antibiotics or phages. The main challenge would be to develop microbiotic targeting interventions that reduce immune related adverse events without compromising therapeutic efficacy.   Now, is microbial modulation relevant only for toxicity from immune checkpoint inhibitors? So, the answer is ‘no'. We know mainly from animal models of hematopoietic cell transplantation, CAR T, and immune agonist antibodies that antibiotic-treated or germ-free mice have markedly reduced immunotoxicity, such as graft versus host disease, cytokine release syndromes, and more. It is also worth mentioning that microbial modulation is relevant not only for reducing toxicity from immunotherapy, but also from chemotherapy and other anticancer modalities. And the best example is the gastrointestinal toxicity of irinotecan that is mediated by the bacterial beta-glucuronidase. And here the targeting may even be a bit less complex. Dr. Diwakar Davar: So, what we take away from that is that starting with actually your paper originally, and papers to be produced, immune-related adverse events can be prevented using microbiome modulation with FMT, and Dr. Wang's data suggesting that eventually FMT can be used to eradicate highly refractive colitis, again, this is important to keep in mind that this approach is not yet FDA-approved. It's being done under IND. It's not currently something that is a certain standard of care. One interesting area of drug development is that there's a French microbiome company named MaaT Pharma where they have an agent that is a very interestingly a pooled microbiome product from multiple different donors. Again, the trials in both Israel and Pittsburgh used individual donors. This is a pooled donor construct. The lead candidate is actually graft versus host disease. The trial is the ARES trial, A-R-E-S, as in the Roman god of war. This trial is actually ongoing in Europe, and I believe there's some effort to try to see whether or not it's going to be a trial that can be done in the United States as well. So, at this point in time, again, we don't know whether or not there are any developmental approaches from a pharmaceutical company in the United States, but certainly this is definitely an area of interest.  So microbial therapies are still relatively early. It's going to be interesting to see how the advanced field of nutritional interventions provide an appealing method for modulating the gut microbiome due to the excellent safety profile, cost effectiveness and noninvasiveness. And certainly, if you are what you eat and your bacteria are what they eat, which goes down to our diet, there's enough rationale to believe that certain nutritional interventions can have an effect via the intermedial gut microbiota modulation. Holistic dietary changes and or supplementation specific nutrients such as prebiotics could therefore be utilized to specifically shape the population of beneficial microbes and shift the immune microbiota landscape. Now, we have seen in data published by several of our colleagues that in patients with cancer, high fiber intake is associated with greater microbial diversity, greater abundance in fiber fermenting microbes such as members of the Ruminococcaceae family, and these are all associated with the response to checkpoint inhibitor therapy. So, what do you think about nutritional interventions? Do you want us to briefly summarize data regarding nutritional data and where it stands in cancer at his time? And can you speculate as to how effective this might be in the context of patients with cancer? Dr. Ben Boursi: So, let's begin with diet. A growing number of clinical and preclinical studies suggest that specific dietary interventions such as a high fiber diet can not only improve response to immune checkpoint blockers, but also reduce immunotoxicity such as graft versus host disease. And there are many other diets that are being tested such as ketogenic diets and intermittent fasting. And the effects of diet may be mediated by both microbiota-dependent and microbiota-independent mechanisms. The limitation of this approach is that changes to the microbiota induced by diet are generally quite variable between patients and can depend on an individual's microbiota prior to intervention. And patient compliance is also a concern, particularly in the very strict diets.  Now, regarding high fiber diets, several large cohorts of melanoma patients from the US, Australia, and the Netherlands demonstrated how a high fiber diet modulates the microbiome and results in a better response to immunotherapy, better progression-free survival. Additional studies that were presented at AACR in 2023 showed that high fiber dietary interventions, in which patients received a fiber-enriched diet for six weeks, was feasible and that the high fiber diet resulted in a rapid shift in the gut microbiota toward fiber-responsive short chain fatty acid-producing taxa and a shift of the metabolome, with increase in the short chain fatty acid acetate, Omega-3, Omega-6, polyunsaturated fatty acid, and tryptophan metabolites. Prebiotics can also promote the growth of beneficial microbial species in the gut by providing targeted nutrition. And one example of a prebiotic that was shown to enhance immunotherapy efficacy in mouse models is castalagin, which is isolated from the camu-camu berry. Castalagin directly binds the outer membrane of ruminococci and promotes their growth, which has been shown to increase the CD8-positive T-cell activity and anti-PD-1 efficacy. Now, since prebiotics rely on the presence of beneficial taxa already in the host microbiota, symbiotics, which refers to the administration of the appropriate prebiotic and probiotic together, may prove in the future to be more effective than using either separately. Dr. Diwakar Davar: Certainly, these dietary interventions can be very exciting and certainly we do know of several colleagues who are doing these diet interventions, though compliance with any kind of dietary intervention may be a challenge that decides how effective such an approach is going to be. So microbial therapies in general are still at a relatively early stage of development. And it'll be exciting to see how they advance. What approaches are you excited about? What is on your radar?  Dr. Ben Boursi: There are many exciting works that are currently ongoing, and to emphasize just a few: there are many clinical trials in immunogenic tumors, in addition to melanoma, for example, renal cell carcinoma, and non-small cell lung cancer, that also evaluate different modulation protocols. We should remember that one size does not fit all, and different tumors have different microbiomes. We have a project in collaboration with MD Anderson in MSI-high patients with exciting initial results. Another study that was initiated at Sheba is using microbial modulation in order to improve TIL therapy (to overcome resistance to TIL and T-cell exhaustion). There are also studies that try to change the pharmaco-microbiome, for example, to eradicate bacteria that inactivates the chemotherapy agent, gemcitabine, in pancreatic cancer patients. And there are groups that try to identify recipients that will respond to microbial modulation and to generate better donor-recipient matching algorithms. There are already signatures like TOPOSCORE that was presented at ASCO 2023 that try to predict response to immunotherapies through the ratio between harmful and beneficial bacteria. Now, there's also more basic science work, for example, bacterial engineering. There was a wonderful study from the Fischbach group in Stanford that demonstrated how Staphylococcus epidermidis engineered to express melanoma tumor antigens was able to generate a systemic tumor-specific response in mice models when applied topically; functional imaging of the microbiome, for example, FDG uptake in the colon can reflect microbial diversity and response to immunotherapy; works that characterizes other microbiomes such as the urinary and skin microbiomes, and their interaction with the gut microbiome; and studies of the nonbacterial component of the microbiome, mainly phages and fungi. But for me, the most important word should probably be collaboration, because without joining forces internationally, we won't be able to understand the human metaorganism, the variations according to geography, ethnicity, lifestyle, diets, and much more in the microbiome. And this is crucial in order to really understand the complex tumor ecological niche within the human host. Dr. Diwakar Davar: I think one of the key points that you just mentioned is collaboration. That's going to be very, very critical as we move this forward for many reasons, including the unexpected impact of geography upon the composition of the gut microbiome in work that has been published by many groups, but also including ours in a paper that we published about a year ago now.  So, Dr. Boursi, thank you for your great work in this area. Thank you for sharing your insights with us today on the ASCO Daily News Podcast. This is a very difficult time for all of you and your colleagues in Israel, and we thank you so much for taking such a great deal of time out of your busy workday to spend some time with us.  Dr. Ben Boursi: Thank you very much. Dr. Diwakar Davar: Thank you to all our listeners today. This is a very exciting area. This is an area where we are discovering more every day than we knew just up until the day prior. You will find the links to the studies that were discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take the time to rate, review, and subscribe wherever you get your podcast.  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. Guests' 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  Dr. Ben Boursi   Follow ASCO on social media:   @ASCO on Twitter    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. Ben Boursi: No relationships to disclose.        

Dr. John Lewis discusses The Benefits of Polysaccharides with Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on my WeitzChiro YouTube page.]    Podcast Highlights 13:26  Polysaccharides.  Polysaccharides are complex sugars and some of them have unique health promoting properties, including those that come from aloe vera and from rice bran.  Aloe vera is 99% water, so you have to extract the polysaccharides out of the aloe vera plant and this acetylated polymannose has amazing properties. 20:25  Polymannose.  Dr. Lewis met Dr. Reg McDaniel who had been working on the aloe plant since the 1980s at the Texas A & M vet school, who is still doing research at 87 years of age.  Dr. McDaniel shared studies that these aloe derived polysaccharides were anti-inflammatory, antioxidant, antiproliferative, and have wound healing benefits.  He found that in addition to the wound healing and stem cell production boosting function of aloe vera, this polymannose is a key sugar when the endoplasmic reticulum and the Golgi of the cell are communicating with each other and making other bioactive compounds that you need.  This polymannose is similar to d-mannose, which is often recommended as part of a protocol along with L-carnitine and CoQ10 for supporting the heart muscle in patients with congestive heart failure, though Dr. Lewis's research was more focused on brain health. 25:51  Aloe polymannose multinutrient complex.  In their study on the polysaccharides for Alzheimer's patients, Dr. Lewis and colleagues used an aloe polymannose multinutrient complex, including aloe polymannose, rice bran, larch tree, cysteine, lecithin, tart cherry, inositol hexaphosphate, yam, flax seed, citric acid, and glucosamine.  They gave the patients this nutritional supplement four times per day in a powdered form that put into a liquid to drink. For the Alzheimer's study, they took patients with moderate to severe disease, which means the sickest of the sick and this group is the hardest to see improvements with.  The neuropsychological testing showed a significant improvement at nine and twelve months. 35:06  Alzheimer's study lab results. The lab results showed statistically significant reductions in VEGF and TNF alpha.  There was an improvement in CD4 to CD8 ratio, which obviously is very important for all of us.  They also showed an improvement of just under 300% in CD14 cells, which is a marker of adult stem cells.  And the average age of these patients were 79.9 years of age.  They theorized that these adult stem cells migrated to the brain and created new neurons, new synapses, and repaired damage to neurons.  Also BDNF levels went up by 11%, though this was not considered to be statistically significant.  They did not ask these Alzheimer's patients to change their diet or to exercise or do anything else to improve their lifestyles.  We can only imagine how much more benefit might have been derived if this nutritional intervention were used as part of a Functional Medicine approach that also put them on a healthy diet and had them perform vigorous exercise and do brain stimulating exercises as well, such as the approach used by Dr. Dale Bredesen. [The Effect of an Aloe Polymannose Multinutrient Complex on Cognitive and Immune Functioning in Alzheimer's Disease.] 44:45  MS study. These patients with relapsing remitting MS were placed on a similar aloe polymannose multinutrient complex four times per day for 12 months.  The FAMS (Functional Assessment for MS) questionaire was used for functional assessment and results showed very significant improvements in every scale.  MS patients frequently get infections and these patients who took the nutritional intervention had much fewer infections.  Serum biomarkers, quality of life, symptom severity, and functioning also improved.

In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash  from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: “Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium”. The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Davide Soldato: Welcome to this JCO Article Insights episode for the July issues of JCO. This is Davide Soldato and today I will have the pleasure of interviewing Dr. Abdul Rafeh Naqash, the author of the manuscript titled "Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium."  Dr. Naqash is an Assistant Professor of Hematology-Oncology at the University of Oklahoma and a Medical Oncologist working at the Stephenson Cancer Center. His research interests revolve around early-phase clinical trials in solid tumors, lung cancer, and the study of immunotherapy, biomarkers, and resistance.  Welcome, Dr. Naqash, and thank you for accepting our invitation today. Dr. Abdul Rafeh Naqash: Dr. Soldato, thanks so much for having me. I'm really excited to discuss this article with you today. Davide Soldato: So I just wanted to go a little bit over the manuscript with you. So basically, this is a retrospective multicenter study that was conducted across the US, Europe, and Australia by the CATCH-IT Consortium. And so the aim of the study was really to investigate the safety and the activity of immune checkpoint inhibitors among patients diagnosed with cancer and also living with HIV. The article examined two different cohorts, and I just wanted to start with a brief explanation of how the two cohorts were built so that our readers can get a little bit of understanding of what you did then. Dr. Abdul Rafeh Naqash: Sure. Before I take a deep dive into the cohorts, Dr. Soldato, I would definitely like to mention the premise and the background for this paper as to why we did what we did. And one of the primary reasons was that people living with HIV, historically, there have been very limited number of trials that have included these individuals. So it becomes a very important question from a disparity standpoint. And most often we end up, in the real world setting, we end up extrapolating data from clinical trials, but not necessarily know what is the outcome of these individuals in the real world setting.  So there have been some very important studies in the last three years or so in people with HIV as far as clinical trials with checkpoint inhibitors go, but most of those trials have been limited by the number of patients, number of people that have been part of those trials. So we wanted to understand it from a broad perspective, whether it is from a broad geographic perspective or from a heterogeneous patient population perspective, which is why we built this consortium called the CATCH-IT Consortium, which basically stands for Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International Consortium. And this required a lot of effort from a lot of different centers, including those in the US, Europe, and Australia, as you mentioned. And then we ended up having data worth around 400 plus patients, close to 400 patients or so. And then we wanted to look at obviously outcomes, whether it's related to a certain tumor such as lung cancer, which we did in this case, or a pan tumor assessment of toxicities and safeties.  So, to your question, the cohorts that we basically had, we had close to approximately 390 patients that we included in the safety analysis. So first we looked at the safety analysis, which was the entire cohort, and then out of those we excluded around 12 patients or so. Those were patients that were treated in the adjuvant setting. So in the metastatic advanced setting, we had close to 378 individuals that we assessed clinical outcomes for. So, response rates, progression-free survival, and overall survival. And then as far as a separate cohort, we looked at non-small cell lung cancer, which was the most commonly represented tumor type, with approximately 111 patients that had non-small cell lung cancer. We did exclude a certain proportion of those that were earlier stage, stage III.  So in the stage IV, basically we ended up matching in this separate cohort, around 60 odd patients or so of non-small cell lung cancer to 110 stage four, non-small cell lung cancers. So basically it was a one-to-two matching and we chose the same site. So if a site had, let's say, two people with HIV and lung cancer treatment checkpoint, we tried to match it to approximately four to five patients from the same site and we used some variables for matching so that we had some level of homogeneity between the HIV patient population and the non-HIV positive lung cancer individuals. So that's basically cohort A was around 370-something patients, tumor agnostic advanced metastatic setting. Cohort B was lung cancer individuals matched to non-HIV positive lung cancer treatment checkpoint inhibitors. Davide Soldato: Thank you very much. That was very clear. Just to go back to what you were saying before because I think that this is very interesting. You mentioned that patients living with HIV were mostly excluded from clinical trials and in the few that included them, there were some restrictive criteria in terms for example of CD4-positive cells in the blood. And so I was wondering if when you included the patients inside of this cohort, you also had this type of exclusion criteria or you chose a broader population to make the results more generalizable and applicable in clinical practice.  Dr. Abdul Rafeh Naqash: Right, a very important question. Thank you, Dr. Soldato. So yes, previous clinical trials have had some level of restrictions as far as the inclusion of these individuals, but in our study, this was a real-world study, basically, patients whoever presents to the clinic with a history of HIV, they were all included. So we did not restrict it to certain CD4 counts or viral loads because the important thing was we wanted to understand the ground situation of how these individuals do, irrespective of some of these limitations. As far as what we identified as baseline CD counts or HIV viral load positivity, we took three months before immune checkpoint initiation as a cut off so obviously there's a limitation there. We didn't have results of these CD4, CD at a viral load assessments done like the day of or the week before in some patients. So we took three months and we included individuals that had received at least one or more dose of immune checkpoint therapy between January of 2015 to October of 2021, which was our database lock.  And then obviously the regimens included immune checkpoint anti-PD1, PD-L1 monotherapy, or in combination with other anticancer agents including anti-CTLA-4 or chemotherapies targets, which is important to point out here. So the trials that have been mostly done in this space are single-agent checkpoint inhibitors or anti-PD1 with anti-CTLA-4. There's not much data for immune checkpoint inhibition combined with other agents such as targeted therapies, chemotherapies. So we had some of that data in this cohort, which kind of made it interesting. Davide Soldato: Yeah, I think that it's very interesting and it's very wise to choose very broad eligibility criteria for these type of studies because it really answered to the question that we identified and that we spoke about in the beginning.  So going back to the results, you said that the cohort A, so the one that included all the patients, irrespectively of the type of tumor that was diagnosed, it was mainly for evaluating what was the safety of immune checkpoint inhibitors in patients living with HIV and with a concurrent cancer diagnosis. So I was wondering if in this cohort you identified some differences compared to historic data in terms of, for example, incidence of grade three or higher toxicities or incidence of immune-related adverse events in general, and if maybe there was some adverse events that was very characteristic or particular in this cohort. Dr. Abdul Rafeh Naqash: So immune-adverse events is a very interesting question not only from this cohort but in general because it overlaps with this question of autoimmunity and cross T cell cross reactivity. And this is a unique patient population where we have the ability, although not fully but to some extent, to look at the role for CD counts and also look for patterns of adverse events.  To answer your first part of the question, we didn't see any significant differences for the types of adverse events. We did see the incident was a little lower than what you would expect in the real-world setting for non-HIV individuals. Whether that has something to do with how the immune system is constructed in these individuals, nobody knows. We did look at CD4 and CD8 counts. As far as absolute CD4 counts, about 200 or below 200, we didn't see a difference as far as the cumulative incidence for immune checkpoint inhibitor-related adverse events. When we did a ratio of CD4 to CD8 of greater than 0.4 and compared it to less than 0.4, we did see that at around 24 weeks, there was a difference in terms of the cumulative incidence for adverse events. It was around 10% versus 26% when we use that cut-off of 0.4, suggesting that there might be some role of how the peripheral immune system results in the related adverse events in these individuals, but it's a very important question.  I think there are ongoing evaluations that are being done from other prospective studies that had collected blood samples in these individuals. But generally, we saw the same range of adverse events, diarrhea, colitis, pneumonitis, hepatitis. We did have a few patients who had  a history of opportunistic infections, but we didn't see any significant reactivation there which was part of the safety assessment in our analysis.    Davide Soldato: So basically, because I think that in HIV patients, even if those included in the study were almost all were on antiretroviral therapy, but you didn't observe any opportunistic infection that developed during the course of immunotherapy. Dr. Abdul Rafeh Naqash: You're absolutely right, we did not. In fact, we are trying to look at that in a different setting, in a different cohort because there have been some data on mycobacterial reactivation in individuals in general, not just HIV, but in our cohort of 400 odd patients, we did not see any new opportunistic infections. Davide Soldato: I think that one aspect that pops into my mind right now is also that we have kind of some data regarding also possible HPV reactivation in these types of patients treated with immune checkpoint inhibitors. So maybe that could be also something that you would be interested to look at in the future, I imagine.  Dr. Abdul Rafeh Naqash: Yes, we are planning to look at HPV-driven cancers actually for starters, anal and head and neck. We are also looking at hepatitis B-related HCC in a separate ongoing cohort. So there are definitely subsequent steps that we are currently involved in as far as viral-driven cancers and concurrent HIV is concerned. Davide Soldato: Thank you. I think that's very interesting. And I was wondering, you mentioned in the beginning that this patient clearly they have some degree of immune dysregulation or at least some type of dysfunction in terms of immune presentation and immune activation. So I think that one of the concerns or one of the worries of using immune checkpoint inhibitors in this population could also be that the efficacy that we see in patients that do not have HIV could be lower. Could you comment on this if you found any differences both in the cohort including all cancer, but also in the cohort B, that I think you had the strategic idea of pairing these patients living with HIV with patients that were not living with HIV. So I think that this brings very important data to the space. Dr. Abdul Rafeh Naqash: Yes, we tried to look at this one from a tumor-agnostic perspective and a tumor-specific perspective. So the tumor agnostic perspective was looking at a different set of cancers which included skin cancer, melanoma, lung cancer, non-Hodgkin's lymphoma, small cell head and neck, and a couple of other cancers. And one of the things we noticed was that there was a trend, so there was differential efficacy as far as the cancer type is concerned. So for example, skin, Hodgkin's lymphoma, Kaposi sarcoma, melanoma had the highest response rates, somewhere in the range of 60s to 40s. On the other hand, viral-driven cancers such as anal cancer, HCC, head and neck actually had very low response rates, less than 15% or so. So that begs the question of what is going on and we don't necessarily know, which is why we are trying to concentrate on the viral-driven cancers first. Because as you know, melanoma, Kaposi's do have historically shown better responses to checkpoint inhibitors.   Now do we know if when we compare these responses or survival to non-HIV individuals in clinical trials, are the outcomes similar? I would say in some of the tumor types the outcomes were somewhat inferior and in some of the tumor types the outcomes were somewhat similar. So for example, lung, we did compare non-small cell lung cancer. As I mentioned, we had two cohorts, we matched it to a non-HIV cohort and there we looked at progression-free survival and overall survival. And again the caveat is that this is a retrospectively matched cohort, this is not a prospectively matched cohort. So these are individuals that are not matched for each and every variable. They're matched for certain top three or four variables as much as we could accommodate. And based on that we didn't see a difference in the progression-free survival and the overall survival when we did an assessment.  In fact, we looked at it at a 42 month period where we looked at the restricted median survival time and it was not different, was around 17.8% for people with HIV and 18.4% for people without HIV as far as progression-free survival, and around 42% and 41% overall survival at the two-year mark. So basically there is not much significant difference which reiterates the fact that in the right setting, these individuals could be safely treated with immune checkpoint inhibition and could perhaps have similar outcomes. Maybe not in all tumor types, but in some tumor types. But at the end of the day, and we mentioned this in our manuscript also in subsequent work that we are trying to do, we have emphasized on the fact that it has to be a multidisciplinary discussion between the patient, the physician, the medical oncologist, the treating oncologist, and the infectious disease person. Because these individuals have a lot of complicated aspects because of the underlying HIV and taking that into perspective and then assessing risk-benefit is an important discussion.  So the goal of this work was not to establish that immune checkpoint inhibitors are absolutely beneficial or absolutely safe. The goal was more to create awareness that people in the real-world setting actually can benefit, which the next step would be to have more trials and perhaps modify inclusion criteria in clinical trials so that you can have a more inclusive approach, including these individuals.  Davide Soldato: Coming back to the multidisciplinary approach because I think that this is very interesting and should be really implemented when we have this type of patient. From the data that you collected, did you add any indication that maybe this patient treated in the real-world setting were not managed in such a multidisciplinary way? Dr. Abdul Rafeh Naqash: The easiest way to point that out is that most of these people or many of these individuals did not have HIV viral loads or CD4 counts done before treatment initiation. And that's an indirect surrogate for telling you that these are things that should have been thought of, but were not thought of if the individual taking care of these people either did not have expertise as far as HIV is concerned or did not have a colleague on the infectious disease side who was actively managing these people.  So that's an important indirect way where we kind of got a sense that there has to be more awareness about multidisciplinary care. And especially the immune adverse event situation in these individuals can get complicated because of the way their immune system is constructed and having that multidisciplinary care is very important. We didn't specifically collect data on what teams or what subspecialists were involved in each individual's care, but I think that would be an important assessment for maybe a future quality improvement project to look at why or how some of those things were not done so that it can lead to future improvements. Davide Soldato: So, just expanding on that, you said that you didn't have much data in terms of CD4 cells or in terms of viral load. But for what you had inside of your cohort, did you see any modification of these parameters that we know that are very important in patients living with HIV under immune checkpoint inhibitors therapy? Dr. Abdul Rafeh Naqash: Again, a very important immunological question, I think as far as what we saw- so we had close to around 74, 75 individuals that had CD4 T cell counts available. And we didn't see differences between baseline and post-immune checkpoint therapy changes in CD4 counts. Similarly, we didn't see a difference as far as HIV viral load and we had HIV viral loads present in around 107 individuals and we didn't see a difference. Now, again, 30% of our cohort was CD4 count less than 200, and 70% was CD4 count more than 200, , which is again, important to highlight because many trials don't take individuals with the CD4 count less than 200. But in general, we did not see a difference in this pre and post-assessment both for viral load and both for CD4 count. Now trials in this space have ongoing assessments that they are doing. The AIDS Malignancy Consortium does have a trial looking at changes in CD4/CD8 counts or viral loads. In fact, the CITN trial which is a pembrolizumab trial published a couple of years back did have an assessment done as far as CD4 counts and viral loads are concerned. And I think they did see a slight increase in the CD4 counts and there are some aspects about how the immune system may change with an immune checkpoint inhibitor. But I think the strength of the data is not that much, and I think we probably need more patient samples to assess why or how some of that could change or what implications it would have for patients.  Now, there is another concept of HIV viral latency removal that some of the listeners might have heard of, especially in the HIV setting, where you were given an immune checkpoint inhibitor and it can lead to reversal or reduction of the HIV reservoir, which can somehow impact the CD4 counts, and also lead to elimination of the viruses through CD8. But again, that's a more complicated assessment and we didn't have data for it.   Davide Soldato: Thank you very much. That was very interesting also for future perspectives in this topic.  I just wanted to ask you if the idea for the research came more from ensuring equity in terms of care delivery for patients living with HIV or if it was more also to investigate the immunological components that we discussed just as far or a good mix of the two. Dr. Abdul Rafeh Naqash: I think the idea actually stemmed from this individual who's the first author, Dr. Talal El Zarif and co-first author Dr. Amin Nasser from Dana-Farber, reached out a year and a half back and they wanted to look at outcomes from an HIV standpoint and see what the real world setting is. And the goal was they would have their data and we would have our data and we would eventually collect the data together or combine the data together. But then after some conversations, we started looking at the available data, the available literature, saw that there was a decent gap in what we know. And I know there are some brilliant groups in the HIV space, especially at the NCI. In fact, Dr. Kate Lurain and Dr. Ramaswami are good collaborators of ours and they worked in this space and are currently developing trials in this space. But it just did seem like this would be a more interesting approach of answering a real-world question and then also looking at the disparities of it because as an early-phase drug development trialist, I still see a lot of trials, in fact, majority of the trials, say people with HIV or history of HIV are excluded.  Now, the NCI has made important efforts in that space of including those individuals, but I think we still have some ways to go. So basically the idea came from two trainees who were extremely enthusiastic and wanted to pursue this. And I, obviously, seeing their level of enthusiasm and excitement, I was excited too. And then importantly, if you look at the paper, we have a bunch of authors, we have close to 79, 80 authors on that paper. And the primary reason was that each center contributed in certain ways, including patients' data and then expertise. And this ended up being a huge community effort from the oncology community, where everybody's individual effort led to something like this coming to fruition.  So it was a multitude of different aspects, but yes, it all started with a question of how these individuals do and the current data where they're missing gaps, and we wanted to sort of supplement those gaps and provide insights using this important real-world data set. Davide Soldato: Thank you very much for the insight on how the idea came to be.  Is there anything else you would like to add or to summarize for our listeners? Dr. Abdul Rafeh Naqash: Well, first of all, I appreciate the opportunity to discuss our paper here. I would like to thank you and of course the JCO staff for organizing this, and also the JCO Journal for giving us the opportunity to publish this important work. Some of the things that we would like to highlight as outcomes from this paper, as we sort of discussed, but to summarize those: we saw that we didn't have any significant safety concerns, obviously. We saw that some patients in certain tumor types do benefit, similar to what you might expect in a non-HIV setting in the real world as well.  And of course, this was the largest real-world data set of people with HIV and cancer. And we have ongoing efforts in different directions, as I mentioned to you. And we are more than happy to collaborate with anybody who has good ideas because this is a community-level data set. It was created for the community, by the community, and the goal is to utilize this data set. So if there is a listener out there who's interested in collaborating, who has an idea, we're more than happy to share the data set in the right setting. And then hopefully, everybody has the opportunity to lead different efforts in the space. Davide Soldato: Thank you again for being with us today, Dr. Naqash. To hear more from Dr. Naqash, please check out ASCO's JCO Precision Oncology Conversation Podcast.  So this is Davide Soldato. In this episode of JCO Article Insights, we discussed the results of the manuscript titled, “Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium.” Thank you for your attention and stay tuned for the next episode.  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. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. 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. Thank you very much. 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 speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

In hour 1, Randy is back, bent but unbowed after the disappointing midterms. What happened? The Libertarian vote would have given Barb Kirkmier the CD8 seat as well as given the CD8 State Board of Education seat to Peggy Propst. IF they would have voted for Republicans. Libertarian PR Director for CD8, Patty McMahon, called in and begged to differ.  Lauren Boebert's Veteran's Day message was great as she holds on to her CD3 seat for dear life, and callers and Randy discuss what happened and why.See omnystudio.com/listener for privacy information.

The January 6 committee holds its likely final hearing; musician Katy Tessman and Angel Foundation executive Jim Thrubis join Matt for an interview and some music; Rep. Jen Schultz joins Matt to discuss her run for CD8.

Al Singer joins immune to discuss mice that have their T cell immune system reversed, revealing the molecular basis for T cell lineage fate determination in the thymus. Hosts: Vincent Racaniello, Cynthia Leifer, Steph Langel, and Brianne Barker Guest: Al Singer Subscribe (free): Apple Podcasts, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode T cell FlipFlop mice reveal lineage determination (Nat Immunol) Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

Immune reveals a CD8+ regulatory subset of T cell subset that suppress pathogenic T cells and are active in autoimmune diseases and infectious diseases including COVID-19. Hosts: Vincent Racaniello, Cynthia Leifer, Steph Langel, and Brianne Barker Subscribe (free): Apple Podcasts, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode KIR+CD8+ regulatory T cells (Science) Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

Resveratrol supplementation associated with improved glucose regulation in diabetics   National University of Medical Sciences (Pakistan) March 30 2022.    The June 2022 issue of Complementary Therapies in Medicine reported findings from a randomized trial that uncovered positive effects for supplementing with resveratrol in the regulation of glucose and the maintenance of healthy levels of inflammation and oxidative stress in type 2 diabetics. The trial included men and women who were being treated with orally administered drugs for type 2 diabetes.  Forty-five participants received 200 milligrams resveratrol per day and 46 received a daily placebo for 24 weeks. Blood samples collected at the beginning and end of the trial were analyzed for plasma glucose, insulin, hemoglobin A1c (a marker of long-term glucose control), lipids, malondialdehyde (a marker of oxidative stress), circulatory microRNAs associated with diabetes, and markers of inflammation that included tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP).   (NEXT)   Eating peanuts may lead to supple arteries and healthy hearts   Pennsylvania State University, March 29, 2022   Eating peanuts with a meal may help protect against cardiovascular diseases which can lead to heart attacks and stroke, according to an international team of researchers. In the study, overweight and obese but otherwise healthy men who ate about three ounces of peanuts with a high-fat meal had a blunted increase of lipids in their bloodstream. According to the researchers eating peanuts can keep the cells that line the arteries healthy, helping them stay more elastic. The researchers showed that when peanuts are eaten with a meal the typical post-meal increase of triglycerides -- a type of fat found in the bloodstream -- is blunted. According to the researchers, there was a 32 percent reduction in the triglyceride levels after the consumption of the peanut meal compared to the control group. Three ounces of peanuts is about three times the amount of an average serving size, according to the researchers.   (NEXT)   NIH Study confirms: Turkey Tail mushrooms boost immunity in women with breast cancer   University of Minnesota and Bastyr University, March 28, 2022   Turkey Tail mushrooms can boost your immune system so significantly that it may even shrink breast cancer tumors. A $2 million, seven-year clinical study funded by the National Institutes of Health and jointly conducted by the University of Minnesota and Bastyr University showed that Trametes versicolor, or turkey tail mushroom, in freeze-dried form, dramatically boosts immune function for women with Stage I-III breast cancer─ possibly shrinking tumors. One theory is that when patients ingest Turkey Tail mycelium, the immune system's increased populations of NK cells and their associated CD8 glycoproteins are better able to discover and bind to receptor sites on the stroma of tumors, thus allowing NK invasion. If true, then the use of this medicinal mushroom as an adjunct or preventative therapy may help many patients better fight the battle when challenged with tumor-forming cancers.”   (NEXT)   Too Much Screen Time is Really Bad for Teen Well-Being   University of Queensland School of Health, March 31, 2022    Whether it's watching TV or playing games, teens experience serious physical and mental health consequences after just two hours of screen time, according to new research The global study of more than 400,000 adolescents is the first to provide evidence that both passive and mentally active screen time adversely affects teens' mental well-being. Teens are more likely to report psychosomatic symptoms, a combination of physical and psychological complaints, if they exceed two hours of screen time and these effects were similar regardless of physical activity levels. Psychological complaints from teens included feeling low, irritable, nervousness, and sleeping difficulty, and somatic complaints included headaches, abdominal pain, backache, and dizziness.   Guest: Jessica Rose Part 2