Podcasts about tgf

In this episode, we're talking all things grassfed whey—a supplement we recommend to nearly every client for good reason. From weight loss and lean body mass to metabolic and immune health, the benefits of whey are powerful and broad spectrum. We break down what whey protein is, how it's made, and why we choose to use a whey concentrate over an isolate. We dive into the synergistic compounds found only in whey concentrates that are low heat processed like lactoferrin, CLA, and immunoglobulins—and how they go beyond muscle to support immune resilience, gut lining integrity, and even antioxidant production via glutathione synthesis. We're thrilled to unveil Whey Protect—our upgraded version of Naturally Nourished Grassfed Whey, now with added serum bovine immunoglobulins to further support immunity and reduce inflammation. We touch on how our formula stacks up in purity compared to mainstream brands and discuss the Clean Label Project's recent findings on heavy metals in popular protein powders. Plus, we share our favorite ways to incorporate Whey Protect into your daily routine for optimal health! Also in this episode:  Whey Protect Now Available - use code NN Whey for 15% off!  Episode 288: Whey Protein: lactoferrin, immunoglobulins, BCAAs and more!  Episode 368 What's up with Armra Colostrum? Serum Bovine Immunoglobulins vs. Colostrum What is whey and how is it made?  Comparing whey concentrate to whey isolate Compounds that make whey a superfood Immunoglobulins (IgG, IgA, IgM) – Immune Defense & Gut Health Lactoferrin – Iron-Binding Protein with Antimicrobial Power Glycomacropeptides (GMPs) – Gut & Brain Health Serum Albumin – Antioxidant & Detox Support Growth Factors (IGF-1, TGF-β) – Muscle Growth & Tissue Repair Why are are adding Serum Bovine Immunoglobulins to Whey Protect Gut Health & Leaky Gut Repair Immune System Resilience Detoxification & Inflammation Control Recovery from exercise induced stress Whey and muscle protein synthesis, workout recovery & fat loss Whey Protein Supplementation Enhances Whole Body Protein Metabolism and Performance Recovery after Resistance Exercise: A Double-Blind Crossover Study The Effect of Whey Protein Supplementation on the Temporal Recovery of Muscle Function Following Resistance Training: A Systematic Review and Meta-Analysis Inulin-type fructans and whey protein both modulate appetite but only fructans alter gut microbiota in adults with overweight/obesity: A randomized controlled trial - PubMed Cocoa and Whey Protein Differentially Affect Markers of Lipid and Glucose Metabolism and Satiety Effects of whey protein and resistance exercise on body composition: a meta-analysis of randomized controlled trials  Whey and antioxidant production Whey Protein Supplementation Improves Nutritional Status, Glutathione Levels, and Immune Function in Cancer Patients: A Randomized, Double-Blind Controlled Trial Concerns with heavy metal toxicity & why you don't need to worry about this with Whey Protect!  Lead and cadmium found in muscle-building protein powders, report says | CNN 2024-25 Protein Powder Category Report How to use Whey Protect Banana Bolt Smoothie Matcha Green Smoothie Cinnamon Almond Keto Shake Cherry Vanilla Nirvana Smoothie How to Make a Keto Protein Shake and The Importance of Protein Easy Keto Green Smoothie (with super foods!) What makes Whey Protect Superior? Grass-fed, low-heat whey concentrate → Preserves bioactive compounds Contains ImmunoLin® serum bovine immunoglobulins → Supports immunity & gut health Rich in cysteine & glutathione → Powerful antioxidant support Boosts muscle growth & recovery → High leucine for optimal muscle synthesis Clean, third-party tested → No heavy metals or contaminants Sponsors for this episode:  Whey Protect: introducing our new Grassfed Whey with added serum bovine immunoglobulins to meet your protein goals and protect the body against infection, toxins, and regulate inflammatory response!   We saw the demands with sales increase of our GI Immune Builder and wanted to incorporate the therapeutic benefits of immunoglobulins in a daily easy to use product that can be used for enhanced immune function, metabolic results, and gut health.   Our Grassfed Whey has always been a top selling product in the Naturally Nourished line due to our quality sourcing and low heat processing to retain antioxidants and beneficial immune compounds such as lactoferrin and immunoglobulins. We wanted to ensure when you take our whey that you are providing your body with a shield of defense against pathogens (bacteria, virus, parasites, mold), toxins, and oxidative stress. Meet Whey Protect, our reformulated and enhanced Naturally Nourished Grassfed Whey.   We've added 350mg serum bovine immunoglobulins to each scoop to ensure you and your family receive a clinical impact to Protect you while helping you reach your daily protein goals with ease.    You're just a scoop a-WHEY from: Muscle gains  Immune resilience Improved bone density Gut health Lower toxicity Enhanced antioxidant status Reduced inflammation Weight loss with satiety and appetite regulation   Added Value at no added cost! We are thrilled to offer you this amazing upgrade at the same price, plus save during our launch sale! Use the code NNWHEY for 15% off    This episode is sponsored by Wild Foods, a company that puts quality, sustainability, and health first in all of their products. They have everything from coffee to turmeric to medicinal mushrooms, and every single product is painstakingly sourced from small farms around the globe. They take their mission seriously to fix the broken food system, and believe real food is medicine. They've partnered with us to give you guys an exclusive discount, so use the code ALIMILLERRD for 12% off your order at WildFoods.co! 

In the final part of this series, Joseph Parambil, MD, walks us through the approach of managing pulmonary hypertension, reviews the pathophysiology and digs into the mechanisms and the differences in the medications. Intro 0:12 In this episode 0:17 Interview with Joseph Parambil, MD 2:53 Reviewing and clarifying pathophysiology prior to initiating therapeutics 4:13 Evaluating patients in terms of their functional status and how does that play a role in initiating therapies 4:25 Vasoreactivity testing 10:21 The categories of medications 14:40 Endothelin receptor antagonists 37:07 TGF pathway 42:13 Scleroderma patient and treatment 50:19 Do patients get a repeat right-heart catheterization? 55:51 What about the TGF-beta? 56:55 Thank you, Dr. Parambil 58:34 Thanks for listening 59:17 We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. Disclosures: Brown and Parambil report no relevant financial disclosures. Joseph Parambil, MD, is a staff member in the Respiratory Institute and the director of the HHT Center of Excellence and the Vascular Anomalies Center at the Cleveland Clinic. He is associate professor of medicine at Cleveland Clinic's Lerner College of Medicine. He is certified by the American Board of Internal Medicine with additional specialty certification in pulmonary medicine and critical care medicine.

Featuring a slide presentation and related discussion from Dr Raajit K Rampal, including the following topics: Overview of the current JAK inhibitor landscape (0:00) Factors predicting clinical benefit in patients with myelofibrosis (MF) receiving ruxolitinib (3:02) Clinical data supporting the use of fedratinib after prior ruxolitinib for MF (9:17) Emerging clinical findings on pelabresib in combination with ruxolitinib for previously untreated MF (12:13) Available clinical data with novel BET inhibitors (15:00) Utility of selinexor in combination with ruxolitinib for MF previously treated with ruxolitinib (16:50) Emerging efficacy and safety findings reported with imetelstat for MF (18:57) Clinical findings reported with the MDM2 inhibitor navtemadlin for MF (21:15) Available clinical data with the TGF-beta inhibitor elritercept for MF (24:05) Other novel agents and strategies under investigation for MF (26:06) CME information and select publications

In this episode, we dive deep into one of nature's most powerful superfoods—colostrum—and explore its incredible benefits for immune function, gut health, and overall well-being. But we're taking it a step further by introducing Immunel, a highly concentrated and bioactive colostrum extract developed by Sterling Technology. Immunel represents the 5th generation of colostrum, setting a new standard for immune and gut support. Topics Covered:  What is Colostrum? The first milk produced after birth, rich in antibodies (IgG), growth factors, and bioactive peptides. The science behind 9,000+ PubMed studies on colostrum's health benefits.  The Health Benefits of Bovine Colostrum Immune Boosting: Clinical research shows colostrum is 3x more effective than the flu vaccine in reducing flu incidence. Gut Healing Properties: Protects the GI lining, reduces diarrhea by 86.6%, and helps in ulcerative colitis management. Anti-Inflammatory Effects: Supports those with NSAID-induced GI issues. Stem Cell & Regenerative Potential.  Immunel: The Next Evolution in Colostrum A concentrated colostrum extract packed with key bioactive compounds: Growth Factors (IGF-1, TGF-ß2) Proline-Rich Polypeptides (PRPs) for immune modulation Enzymes (lysozyme, lactoperoxidase, lactoferrin) for pathogen defense Sialic Acid & Nucleotides essential for immune function & DNA synthesis  Immunel vs. Standard Colostrum Unlike standard colostrum, which focuses on IgG content, Immunel is clinically validated for immune activation and pathogen defense. Outperforms β-glucans and vitamin C in immune response.  Scientific Evidence on Immunel Enhances phagocytosis & innate immunity Activates Natural Killer (NK) cells (↑ CD69 expression) Reduces bacterial lung infections by 70.2% Lowers viral load by 64% in influenza  Why This Matters for Public Health The economic burden of flu & colds: 75M lost workdays annually, costing $37.5B. Growing consumer interest: 47% of people prioritize immune health, driving demand for functional foods. Immunel is a next-generation, scientifically backed immune and gut health solution—more bioavailable and effective than traditional colostrum. Perfect for daily supplementation to support overall health and resilience.

Don't miss this one. Quick housekeeping, the wonderful Mike Clelland aka the Owl Guy, will be joining us in a Community Gathering on Sunday February 16th at 10am MST. If you'd like to join in, you can become a patron at the EarthLovers $10 tier by visiting patreon.com/robinlassiter. This time on the podcast, I speak with the one and only Kelly Chase. Kelly is the host of The UFO Rabbit Hole Podcast, Co-founder of Ontocalypse Productions, writer and Executive Producer of Cosmosis: UFOs & A New Reality, and Guest Host on Whitley Strieber's Dreamland. Our conversation was very deep, very beautiful, very connected. The same day that I interviewed Kelly, I woke up with at 530 with a fire in my head and wrote for a couple of hours. Both the talk with Kelly and what came through that morning feel so pertinent to the present moment. I put out a poll asking what you guys wanted me to do – one mega episode with it all, separate episodes, release part now, part later, etc., and the results are in, so one mega episode coming up. We'll start with the interview with Kelly and then if you want you can stick around to hear me talk about the Honeycomb Matrix and TGF and how I think we make it through what's here. What's all around us. The elephant in the room. Work with Diederik Rijkens at ⁠⁠Coded to Thrive⁠⁠ and check out his YouTube channel ⁠⁠The Projector Project⁠⁠ Earth: A Love Story is now an ⁠⁠⁠⁠⁠⁠AUDIOBOOK!⁠⁠⁠⁠⁠⁠ ⁠⁠⁠⁠⁠⁠⁠⁠The Experiencer Group⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ My book ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Earth: A Love Story ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠exists as a physical object in the world. Deep forever gratitude to those of you who have purchased the book and left reviews on Amazon. Thank you, thank you, thank you. Our beautiful musical soundscapes are provided by Morgan Jenks. You can support ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠his new album on bandcamp⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠, or find out more at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠morganjenks.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Find me on instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@robin_lassiter_honeyheart⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ and ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@earth_a_love_story⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ To join my mailing list or book a 1:1 session with me, visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠robinlassiter.com

Thank you so much for tuning in for another episode of the Wet Net Outdoors Podcast. Please be sure to share us out there with your friends, Hit that thumbs up button, and subscribe! We can be found on Youtube, Spotify, Apple Podcasts, or anywhere else you get your podcast. HUGE ANNOUNCEMENT!!!Saturday, January 11th 2025, 9:00am, New Anglers Unlimited location Grand Opening, Ribbon Cutting ceremony, Food & Espresso carts, Raffle drawing. On this episode, I had the pleasure of sitting down with Bob Rees, & Seth Kolshinski with The Guides Forecast. We got a background on these gentlemen, talked about TGF, and got into the nitty gritty on some current events happening in our fisheries. Huge shoutout to our awesome sponsors Fishsos, Anglers Unlimited, Northwild Outdoors, Coldwater Strong, & Talon Rods! Have a great week! #fishing #addictedfishing #flatoutfishing #anglersunlimited #talonrods #northwildoutdoors #coldwaterstrong #fishsos #columbiariver #columbiariverbar #salmon #steelhead #pnw #washington #oregon #sockeye #chinook #pacificocean #salmoneggs #bobberdown #coonshrimp

In this episode, we delve into the remarkable benefits of colostrum and how it can support hormone balance across various stages of a woman's life. From improving period health to promoting a healthy pregnancy, aiding postpartum recovery, and regulating hormones during perimenopause, colostrum's nutrient-rich properties make it an effective tool for women seeking natural solutions. We'll discuss how colostrum works at the cellular level, with scientific insights on its anti-inflammatory effects, gut health benefits, and hormone-regulating capabilities. Berri's Favorite Colostrum & Save with Code: BERRION Key Topics Discussed: 1. How Colostrum Improves Period Health Gut Barrier Repair: Colostrum contains growth factors like IGF-1 and TGF-β that aid in repairing the gut lining, preventing "leaky gut." A healthy gut helps metabolize and eliminate excess hormones, reducing PMS symptoms. Reducing Inflammation: Anti-inflammatory compounds like lactoferrin decrease inflammation, alleviating menstrual cramps and pelvic pain. Enhancing Nutrient Absorption: Colostrum supports better absorption of magnesium and vitamin B6, which are essential for mood stability and reducing PMS symptoms. 2. Colostrum's Role in Promoting a Healthy Pregnancy Immune Modulation: Immunoglobulins in colostrum help balance the immune response, protecting the mother and developing baby from pathogens without causing excessive inflammation. Nutrient Absorption: Supports the growth of beneficial gut bacteria to enhance absorption of vital nutrients like calcium, iron, and folate, crucial for fetal development. Growth Factors for Fetal Development: Contributes to the development of essential organs, such as the lungs and gut, potentially reducing the risk of preterm birth. 3. Easing Postpartum Recovery with Colostrum Tissue Healing: Growth factors aid in repairing tissues affected by childbirth, speeding up recovery. Hormone Metabolism and Mood Stability: Supports the breakdown and elimination of excess hormones, helping stabilize hormone levels post-delivery. Immune Support: Boosts immunity with compounds like lactoferrin, enhancing the body's defense against infections during the postpartum period. 4. Regulating Hormones During Perimenopause Improving Insulin Sensitivity: Helps stabilize blood sugar levels by improving insulin sensitivity, which can alleviate fatigue and irritability. Gut Health and Hormone Detoxification: Assists in the elimination of hormones like estrogen, reducing symptoms of estrogen dominance. Anti-Aging and Tissue Repair: Supports tissue regeneration, countering symptoms associated with aging, such as thinning skin or joint discomfort. Episode Highlights: Colostrum's Unique Nutrients: Why this pre-milk fluid is more than just a newborn's first food. Scientific Evidence: Insights from studies on colostrum's role in inflammation, gut health, and hormonal balance. Practical Tips: How to incorporate high-quality colostrum supplements into your routine. Resources Mentioned: Studies cited from journals such as Reproductive Biology and Endocrinology, Journal of Obstetrics and Gynaecology, and International Journal of Immunopathology and Pharmacology.

BUFFALO, NY- October 15, 2024 – A new #research paper was #published on the #cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), Volume 16, Issue 19 on October 12, 2024, entitled, “A proteomics approach to study mouse long bones: examining baseline differences and mechanical loading-induced bone formation in young-adult and old mice.” As noted in the abstract, bone mass declines with age, and the anabolic effects of skeletal loading decrease. While much research has focused on gene transcription, how bone ages and loses its mechanoresponsiveness at the protein level remains unclear. In their paper, researchers Christopher J. Chermside-Scabbo, John T. Shuster, Petra Erdmann-Gilmore, Eric Tycksen, Qiang Zhang, R. Reid Townsend, and Matthew J. Silva from Washington University School of Medicine and Washington University in St. Louis, Missouri, describe how they developed a novel proteomics approach and conducted paired mass spectrometry and RNA-seq analyses on tibias from young-adult (5-month) and old (22-month) mice. The researchers report the first correlation estimate between the bone proteome and transcriptome (Spearman ρ = 0.40). While this is consistent with findings from other tissues, it suggests that only a relatively low amount of variation in protein levels is explained by variation in transcript levels. Of the 71 shared targets that differed with age, eight were associated with bone mineral density in previous GWAS, including the understudied targets Asrgl1 and Timp2. Using complementary RNA in situ hybridization, the researchers confirmed that Asrgl1 and Timp2 showed reduced expression in osteoblasts/osteocytes in aged bones. Additionally, they found evidence of reduced TGF-beta signaling with aging, particularly Tgfb2. The researchers also identified proteomic changes following mechanical loading, noting that at the protein level, bone differed more with age than with loading, and aged bone exhibited fewer loading-induced changes. "Overall, our findings underscore the need for complementary protein-level assays in skeletal biology research.” DOI - https://doi.org/10.18632/aging.206131 Corresponding author - Christopher J. Chermside-Scabbo - ccherms@wustl.edu Video short - https://www.youtube.com/watch?v=xm6o7gWH8p4 Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206131 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, bone, mechanical loading, proteomics, RNA-seq/transcriptomics About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Um grupo de pesquisadores franceses descobriu que a presença de um subtipo do linfócito Th17, uma das células que compõem nosso sistema de defesa, pode contribuir em alguns casos ao desenvolvimento de certos tipos de tumores, como os do intestino, fígado ou pâncreas. Taíssa Stivanin, da RFI em ParisO estudo foi realizado durante quatro anos por especialistas do CNRS (Centro Nacional de Pesquisa Científica da França), do Inserm (Instituto de Pesquisas Médicas da França), da universidade Claude-Bernard Lyon 1 e do Centro de Pesquisa Oncológica de Lyon.Os cientistas franceses identificaram um dos mecanismos do processo inflamatório presente em algumas doenças crônicas que levaria ao surgimento de certos cânceres, disse à RFI Brasil o imunologista francês Julien Marie, que participou da pesquisa, publicada no final de julho na revista científica Nature Immunology.Para entender como os pesquisadores chegaram a essa conclusão, é necessário compreender o papel dos glóbulos vermelhos ou brancos, os linfócitos, em nosso organismo. “Os glóbulos vermelhos são responsáveis pelo transporte do oxigênio no sangue e os brancos combatem os agentes infecciosos e as células defeituosas”, explicou o cientista francês.Os glóbulos brancos são divididos em dois grandes grupos, formados pelos linfócitos B, que produzem os anticorpos, e os linfócitos T. A função deles é destruir células defeituosas ou que foram contaminadas por um vírus ou uma bactéria, por exemplo. Para isso, libera moléculas como as citocinas, que vão criar a inflamação e favorecer a cicatrização e a cura.O problema é que esse processo às vezes pode sofrer alterações e gerar doenças ou agravar infecções – um exemplo é a forma grave da Covid-19. A equipe francesa descobriu que o linfócito Th17, presente na Doença de Crohn, uma patologia crônica intestinal, poderia atuar no aparecimento de células cancerígenas.Muitos tumores, lembra Julien Marie, surgem a partir de uma inflamação crônica. Quando ela atinge uma parte específica do intestino, como é o caso dos pacientes que têm Crohn, as células vão se modificar e se tornar cancerígenas exatamente na porção inflamada. “No nosso estudo, tentamos entender quais eram as células do sistema imunológico na origem dessa inflamação que vai gerar o câncer. São etapas extremamente precoces do desenvolvimento da doença”.Esse mecanismo localizado ajudou a equipe a “cercar” a área onde ocorre todas as modificações celulares. Os cientistas então constataram que um subtipo dos linfócitos Th17 estava na origem de alguns tumores. “Hoje temos técnicas que permitem analisar uma célula de cada vez. Percebemos que as células Th17 tinham oito subtipos, e um deles podia desencadear o câncer através da inflamação criada por ela mesma”, explica.Citocina bloqueia aparecimento do câncerO estudo analisou os linfócitos invitro, no laboratório, as células das biópsias de pacientes que tinham a Doença de Crohn. Eles têm, em geral, quase seis vezes mais chances de desenvolver um câncer colorretal que um indivíduo normal, explicou o cientista francês, e entender o porquê era um dos objetivos da equipe.Durante o estudo, os pesquisadores conseguiram provar que o linfócito Th17 estava presente nos pacientes que desenvolveram os tumores. “No nosso artigo científico caracterizamos os linfócitos que geram o câncer, fazemos uma descrição deles e definimos um certo número de marcadores que propomos para defini-los", explicou. "Fomos ainda mais longe, porque toda a questão por trás da nossa pesquisa era saber se podíamos bloquear o aparecimento do câncer”, acrescenta.Foi justamente essa uma das grandes descobertas da pesquisa. “O desenvolvimento das células cancerígenas pode ser bloqueado pela presença de uma citocina, TGF–β (TGFBETA)”. Se o nível dessa citocina diminui no intestino, por exemplo, favorecerá o aparecimento do câncer, reitera Julien Marie.A descoberta pode ajudar no desenvolvimento de novas terapias contra o câncer e também na prevenção, através da utilização dos marcadores propostos no estudo. Eles são preditivos do risco de desenvolvimento da doença e permitirão um diagnóstico precoce ou até mesmo antecipar o risco do paciente antes de o câncer aparecer.Para Julien Marie, o estudo também é importante porque quebra um paradigma: o nosso sistema imunológico, criado para proteger o organismo, às vezes pode ser nocivo. De cada três cânceres, lembra, um se desenvolve a partir de uma inflamação crônica – um mecanismo que ainda continua sendo, em parte, um mistério para a Ciência.

In this week's episode we'll learn how cytomegalovirus infection early in life depletes preleukemic cells in a mouse model of B-cell acute lymphoblastic leukemia. After that we'll discuss new research, where GVHD targets organoid-forming bile duct stem cells in a TGF-beta-dependent manner. Conversely, a TGF-beta inhibitor protects these stem cells against GVHD and mitigates biliary dysfunction. Finally, we'll hear about the seven-year outcomes for venetoclax-ibrutinib in relapsed or refractory mantle cell lymphoma. In addition to long-term survival benefits, researchers report durable treatment-free remissions and effective retreatment in patients with MRD-negative complete responses. Featured Articles: Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblasticleukemiaGVHD targets organoid-forming bile duct stem cells in a TGF-β–dependent mannerSeven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses andtreatment-free remissions

Roy L Hales/Cortes Currents - As anyone passing through Squirrel Cove in recent months knows, there has been a great clearing in the upper part of the new Klahoose property. QXMC, the business arm of the Klahoose First Nation, hopes to open a store and gas bar there by March 2025. Ron Buchhorn, Chair of the Board of QXMC, explained, ”We retained a project manager back in November of last year and we have signed a letter of intent with Chevron for the gas station component of the store and gas bar. We have a commitment from Co-op that they will assist us with stocking the store and helping us basically manage to their standards.  Co-op will supply us with all the products in the store through their wholesale distributor TGF. We're very happy about that. It won't be branded Co-op because obviously with the Chevron branding on the facility, you can't have two brands.”  “The footprint of the store will be about 4,000 square feet. Full service with everything from groceries to produce, to meat, to deli to some prepared warm foods. It looks as though we'll have four suites upstairs. A 2 bedroom and three 1 bedroom suites, to ensure that we have accommodation for staff at the store.” “If we proceed with phase two, which is the campground next door, our plan is to have the General Manager and potentially a couple of the other department managers living at the facility. We want to have someone there full time.” “In terms of the store layout and the external architecture of the store, we're trying to keep the architecture consistent with the cabins that we've had an architect design. He's done a lot of research on Coast Salish buildings, during the last couple hundred years and tried to factor in that type of architecture.  It'll be very similar to the Klahoose Administration Building as well, so it'll be a shed roof with some nice exterior wood paneling. Our hope is that the sawmill will be able to provide all of the beams and most of the wood that will be required for the structure.”

In this week's episode we'll discuss the mutational and transcriptional landscape of pediatric BCP lymphoblastic leukemia; learn more about the role of platelet-derived TGF-β1 in immune thrombocytopenia; and discuss the findings from a phase 3 trial of mavorixafor in WHIM syndrome.Featured Articles:Mutational and transcriptional landscape of pediatric B-cell precursor lymphoblastic lymphoma Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia Phase 3 randomized trial of mavorixafor, CXCR4 antagonist, in WHIM syndrome 

In today's episode, we explore the role of Thymosin Alpha 1 Peptide in modulating the immune system, specifically its effects on Th1 and Th2 responses. The episode further delves into the mechanisms by which Borrelia burgdorferi evades immune detection and offers strategies to enhance immune effectiveness against this stealthy pathogen. Additionally, we discuss the broader implications of immune modulation in chronic Lyme disease and mold exposures. Topics: Introduction Recap of the series on Lyme and mold Highlighting the key steps in the biotoxin illness resolution process Importance of working with a medical professional Key Steps in Biotoxin Illness Resolution Lowering inflammation Lipid replacement therapy (phospholipids) Use of antimicrobial and antiparasitic herbs for Lyme and coinfections Employing binders to eliminate toxins and reduce inflammation Checking for MARCoNS and utilizing treatments like silver spray or biofilm busters (e.g., xylitol) Detoxification post-MARCoNS clearance using agents like chlorella and glutathione Assessing and normalizing various health markers (e.g., ADH, osmolality, MMP9, C4a, C3a, TGF-beta, sex hormones) Additional Resources and Episodes Early stages of Lyme infection and Herxheimer reaction: Episode 116 Chronic inflammation and biotoxin management: Episode 117 Role of binders in interrupting enterohepatic circulation and toxin elimination Discussion on Biofilm Importance of addressing biofilm in antimicrobial therapies Potential supplements and strategies (e.g., garlic, oil of oregano, stevia) Overview of Lyme Disease Impact & Immune Function Chronic inflammation due to miscommunication between the innate and adaptive immune systems + dysregulated adaptive responses How borrelia evades the immune responses Immunomodulation in Lyme Disease Background on immune modulation Role of T cells in adaptive immune response Th1 and Th2 cell imbalance in chronic Lyme Strategies to support Th1 cells and decrease Th2 response Focus on Thymosin Alpha 1 Benefits of Thymosin Alpha 1 in modulating immune function Promoting Th1 response and managing Th2 dominance Effects on regulatory T cells (Tregs) and immune tolerance Conclusion Reminder to work with a Lyme literate or biotoxin illness literate medical professional Thanks for tuning in! Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Or visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠linktr.ee/synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

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

For more information, visit https://thecirsgroup.com CIRS, or Chronic Inflammatory Response Syndrome, is a complicated illness. Thankfully, there are specific blood markers you can test to confirm whether or not you are suffering from this illness. Today, we're going to take you through each of these blood markers and what they mean when they're out of range. For more information, support, and resources in your own CIRS healing journey, visit TheCIRSGroup.com TIME STAMPS: 0:00 Intro and disclaimer 0:33 Why these blood markers matter 2:15 MMP9 4:32 VEGF 8:03 TGF-b1 10:49 MSH 17:03 C4A and C3A 18:30 Tips about getting your blood drawn Helpful Links: Hoffman Center resource for what the blood markers mean, how it manifests in your body and proper treatment: https://hoffmancentre.com/chronic-inflammatory-response-syndrome-cirs-evaluation-and-treatment/ Biotoxin Pathway: https://www.instagram.com/p/Cz4B3gKpVIn/?utm_source=ig_web_copy_link&igshid=MzRlODBiNWFlZA== Jacie is a 4 year carnivore, certified nutrition coach, and carnivore recipe developer determined to share the life changing information of carnivore and CIRS to anyone who will listen. Barbara is a coach, facilitator, speaker, 3 year carnivore, and a big fan of health and freedom. Together, they co-founded The CIRS Group, an online support community to help people that are struggling with their CIRS diagnosis and treatment. Catch Jacie and Barbara on Judy Cho's podcast to learn more about their health journeys and why they started The CIRS Group: When Carnivores are Affected by Mold Illness - Jacie Gregory & Barbara Williams - https://youtu.be/CR8Uj-d_fok

Welcome to a special update episode of Inside the Epicenter, sharing Stories From The Frontlines. In this episode, host Carl Moeller is joined by Joel and Lynn Rosenberg from Jerusalem to discuss how God can use humanitarian aid amid a war crisis to bring hope and healing to the land of Israel. Lynn shares her experiences volunteering with humanitarian aid teams throughout the country, delivering much-needed supplies to displaced families and individuals living in bomb shelters. She recounts touching stories of distributing water, toys, and clothing to those in desperate need. The Rosenbergs also shed light on the full mobilization of believers who have been called up as reservists in the army and the impact it's having on their community. Join us as we delve into the remarkable stories and witness the power of God's love amid crisis.    (1:40) Intense week helping crisis victims and supplying resources. (4:41) Monitoring partners' safety on country-wide trips. (7:44) Soldiers in need of supplies receive assistance. (10:26) Drama-filled drive witnessing rocket attacks in Gaza. (13:21) Supporting Joshua Fund helps fulfill Jesus's call. (17:32) Trusted partners provide logistical support and supplies. (21:02) Pray for TGF volunteers providing aid.   Learn more about The Joshua Fund Make a tax-deductible donation The Joshua Fund Stock Media provided by DimmySad/Pond5   Related Episodes: Challenges for Christian Organizations in the Holy Land #129 Special Update: The Ground War About To Begin #128 Special Update: Israel at War #127 What It's Like Living in a Missile Zone #126 Discover more Christian podcasts at lifeaudio.com and inquire about advertising opportunities at lifeaudio.com/contact-us.

BUFFALO, NY- October 23, 2023 – A new research paper was published in Oncotarget's Volume 14 on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.” Intravital microscopy in live mice has shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays an essential role in death induction. Given that DP cells are not necessary for completion of the cycle, only for its initiation, it is still an open question as to the mechanism that leads to the propagation of apoptosis towards the regenerative stem cell population. In their new study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université performed a quantitative analysis of the length of hair follicles to investigate their regression cycle. “In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.” The data are consistent with a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. The observation that the apoptosis slows down as the apoptotic front approaches the stem cells at the end of the follicle is consistent with a gradient of a pro-survival signal sent by these stem cells. An experiment that can falsify this mechanism is proposed. “In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. The class of models introduced here can be used to describe the renewal kinetics of other stem cell niches like the intestinal stem cell niche [18].” DOI - https://doi.org/10.18632/oncotarget.28529 Correspondence to - Krastan B. Blagoev - kblagoev@nsf.gov Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28529 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, hair follicle, stem cells, regression cycle, mathematical model, analysis About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

The intro sees Jon joined by Stephen Carter, of benevolent sponsorship overlords Clarion Gaming, to discuss the really-very-close-now iGaming Affiliate Awards [0:00 - 16:56], how you can nominate entries and all that jazz – go to https://www.igbaffiliate.com/igba-awards/ to cast yours. NOW. This week's guest is Brad Allen, senior analyst at Eilers and Krejcik, who joins Jon on TGF's casting couch to discuss the state of modern business-to-business publishing, the importance of data in the gambling industry, and Brad's role in the Zero Latency podcast. The quality of casino apps in the US is a hot topic, with many apps having broken journeys and glitches – Brad unveils the surprising top-rated casino app in a recent test, and much more [16:57 - 1:18:32]! Thank to our benevolent sponsors BWise Media – for all your sports media buying needs – and Clarion Gaming. Both legends.

Certainly, here are the show notes with the addition of research studies: Review of Bovine Colostrum: Let's begin by delving into what bovine colostrum (BC) is all about: Bovine colostrum is the initial milk produced immediately after birth, brimming with essential macro- and micro-nutrients, immunoglobulins, and peptides boasting antimicrobial properties and growth factors. Now, let's explore the potential advantages: Immune Support: Colostrum is abundant in immunoglobulins, particularly IgG, IgM, and IgA, which can fortify the immune system. Additionally, it contains lactoferrin, lysozyme, and other immune components that might aid in enhancing immunity. Gut Health: Colostrum is said to assist in maintaining a healthy gut lining. Its growth factors could contribute to the repair of damaged intestinal tissue and play a role in preserving gut permeability. Nutritional Content: Bovine colostrum is replete with proteins, vitamins, and minerals that can contribute to overall nutrition. Growth Factors: It encompasses various growth factors such as insulin-like growth factors (IGF-1 and IGF-2), transforming growth factors (TGF-alpha and TGF-beta), and epithelial growth factor (EGF), potentially promoting tissue growth and healing. Antimicrobial Properties: The presence of lactoferrin, lysozyme, and immunoglobulins in colostrum imparts antimicrobial properties, which may combat harmful bacteria and viruses. Athletic Performance and Recovery: Some athletes turn to colostrum supplements with the belief that it aids in recovery and enhances performance, although scientific evidence in this area is still evolving. Anti-inflammatory: Colostrum has been suggested to possess anti-inflammatory properties, potentially benefiting conditions involving inflammation. May reduce the risk of upper respiratory infections: Studies have indicated that athletes who consumed colostrum had fewer instances of upper respiratory infections compared to those who received a placebo. So, what does the research reveal? Processing and Heat Treatment: Processing and heat treatment, necessary for safety, can diminish the bioactive composition and the inhibitory and immunomodulatory capabilities of colostrum. Rich in Bioactive Components: Bovine colostrum is notably rich in biologically active peptides, antioxidants, anti-inflammatory agents, and growth-promoting factors, distinguishing it from mature milk. Intestinal Permeability Study: One study involving 12 athletes vulnerable to intestinal permeability due to intense exercise found that daily consumption of 20 grams of bovine colostrum prevented 80% of the increase in intestinal permeability experienced by those who received a placebo. (Reference: Trusted Source) Saliva IgA Antibodies Study: In a 12-week study with 35 adult distance runners, taking a daily bovine colostrum supplement increased saliva IgA antibodies by 79% compared to baseline levels. (Reference: Trusted Source) It's important to keep in mind that bovine colostrum supplements and powders can be relatively costly, ranging from $50 to $100 per 16 ounces (450 grams), with a typical daily dosage of half a teaspoon (1.5 grams). Additionally, the composition of bovine colostrum may vary depending on how the cows are raised, potentially containing antibiotics, pesticides, or synthetic hormones.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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 this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. The theme of the 2023 ASCO Annual Meeting was “Partnering With Patients: The Cornerstone of Cancer Care and Research.” From June 2 to 6 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest cancer research and how to ensure that all people receive the cancer care they need. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field presented at the meeting and explain what it means for people with cancer. In today's episode, our guests will discuss new research in gynecologic cancers [2:06], multiple myeloma [9:15], and head and neck cancer [16:03]. First, Dr. Lan Coffman discusses new research in ovarian cancer, uterine cancer, and cervical cancer. Dr. Coffman is a physician-scientist and gynecologic oncologist at the Magee-Womens Research Institute and Foundation, and assistant professor in Hematology-Oncology at the University of Pittsburgh School of Medicine. She is also the 2023 Cancer.Net Associate Editor for Gynecologic Cancers. You can view Dr. Coffman's disclosures at Cancer.Net. Dr. Coffman: Hi, my name is Lan Coffman. I'm a physician-scientist at the University of Pittsburgh. I'm a medical oncologist that specializes in gynecologic cancers, and I'm happy to discuss research that was presented on gynecologic cancers at the 2023 ASCO Annual Meeting. I do have a relevant disclosure. I participated in one of the trials I'm going to discuss, a trial called MIRASOL. I was the site principal investigator at University of Pittsburgh. I think there were a lot of interesting studies to highlight, and I wanted to focus on studies involving ovary cancer, endometrial cancer, and cervix cancers as the main sites that we study in the gynecologic oncology world. So when we talk about ovary cancer, I think there was one really impactful study that was presented at ASCO this year, and it was called MIRASOL. And again, this is the study that I also participated in at our hospital at University of Pittsburgh. So it was a large study, so a randomized phase 3 study looking at a drug called mirvetuximab, which is an antibody-drug conjugate. So basically, it's an antibody against a protein that is expressed on ovarian cancer cells and the protein's called folate receptor-alpha. And that antibody basically carries a little poison. And so it's kind of like a Trojan horse. This antibody goes, finds that protein on the tumor cells, and then delivers that poison. And so this drug has been studied and actually was presented last year in a different trial called SORAYA, which showed that it had activity, meaning the drug helped to kill ovarian cancer cells, and actually led to the first approval of this drug in ovary cancer. So this trial was the confirmatory trial, so enrolling more patients to see, actually, is it better than standard-of-care chemotherapy? So this was in women with ovarian cancer that had come back and was platinum resistant, meaning the cancer started to grow within 6 months from the last platinum-based therapy. Women were eligible if they had high expression of this folate receptor-alpha, and they had to have a couple of prior lines of therapy. And then they were randomized, so kind of chosen out of a hat to either be treated with mirvetuximab or with investigator's choice chemotherapy. So one of the chemotherapies we'd use standardly. And so that would be something like taxol, or liposomal doxorubicin, or topotecan. And basically, this study was comparing how well does mirvetuximab work compared to chemotherapy. And importantly, it showed that it improved survival, both progression-free survival, so how long it took before the disease started to grow again, but probably more importantly, actually improved overall survival, so how long a woman lived. And actually changed overall survival from about 16 and a half months compared to 12 months with chemotherapy. And so this was really important and demonstrated that mirvetuximab does actually impact women with ovarian cancer and actually helps women live longer. And that's really hard to do in this setting. And the other nice thing about this trial was that not only did it work well, but there are actually lower side effects with it, and so less women actually had to discontinue their treatment, and they had less what we call adverse events, or basically bad things that had happened from the treatment themselves. So just telling us that this drug is actually well tolerated. Women feel well on it, even when their cancer is shrinking. So I think that was one of the most impactful studies in ovary cancer. Moving on to endometrial cancer. We recently had 2 studies, one called RUBY and one called GY018 that looked at using immunotherapy in combination with chemotherapy in endometrial cancer. And what was presented at ASCO was some follow-up from this RUBY trial, which was basically validating that this combination of adding immunotherapy actually helped. To give you a background, traditionally, women that have endometrial cancer that is advanced staged, meaning spread outside of the uterus itself or has come back, we treat it with chemotherapy. But this study added an immunotherapy called dostarlimab in combination with our standard chemotherapy and actually showed that women were living longer with this, at least in that progression-free survival. We're still waiting on final evaluation. But at ASCO, what they reported was another independent blinded review of the data to show that even when we're really carefully looking at this data, it looks like immunotherapy helps women with endometrial cancer live longer. They also presented quality-of-life data showing that women actually feel better with the addition of the immunotherapy. So I think this is practice changing. And again, this data has been coming out over the last year or so, but I do think this will change the way in which endometrial cancer is treated. And then the final thing I wanted to discuss would be in cervix cancer. And while there wasn't a lot of new data presented here in terms of kind of paradigm shifts or large changes, we did have final survival [data] from the KEYNOTE-826 presented, which is also using immunotherapy along with chemotherapy in cervix cancer. And so this was in women that, again, had advanced-stage cervix cancer. So it was a cervix cancer that had moved beyond the cervix itself or cervix cancer that had come back and was treated with chemotherapy along with another immunotherapy called pembrolizumab. And this was the final survival data that confirmed that the immunotherapy did help women live longer. The survival data was impressive with about a 10-month improvement in overall survival. So how long a woman lived. And so that was really confirmatory of the previous trials. So again, that emphasizes that immunotherapy is moved towards the standard of care in cervix cancer as well. I can't hit all the highlights of the impressive research coming out of ASCO 2023, this is a brief summary of some of the critical studies in gynecologic cancers. ASCO: Thank you, Dr. Coffman. Next, Dr. Sagar Lonial discusses new research in multiple myeloma. Dr. Lonial is a professor of Hematology and Medical Oncology at Winship Cancer Institute at Emory University, where he also serves as Department Chair. He is also the 2023 Cancer.Net Associate Editor for Myeloma. You can view Dr. Lonial's disclosures at Cancer.Net. Dr. Lonial: Hello, I'm Dr. Sagar Lonial from the Emory School of Medicine and the Winship Cancer Institute in Atlanta, Georgia. And today I'm going to discuss some of the really exciting research in the context of multiple myeloma that was presented at the 2023 ASCO Annual Meeting. In terms of my conflicts of interest, I have enrolled patients on many CAR T trials as well as bispecific trials from all of the different companies involved here. So, I do have some engagement with those trials. And one of the studies that I may talk about at the end came from our institution. So I was an investigator on that study as well. When I think about some of the really exciting work that was presented at ASCO this year, there are really 2 big categories of trials that I think were most exciting. And the first is CAR T-cells and moving them earlier and earlier in the disease state. And what we saw at ASCO this year was the CARTITUDE-4 study, which was a randomized phase 3 trial comparing CAR T-cells versus standard treatment in the context of first or second relapsed multiple myeloma. And this was a really important study for us to hear because we know that CAR T-cells are highly effective in the later lines of therapy. A big question at this point is, "Does their efficacy hold up in earlier lines of therapy? And how does it compare in a randomized setting against what we might normally use in that clinical context?" And what I think we were really excited to see at ASCO this year was that CAR T-cells appear to be superior to standard treatment in the context of that randomized phase 3 trial. Now, there were a few patients who were randomized to CAR T-cells who didn't get to the CAR T-cell infusion because their disease progressed in that interval. And that is a challenge that many of us deal with on a regular basis when we think about using a CAR T in a patient. But in general, the treatment was available for almost all patients. And the analysis of benefit as measured by a longer remission duration for the patients who received CAR T cells versus those who didn't was really done on what we call an intent to treat basis. And what that means is if you were randomized to the CAR T arm, even if you didn't get the CAR T, which again was a very small number of patients, you were still evaluated as if you got a CAR. And what I think that tells us is that even taking into account some of those patients who may not get there, there still was significant clinical benefit. And this is really important data for us to have insight into. We've seen this with cilta-cel in CARTITUDE-4. We'd seen similar kinds of findings in KarMMa using ide-cel as the CAR T-cell, although it does appear that the remission duration, at least when you're comparing across trials, appears to be a little bit longer for cilta-cel than what we've seen with ide-cel. But nonetheless, it suggests that even in the context of early relapse, there may be some benefit for CARs over standard therapy. Now, does this mean that CARs are going to replace standard therapy in terms of early relapse? I don't think we know the answer to that right now. I think there's a lot of information that we need to look at to really feel comfortable making that step. The other big set of data I think that we were all very excited about to see at ASCO this year were the T-cell engagers or the bispecifics. And what we saw from a number of different bispecifics was that the efficacy data looks like it continues to hold up. But what to me was really quite exciting was the idea that the T-cell engager could be highly effective even if a patient had seen prior BCMA-directed therapy. And what this means to me is that perhaps if you're progressing on a CAR T-cell, you still may have a pretty reasonable chance at a response, again, to a BCMA-directed therapy with a bispecific. The other way around may not necessarily be the same. And so I think what we learned at this meeting is that the bispecific or T-cell engagers clearly could have activity in the context of prior BCMA-exposed therapy. And I think, as a field, we need to think more about how we define what it means to be resistant to a BCMA-directed therapy. So that I think was really important and exciting and will have relevance in our daily clinical practice. We also saw updates on a different non-BCMA-directed target. So we saw updates on GPRC5D-targeted bispecifics, also known as talquetamab. What I think was really exciting here is we saw a very high overall response rate, modest infectious complications compared to what we've seen with BCMA-directed therapy.   Finally, what I want to wrap up with was a very small study addressing what I think is a pretty significant unmet medical need. And that was a trial from Dr. Nooka at my institution, where we evaluated a combination of carfilzomib with pomalidomide and dexamethasone, or KPD. And we used that specifically as maintenance in the high-risk group. And what we learned from that evaluation is that it appears for patients with high-risk disease that KPD maintenance is better than either carfilzomib and len [lenalidomide] or even bortezomib and lenalidomide, which historically has been what we're using. But there remains an unmet medical need patient population, particularly the double-hit patient population, that even with KPD still didn't have a great outcome overall. So more work for us to do down the road. But certainly, food for thought for many of those other patients that perhaps don't fit into that double-hit classic category. So I think what I've given you is a nice sort of overview of many of the exciting data that were presented at ASCO 2023. Again, go to the website to see additional ones. And thank you again for listening to this brief summary of research in myeloma updates from the 2023 ASCO Annual Meeting. ASCO: Thank you, Dr. Lonial. Finally, Dr. Cristina Rodriguez discusses new research in treating head and neck cancer. Dr. Rodriguez is a medical oncologist at Seattle Cancer Care Alliance, an Associate Professor in the Division of Medical Oncology at the University of Washington, and an Associate Member for solid tumor clinical research at the Fred Hutchinson Cancer Research Center. She is also the 2023 Cancer.Net Associate Editor for Head and Neck Cancers. You can view Dr. Rodriguez's disclosures at Cancer.Net. Dr. Rodriguez: Hello, my name is Cristina Rodriguez, and today I'm going to discuss some new research focusing on head and neck cancer that was presented at our annual ASCO 2023 meeting. As part of my disclosures, my institution receives research funding from CGEN. My takeaway from this meeting was there were a few major themes represented by the research. One of them was research on uncommon cancer types, such as nasopharyngeal cancer and salivary gland cancer. The other major theme and what was exciting for me was research on groups that were typically not represented in clinical trials in head and neck cancer. These include elderly or frail patients with many other comorbid illnesses that might have excluded them from clinical trials. Another theme was research in areas outside the developed world. In other words, resource-restricted countries. There was some exciting research coming out of that. And finally, a few new agents, novel agents that looked to have activity in patients with head and neck cancer that are going to be studied further. So with that, I'm going to start with talking about research that came out of France, presented by Dr. Fayette. This was a clinical trial that focused primarily on the frail elderly population. A group that might make very difficult for one to enter clinical trial because of many different illnesses or not being fit enough. And this group, out of France, looked at a combination of immunotherapy and a gentler lower dose chemotherapy called carboplatin and paclitaxel. Interestingly, in this group, there was very encouraging results, including 71% of patients having an objective response or a reduction in the size of their tumor, and very few patients, less than 5% of patients, having toxicity that required permanent discontinuation of the drug. So I thought this study was particularly interesting and gives us physicians and patients who are in this situation some more options to use when we're in the treatment of head and neck cancer. The next study that I thought was particularly interesting came out of India and was presented by Dr. Kothari. The special thing about this study was that it asked the question of the efficacy of a very low-cost combination for patients with recurrent or metastatic head and neck cancer. It's a combination that we don't tend to use here in the United States, one that involves methotrexate, celecoxib, and erlotinib. This particular clinical trial was carried out in several sites in India, and it randomized patients to this low-cost oral regimen versus physician's choice. In other words, any type of treatment that might involve immunotherapy or antibody therapy. The main issue here being that sometimes many of these therapies are not easily accessible to patients in low-resourced situations. The investigators observed an overall survival advantage, what that means is more patients lived longer when they use the low-cost oral regimen, which was much more practical, much easier for patients to take, and had more success in improving and prolonging the lives of patients. So I thought that that was a particularly important observation. And we forget a lot of times when we're practicing in the United States that a lot of our practice patterns here may not be applicable to low-resource settings. And I think it's very exciting that research is being carried out to answer questions that are relevant to this area. The third abstract that I thought was particularly intriguing was one presented by Dr. Glenn Hanna from Dana-Farber. And it looked at a new drug called BCA101. BCA101 is an antibody that has 2 functions. It inhibits EGFR, or epidermal growth factor receptor, very commonly overexpressed in head and neck squamous cell carcinomas. And it has a dual function, which is it modulates TGFβ, which is an immunosuppressive cytokine within tumor cells. This drug was combined with pembrolizumab in this small study and offered to patients who have never received treatment for recurrent or metastatic head and neck cancer. There was a lot of enthusiasm for this drug because in the 33 patients enrolled in the trial, 48% of them had an objective response, meaning a reduction in the size of their tumor. Anemia was one of the more common side effects that were noted. But the efficacy of this agent in this population, these patients expressed PD-L1 or had a CPS score of 1, was enough to support further study of this drug and a larger clinical trial is going to be carried out looking to see if this drug will have similar efficacy or better efficacy in a larger population. Finally, the last abstract is one that was presented by Dr. Swiecicki. And it was an interesting abstract to me because it examined the activity of another novel agent not FDA-approved for head and neck cancer, called enfortumab vedotin. This is a class of drugs that belong to a group called antibody-drug conjugates. This is an antibody that's directed toward the target called Nectin-4 and has a small chemotherapy payload that's attached to the antibody. Unlike Dr. Hanna's study, this study was a small phase 2 trial that focused on patients who've previously been treated in the recurrent or metastatic setting and are now receiving this drug either as their second or third option after they developed recurrent or metastatic disease. 46 patients were enrolled in this trial, and 24% of patients had an objective response or reduction in the size of this tumor. Although that number doesn't seem very high, it is an encouraging signal because in patients who previously received treatment for head and neck cancer, we tend to see very poor response rates. So this is encouraging given the population that was studied. Another 32% of these patients had what's called stable disease or no significant change in the size of their tumor. So that too is quite encouraging. This drug is going to also move on for further study in head and neck cancer. So I thought that these themes really brought about a lot of excitement for me for the future of treatments in patients with head and neck cancer, not only in developed countries but also in resource-restricted environments. And I look forward to next year and more work being done in these areas. And I'd like to thank you for listening to this brief summary of developments and head and neck cancer presented in the 2023 ASCO Annual Meeting. ASCO: Thank you, Dr. Rodriguez. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Welcome back to our weekend Cabral HouseCall shows! This is where we answer our community's wellness, weight loss, and anti-aging questions to help people get back on track! Check out today's questions:    Cyn: Hello doctor Cabral! What are your thoughts on laser hair removal? Is it safe? thank you! Cyn   Greg: Hi Dr. Cabral, Thank you so much for all that you do. I am a student of all that you teach and I greatly appreciate all the time and effort you put in to doing the research and sharing your knowledge. My question is regarding fiber intake. I maintain a healthy diet and track my meals daily. I have noticed that my daily fiber intake is 50-60g due to all the vegetables and other healthy foods that I consume. Is this too much? I understand that everything is based on bio-individuality but do you recommend a specific range for daily fiber intake? Thanks again for all that you do!    Leslie: As I get older, certain joints bother me after strength training, walking, etc. Not anything that stopping me from doing it, but definitely tell a difference some days. Are turmeric shots good for joint pain and recovery or would a supplement be more affective?   Andrea: Thank you for your podcast, so grateful for you! What is your opinion on ozone therapy and hydrogen peroxide therapy in regards to curing cancer. Thank you!!!   Anonymous: Hello! I got saline implants 10 years ago because I had extremely uneven breasts. I have learned about breast implant Illness and don't know if I really have that but am just worried about toxic load on my body. I really don't want to get them out because the unevenness is noticeable in shirts and bathing suits. Are there tests to check if it is negatively impacting my health or things to do to make sure it's not? Thank you   Kate: Hi Dr Cabral, Recently, I got some blood work back and it showed a very high TGF Beta 1 number. I pointed this out to my doc who seemed nonchalant. This can't be good. I googled and have mostly seen complex academic papers that are hard to understand. Can you explain what TGF beta 1 is, why it might be high, and what to do about it?   Thank you for tuning into today's Cabral HouseCall and be sure to check back tomorrow where we answer more of our community's questions!      - - - Show Notes and Resources: StephenCabral.com/2724 - - - Get a FREE Copy of Dr. Cabral's Book: The Rain Barrel Effect - - - Join the Community & Get Your Questions Answered: CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - Get Your Question Answered On An Upcoming HouseCall: StephenCabral.com/askcabral - - - Would You Take 30 Seconds To Rate & Review The Cabral Concept? The best way to help me spread our mission of true natural health is to pass on the good word, and I read and appreciate every review!  

For more information, visit https://thecirsgroup.com Today we're talking about Phase 5 of the Shoemaker Protocol: Repair and Restoration. This phase includes correcting MMP9, C3a and C4a, and TGF-beta 1, and taking Vasoactive Intestinal Peptide, or VIP, Spray. The Shoemaker Protocol is the only clinically proven and peer reviewed method for treating Chronic Inflammatory Response Syndrome. For more information, visit TheCIRSGroup.com TIME STAMPS: 0:25 Phase 5: Maybe the most exciting 2:00 This phase is about Repair and Restoration 2:49 Correcting MMP9 5:43 Correcting C3a and C4a 6:24 Correcting TGF-beta 1 8:48 VIP Spray 10:13 Jacie's experience with VIP Spray 12:03 Barbara's experience with VIP Spray 13:09 Why you may want to track your symptoms 13:45 Reasons to join The CIRS Group Jacie is a 3.5+ year carnivore, certified nutrition coach, and carnivore recipe developer determined to share the life changing information of carnivore and CIRS to anyone who will listen. Barbara is a coach, facilitator, speaker, 2.5+ year carnivore, and a big fan of health and freedom. Together, they co-founded The CIRS Group, an online support community to help people that are struggling with their CIRS diagnosis and treatment. Catch Jacie and Barbara on Judy Cho's podcast to learn more about their health journeys and why they started The CIRS Group: When Carnivores are Affected by Mold Illness - Jacie Gregory & Barbara Williams - https://youtu.be/CR8Uj-d_fok

Dr. John Sweetenham and Dr. Marc Braunstein discuss the role of maintenance therapy in high-risk multiple myeloma, advances in myelodysplastic syndromes in the COMMANDS study, the promise of bispecific antibodies in the pivotal EPCORE NHL-1 in relapsed/refractory large B-cell lymphoma, and improving outcomes for patients with chronic lymphocytic leukemia in the CAPTIVATE trial.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Today, we'll be discussing key posters and oral abstracts highlighting advances in hematologic malignancies that will be featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Dr. John Sweetenham: So, Marc, thanks for returning to us and coming to join us on the podcast today. Dr. Marc Braunstein: Thanks for inviting me back. Dr. John Sweetenham: I'd like to start out with Abstract 8001. This is a study which is addressing the role of maintenance therapy in patients with high-risk multiple myeloma. Could you take us through this study and the key take-home points that you think are the most important ones? Dr. Marc Braunstein: Sure, absolutely. So, the first abstract that we're going to discuss is an oral abstract being presented by Dr. Nooka regarding maintenance therapy in high-risk multiple myeloma patients. Outcomes of patients with multiple myeloma are clearly improving, yet those with high-risk cytogenetic abnormalities, which represent about 10-20% of all multiple myeloma, tend to have poorer survival, and worst among these are those with what's called ultra-high-risk or double-hit multiple myeloma who have more than 1 high-risk cytogenetic abnormality. So, this study looked at maintenance therapy following stem cell transplantation in 26 high-risk patients, about 59% of whom had double hit disease, representing very high-risk disease. This was a phase II study looking at using carfilzomib, pomalidomide, and dexamethasone in high-risk multiple myeloma patients who achieved at least a partial remission following stem cell transplant. There were 26 patients enrolled. The median age was 60. Of note, about 59% of patients were Black, which is important because these patients tend to be historically underrepresented in studies. And what they found was that at study entry, about 24% of patients were in a complete remission or better, and that deepened to 79% while on the study. And the median time to best response was 2 months, which is fairly brisk. With a median follow-up of about 26 months, the 36-month progression-free survival was 63%, and the overall survival was 72%, which is impressive, again in the context of patients who have very high-risk disease. So, although it remains to be determined what the optimal regimen or duration of maintenance should be in multiple myeloma, clearly, combination therapy is effective and should be used in patients who have high-risk or ultra-high-risk multiple myeloma. Dr. John Sweetenham: Great. Thanks, Marc. So, as you say, I mean, clearly the take-home message is around the effectiveness of this type of maintenance therapy. I just have a couple of quick follow-up questions for you. The first of those is, where do you see this going next? I mean, in your opinion, what would be the next logical study with this combination or similar combinations? And then secondly, what do you see on the horizon for those patients with very high-risk myeloma, particularly the double-hit population that you just mentioned? Dr. Marc Braunstein: It's a paradigm in multiple myeloma that combination therapy tends to be more effective as long as we're able to manage the adverse events that come with additional combinations. And we've been able to succeed in that regard with quadruplet regimens, even now that we have monoclonal antibodies that tend to be better tolerated and more targeted in nature. In terms of maintenance therapy, single-agent lenalidomide has been the long-standing agent of use for the majority of patients. But we now understand that the combination of an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib or carfilzomib is more effective for patients with higher risk disease.   We also have data from various upfront studies of quadruplet regimens, such as the FORTE study, which looked at carfilzomib and lenalidomide maintenance after transplant that shows that we can improve progression-free survival in all comers with multiple myeloma following transplants. So, I think down the road we're going to be looking at more use of combination therapies and maintenance. And as far as for high-risk patients, whether that's going to be using monoclonal antibodies in maintenance or combination proteasome inhibitors and immunomodulators or even other immunotherapies like bispecific antibodies as maintenance in the future remains to be determined, but clearly, for high-risk patients, we should be using combination therapies. Dr. John Sweetenham: Thanks, Marc. Let's change gears a little now and take a look at Abstract 7003, which addresses patients with myelodysplastic syndrome. This study addresses the efficacy and safety results from a study of luspatercept versus epoetin alfa in low-risk myelodysplastic syndrome. I wonder if you could describe this study and the results to us and maybe also for the benefit of our listeners, just mention quickly the mechanism of action of the experimental agent here.  Dr. Marc Braunstein: This is an oral abstract being presented by Dr. Garcia-Manero looking at a phase 3 study, as you mentioned, called the COMMANDS study, and this is looking at an agent called luspatercept in patients with low-risk myelodysplastic syndrome (MDS). So, patients with MDS can have inferior quality of life and survival when they become transfusion dependent. An earlier study called the MEDALIST study, which was published in the New England Journal of Medicine in 2020, randomized low-risk or intermediate-risk patients with MDS who were refractory or unlikely to respond to erythropoietin stimulating agents to either luspatercept, which is an agent that binds to TGF-beta family members and helps stimulate erythropoiesis. Patients were randomized in the MEDALIST study to luspatercept or placebo. And that study showed that luspatercept could improve a degree of anemia and lead to transfusion independence in certain patients. So, the COMMANDS study is a randomized controlled study that randomized 354 patients with low-risk MDS who were transfusion dependent and naive to an erythropoietin stimulating agent to receive either luspatercept or the erythropoietin stimulating agent erythropoietin alfa with the primary endpoint of transfusion independence at some time between 12 to 24 weeks. So, patients were randomized 1:1 to receive either luspatercept or epoetin alfa, and the primary endpoint again was transfusion independence. So, 354 patients were randomized in the study and the median treatment durations were 42 weeks of luspatercept and 27 weeks of epoetin alfa. And transfusion independence occurred in greater quantity in the patients who got luspatercept. For example, in the patients who received luspatercept at 8 weeks, transfusion independence was achieved in 74 versus 51% in the epoetin alfa group. So, in terms of treatment-related adverse events, they were fairly similar between the groups and consistent with the classes -  they were reported in 30% in the luspatercept group and 17% in the erythropoietin group, with no difference in patients who progressed to acute myeloid leukemia.  So, I think when it comes to MDS in low-risk patients, it's really important to preserve their quality of life by limiting their transfusion burden. And I think this study demonstrates that luspatercept continues to be an important part of the management in these low-risk patients. And whether or not you would start a patient with low-risk transfusion-dependent MDS on an erythropoietin stimulating agent or luspatercept is really addressed by this study showing that you can achieve greater rates of improvement in anemia and transfusion independence with luspatercept.  Dr. John Sweetenham: Great. Thanks, Marc. A really interesting study. And I do have one question for you about this study, which I think will make it clear to you that I am an expert neither in myelodysplastic syndrome nor in erythropoiesis. But my question is based on the mechanism of action. Is there any rationale for combining these 2 agents in future studies?  Dr. Marc Braunstein: Yes, it would potentially make sense to use 2 synergistic mechanisms to improve erythropoiesis. We would have to see what the potential for adverse events are. I think epoetin alfa tends to be a fairly low burden in terms of its side effect profile. Luspatercept can have some potentially dose-limiting side effects, such as GI side effects, but you can make dose adjustments to both of these medications. So we may need to find the correct doses of either of them in combination. But from a theoretical standpoint, it makes sense that these could potentially be synergistic, especially in patients who are likely to respond to erythropoietin by having a baseline lower erythropoietin level. Dr. John Sweetenham: Okay, let's move on in another change of gear now. And for the rest of the podcast, we're going to be talking about some studies in lymphoid malignancy, beginning with Abstract 7535, which is a follow-up of the phase 2 CAPTIVATE study which now has significantly extended follow-up from the original report. So Marc, can you walk us through this study and the outcomes to date? Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Barr and it is looking at CLL, which is a field that is really moving away from chemotherapy for newly diagnosed patients, thanks to the development of novel targeted agents. The CLL14 trial, which was published in the New England Journal of Medicine in 2019, showed that fixed-duration venetoclax plus obinutuzumab improved progression-free survival and rates of negativity of minimal residual disease, or MRD, when compared to chlorambucil and obinutuzumab. So building on the success of that study, combining a monoclonal antibody and a BCL2 inhibitor, the CAPTIVATE study is a phase II study, which examines venetoclax with ibrutinib, the BTK inhibitor, and previously untreated CLL. So it's kind of combining 2of the novel targeted therapies in a fixed duration, similar to what was done in the CLL14 study where patients received 1 year of therapy and then stopped treatment.   So in the CAPTIVATE study, 154 patients were enrolled. This was a phase 2 study that included about 56% of higher-risk patients who had unmutated IGHV, and the median time on the study was 50 months, with a CR rate of 58% at a 4-year follow-up and an overall response rate of 96%, which is quite high, especially considering that more than half of patients had high-risk disease. The progression-free survival was 79% and the overall survival rate was 98% at 4 years. And when they looked at patients who had undetectable minimal residual disease, the 4-year overall survival rate was 100%, which also suggests that MRD can help serve as a predictive marker of longer-term survival. So I think we have to also consider what the side effects are of combining these 2 agents and the most common adverse events were hematologic, which is expected based on what we know about the 2 classes. So I think the implication of the study is that giving 2 oral agents for a fixed period of treatment for 12 cycles is a rational approach that may spare patients indefinite therapy and can lead to positive outcomes, including in patients who have high-risk features with CLL.  Dr. John Sweetenham: Yeah, the other interesting observation that was made in the abstract, which I found to be really encouraging, was the fact that a number of these patients apparently have been re-treated successfully upon progression with ibrutinib again, which seems to be somewhat reassuring as well.  Dr. Marc Braunstein: That's right. There were 4 patients who started re-treatment in the study and perhaps we'll see the outcomes of that small subgroup are at the poster presentation. But I think when we discuss fixed-duration treatment, it also opens the door to potentially re-challenging patients when they relapse. We know that when we stop single-agent BTK inhibitors, which are historically given indefinitely in patients with CLL, those patients who stop, many will relapse, but you can potentially re-challenge them with the BTK inhibitor. So this study with the CAPTIVATE trial gives us some liberty to discontinue therapy, but also considering re-challenging upon relapse.   Dr. John Sweetenham: Yeah, absolutely. Moving on to aggressive B-cell lymphoma, now, the next abstract I'd like to discuss with you is Abstract 7525. I find this one particularly interesting as the continued excitement around CAR T cell therapy for relapsed aggressive lymphoma remains high at the moment. It's intriguing that t cell-engaging antibodies also have been reported, at least, to have remarkable activity in this set of diseases. So can you take us through Abstract 7525 and what they're reporting?  Dr. Marc Braunstein: Absolutely. Bispecific antibodies represent an emerging field in multiple hematologic malignancies, and this is a class of antibodies that bind to both the tumor cell as well as T-cells, and activate T-cell immunity against the tumor cell. So epcoritamab is a bispecific antibody that binds to CD3, which is expressed on T cells, and CD20, which is expressed on B cells. And Thieblemont et al published results in the Journal of Clinical Oncology last year in a phase I/2 study that looked at epcoritamab in patients with diffuse large B cell lymphoma following 2 prior lines of therapy, and this was given subcutaneously until progression of disease. In that study, at a median follow-up of about 11 months, the overall response rate was 63% with 39% complete remissions.   So the EPCORE NHL-1 study, which is being presented at this year's ASCO meeting, is presenting the updated results of that study looking at patients with diffuse large B cell lymphoma that includes a small population as well of patients with high-grade B cell lymphomas and primary mediastinal B cell lymphomas who had at least 2 prior lines of therapy. In this presentation, 157 patients were included in this study, and 61% had primary refractory disease, and actually, 39% had prior CAR T-cell therapy, of whom 75% progressed within 6 months. So these were patients who were not only refractory to treatment but also had prior T-cell therapy.   So at a median follow-up of 20 months, the overall response rate was 63% and the complete response rate was again about 39%, and the median duration of complete remission was 21 months. In terms of overall survival, the median was about 19 months, which is substantial for this group of patients who really wouldn't be expected to respond very well to conventional therapies.   As we know, T-cell-engaging therapies, such as these bispecific antibodies or CAR T-cells have the potential risk for certain immune-related adverse events, including cytokine release syndrome or icons, and a neurologic syndrome related to the therapy. And it's worth noting that the CRS in this study was predominantly low-grade. There were only 3% of patients who had grade III CRS, and 9 patients, or 6% had grade I to II icons. I think that also reflects how we're better managing those side effects and intervening earlier. So I think the results are impressive from the standpoint of the population studied, who were quite refractory to treatment and show relatively high rates of response. In fact, the median overall survival was not reached in the overall population.   So I think what we take away from this abstract is that bispecific antibodies are going to play a vital role in the relapse-refractory setting for large cell lymphoma and may also offer an alternative to patients who aren't necessarily fit for CAR T-cell therapy, which plays a vital role in patients who are both refractory to first-line therapy or relapse-refractory to subsequent disease. So these are very encouraging results, and I'm sure we'll see randomized data as well in the future, further supporting the use of bispecific antibodies like epcoritamab.  Dr. John Sweetenham: Yeah, I agree. Thanks, Marc. I think that's a great summary. And it's particularly exciting to me that the investigators were able to achieve this kind of level of response and progression-free survival with a subcutaneous treatment. It's really quite remarkable and really exciting to see that.  We're going to wind up with our final abstract today, which is looking at the utilization of circulating tumor DNA in, again, in patients with aggressive B cell lymphoma. This is Abstract 7523, so maybe you could walk us through this one, Marc.  Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Herrera looking at a, I guess you could call it a biomarker in the blood using circulating tumor DNA in patients with newly diagnosed diffuse large B cell lymphoma in the POLARIX study. So the results of the phase 3 POLARIX study were published last year in the New England Journal of Medicine and showed improvement in progression-free survival with the addition of these anti-CD79b antibody polatuzumab to standard R-CHOP chemotherapy compared to R-CHOP alone. And this study actually led to the approval of first-line treatment that includes polatuzumab.   In the abstract being presented by Dr. Herrera, the investigators looked at the value of circulating tumor DNA as a potential marker to serve as a guide for prognosis and predicting longer-term responses, particularly when the blood is cleared of circulating tumor DNA. So the study involved 654 patients who had ctDNA results both at baseline and then with longitudinal assessment, and they used an assay called the CAPP-Seq assay to assess circulating tumor DNA and assess for its clearance. In the study, undetectable circulating tumor DNA was achieved in 57% of patients who got the polatuzumab R-CHP combination and 59% of the patients who got R-CHOP by cycle 5 and then 6% in the polatuzumab group at 67% in the R-CHOP group.  So the rates of circulating tumor DNA clearance were similar between the 2 arms. But what's notable is that patients in the polatuzumab arm who achieved a complete response at the end of treatment plus cleared their circulating tumor DNA had superior progression-free and overall survival compared to patients who achieved a CR but retained circulating tumor DNA in their blood.   And this has implications because it might help gauge, for example, if patients may need additional cycles to clear the circulating tumor DNA, although we still need more data to answer whether that's necessary or not. And it may help serve as a predictive marker for longer-term remission, particularly in patients who perhaps have higher risk factors at baseline. So I don't think this is necessarily ready for primetime to use in clinical practice, but it is intriguing to know that we could finally have a tumor-specific biomarker in the blood to help monitor patients and potentially predict their longer-term remissions.  Dr. John Sweetenham: Thanks, Marc. I agree. Great summary, and obviously there's still something to learn about the kinetics of the response and so on. And also, I suppose it raises the question of whether those patients who still have detectable levels should be switched at the end of therapy to some kind of preemptive second-line therapy. And these are obviously all questions for the future, but it's going to be very interesting to watch this space, I think, and see how this story develops. Dr. Marc Braunstein: Absolutely. And my colleagues in the solid tumor space are already using circulating tumor DNA, for example, in colon cancer, to help with surveillance. So perhaps this could be a tool to use to predict relapse also in patients who are on surveillance after their treatment. But again, as you alluded to, we need more data to address that.  Dr. John Sweetenham: Well, thanks so much, Marc, for sharing your insights with us today on a really interesting set of abstracts coming up at the June meeting. And thanks for joining us on the ASCO Daily News Podcast. Dr. Marc Braunstein: Thank you for inviting me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Join us again after the annual meeting for key takeaways on the late-breaking abstracts and other key advances from the ASCO Annual Meeting. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. John Sweetenham Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham:Consulting or Advisory Role: EMA Wellness Dr. Marc Braunstein:Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers' Bureau: Janssen OncologyResearch Funding (Institution): Janssen, Celgene/BMS

A new research paper was published on the cover of Aging (Aging-US) Volume 15, Issue 9, entitled, “In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers.” Zoledronic acid has been found to reduce fracture risk and, in some studies, to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple comorbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype (SASP)) actions. In this new study, researchers Parinya Samakkarnthai, Dominik Saul, Lei Zhang, Zaira Aversa, Madison L. Doolittle, Jad G. Sfeir, Japneet Kaur, Elizabeth J. Atkinson, James R. Edwards, Graham G. Russell, Robert J. Pignolo, James L. Kirkland, Tamar Tchkonia, Laura J. Niedernhofer, David G. Monroe, Nathan K. Lebrasseur, Joshua N. Farr, Paul D. Robbins, and Sundeep Khosla from the Mayo Clinic, Phramongkutklao Hospital and College of Medicine, Eberhard Karls University, University of Minnesota, University of Oxford, and University of Sheffield tested the above hypothesis using multiple complementary approaches (in vitro, in vivo, and in silico) to evaluate possible effects of zoledronic acid on modulating cellular senescence. The researchers first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, the team used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated that zoledronic acid significantly reduced the number of pre-osteoclastic (CD115+/CD3e-/Ly6G-/CD45R-) cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations. “Collectively, our findings demonstrate that zoledronic acid has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo. These data point to the need for additional studies testing zoledronic acid and/or other bisphosphonate derivatives for senotherapeutic efficacy.” DOI - https://doi.org/10.18632/aging.204701 Corresponding author - Sundeep Khosla - khosla.sundeep@mayo.edu About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

A new research paper was published in Aging (Aging-US) Volume 15, Issue 7, entitled, “Effect of deferoxamine and ferrostatin-1 on salivary gland dysfunction in ovariectomized rats.” Xerostomia can be defined as a subjective sensation associated with reduction of lubrication and dehydration of the oral mucosa. Xerostomia is known to be common in elderly people, especially women, and its prevalence is thought to range from 5.5% to 46%. The mechanism underlying xerostomia after menopause has not yet been fully elucidated. In this new study, researchers Yong-Il Cheon, Ji Min Kim, Sung-Chan Shin, Hyung-Sik Kim, Jin-Choon Lee, Gi Cheol Park, Eui-Suk Sung, Minhyung Lee, and Byung-Joo Lee from Pusan National University and Sungkyunkwan University School of Medicine aimed to investigate the mechanism of xerostomia and the effect of the ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (FER) on salivary gland dysfunction in a postmenopausal animal model. “Recently, it was reported that ferroptosis in the salivary gland may be related to the xerostomia that occurs after menopause [30]. However, no studies to date have used anti-ferroptosis drugs to investigate the mechanisms underlying postmenopausal salivary gland dysfunction.” Twenty-four female Sprague–Dawley rats were randomly divided into four groups: a SHAM group (n = 6, sham-operated rats), an OVX group (n = 6, ovariectomized rats), an FER group (n = 6, ovariectomized rats injected intraperitoneally with FER), and a DFO group (n = 6, ovariectomized rats injected intraperitoneally with DFO). GPX4 activity, iron accumulation, lipid peroxidation, inflammation, fibrosis, and salivary gland function were analyzed. Recovery of GPX4 activity and a decrease in iron accumulation and cytosolic MDA + HAE were observed in the DFO group. In addition, collagen I, collagen III, TGF-β, IL-6, TNF-α, and TGF-β levels were decreased in the DFO group compared to the OVX group. Recovery of GPX4 activity and the morphology of mitochondria, and reduction of cytosolic MDA + HAE were also observed in the FER group. In addition, decreased expression of inflammatory cytokines and fibrosis markers and increased expression of AQP5 were observed in both the DFO and FER groups. Postmenopausal salivary gland dysfunction is associated with ferroptosis. This is the first study to investigate the effect of ferroptosis inhibitors (DFO and FER) on the salivary glands of ovariectomized rats. DFO and FER are considered promising treatments for postmenopausal xerostomia. “In the absence of a standard treatment for postmenopausal dry mouth, this study is expected to be helpful in understanding the mechanism of postmenopausal salivary gland dysfunction and developing a treatment for postmenopausal dry mouth.” DOI: https://doi.org/10.18632/aging.204641 Corresponding author - Byung-Joo Lee - voicelee@pusan.ac.kr Keywords - aging, menopause, ferroptosis, xerostomia, deferoxamine, ferrostatin-1 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ MEDIA@IMPACTJOURNALS.COM

This month on Episode 47 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the March 31 issue of Circulation Research. We'll also provide an overview of the Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease published in the April 14 issue. Finally, this episode features an interview with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   Article highlights:   Shi, et al. LncRNAs Regulate SMC Phenotypic Transition   Chen, et al. Bilirubin Stabilizes Atherosclerotic Plaque   Subramaniam, et al. Mapping Non-Obvious cAMP Nanodomains by Proteomics   Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease   Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to share three articles selected from our March 31st issue of Circulation Research and give you a quick summary of our April 14th Compendium. I'm also excited to speak with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   So first the highlights. The first article we're going to discuss is Discovery of Transacting Long Noncoding RNAs that Regulates Smooth Muscle Cell Phenotype. This article's coming from Stanford University and the laboratory of Dr Thomas Quertermous. Smooth muscle cells are the major cell type contributing to atherosclerotic plaques. And in plaque pathogenesis, the cells can undergo a phenotypic transition whereby a contractile smooth muscle cell can trans differentiate into other cell types found within the plaque, such as macrophage-like cells, osteoblast-like cells and fibroblast-like cells. These transitions are regulated by a network of genetic and epigenetic mechanisms, and these mechanisms govern the risk of disease.   The involvement of long non-coding RNAs, or Lnc RNAs as they're called, has been increasingly identified in cardiovascular disease. However, smooth muscle cell Lnc RNAs have not been comprehensively characterized and the regulatory role in the smooth muscle cell state transition is not thoroughly understood. To address this gap, Shi and colleagues created a discovery pipeline and applied it to deeply strand-specific RNA sequencing from human coronary artery smooth muscle cells that were stressed with different disease related stimuli. Subsequently, the functional relevancy of a few novel Lnc RNAs was verified in vitro.   From this pipeline, they identified over 4,500 known and over 13,000 unknown or previously unknown Lnc RNAs in human coronary artery smooth muscle cells. The genomic location of these long noncoding RNAs was enriched near coronary artery disease related transcription factor and genetic loci. They were also found to be gene regulators of smooth muscle cell identity. Two novel Lnc RNAs, ZEB-interacting suppressor or ZIPPOR and TNS1-antisense or TNS1-AS2, were identified by the screen, and this group discovered that the coronary artery disease gene, ZEB2, which is a transcription factor in the TGF beta signaling pathway, is a target for these Lnc RNAs. These data suggest a critical role for long noncoding RNAs in smooth muscle cell phenotypic transition and in human atherosclerotic disease.   Cindy St. Hilaire:              The second article I want to share is titled Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency. This article is coming from the Heart Research Institute and the corresponding author is Roland Stocker. The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin, a byproduct of heme catabolism, is inversely associated with risk of cardiovascular disease, but the link between bilirubin and atherosclerosis is unknown.   Chen et el addressed this gap by crossing a bilirubin knockout mice to a atherosclerosis prone APOe knockout mouse. Chen et el addressed this gap by crossing the bilirubin knockout mouse to the atherosclerosis-prone APOE knockout mouse, and used the tandem stenosis model of plaque instability to address this question. Compared with their litter mate controls, bilirubin-APOE double knockouts showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia. And they had higher atherosclerotic plaque burden.   Hemeatabolism was increased in unstable plaques compared with stable plaques in both of these groups as well as in human coronary arteries. In mice, the bilirubin deletion selectively destabilized unstable plaques and this was characterized by positive arterial remodeling and increased cap thinning, intra plaque hemorrhage, infiltration of neutrophils and MPO activity. Subsequent proteomics analysis confirmed bilirubin deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils and associated oxidative stress in the unstable plaque. Thus, bilirubin deficiency generates a pro atherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaques, thereby providing a link between bilirubin and cardiovascular disease risk.   Cindy St. Hilaire:              The third article I want to share is titled Integrated Proteomics Unveils Regulation of Cardiac Monocyte Hypertrophic Growth by a Nuclear Cyclic AMP Nano Domain under the Control of PDE3A. This study is coming from the University of Oxford in the lab of Manuela Zaccolo. Cyclic AMP is a critically important secondary messenger downstream from a myriad of signaling receptors on the cell surface. Signaling by cyclic AMP is organized in multiple distinct subcellular nano domains, regulated by cyclic AMP hydrolyzing phosphodiesterases or PDEs.   The cardiac beta adrenergic signaling has served as the prototypical system to elucidate this very complex cyclic AMP compartmentalization. Although studies in cardiac monocytes have provided an understanding of the location and the properties of a handful of these subcellular domains, an overview of the cellular landscape of the cyclic AMP nano domains is missing.   To understand the nanodynamics, Subramanian et al combined an integrated phospho proteomics approach that took advantage of the unique role that individual phosphodiesterases play in the control of local cyclic AMP. They combined this with network analysis to identify previously unrecognized cyclic AMP nano domains associated with beta adrenergic stimulation. They found that indeed this integrated phospho proteomics approach could successfully pinpoint the location of these signaling domains and it provided crucial cues to determine the function of previously unknown cyclic AMP nano domains.   The group characterized one such cellular compartment in detail and they showed that the phosphodiesterase PDE3A2 isoform operates in a nuclear nano domain that involves SMAD4 and HDAC1. Inhibition of PDE3 resulted in an increased HDAC1 phosphorylation, which led to an inhibition of its deacetylase activity, and thus derepression of gene transcription and cardiac monocyte hypertrophic growth. These findings reveal a very unique mechanism that explains the negative long-term consequences observed in patients with heart failure treated with PDE3 inhibitors.   Cindy St. Hilaire:              The April 14th issue is our compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease. Dr Heidi Noels from the University of Aachen is our guest editor of the 11 articles in this issue. Chronic kidney disease is defined by kidney damage or a reduced kidney filtration function. Chronic kidney disease is a highly prevalent condition affecting over 13% of the population worldwide and its progressive nature has devastating effects on patient health. At the end stage of kidney disease, patients depend on dialysis or kidney transplantation for survival. However, less than 1% of CKD patients will reach this end stage of chronic kidney disease. Instead, most of them with moderate to advanced chronic kidney disease will prematurely die and most often they die from cardiovascular disease. And this highlights the extreme cardiovascular burden patients with CKD have.   The titles of the articles in this compendium are the Cardio Kidney Patient Epidemiology, Clinical Characteristics, and Therapy by Nicholas Marx, the Innate Immunity System in Patients with Cardiovascular and Kidney Disease by Carmine Zoccali et al. NETs Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney disease by Yvonne Doering et al. Accelerated Vascular Aging and Chronic Kidney Disease, The Potential for Novel Therapies by Peter Stenvinkel et al. Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients with Chronic Kidney Disease by Heidi Noels et al. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease by Claudia Goettsch et al. Fibrosis in Pathobiology of Heart and Kidney From Deep RNA Sequencing to Novel Molecular Targets by Raphael Kramann et al. Cardiac Metabolism and Heart Failure and Implications for Uremic Cardiomyopathy by P. Christian Schulze et al. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease by Michael Burnier et al. Role of the Microbiome in Gut, Heart, Kidney crosstalk by Griet Glorieux et al, and Use of Computation Ecosystems to Analyze the Kidney Heart Crosstalk by Joachim Jankowski et al.   These reviews were written by leading investigators in the field, and the editors of Circulation Research hope that this comprehensive undertaking stimulates further research into the path flow of physiological kidney-heart crosstalk, and on comorbidities and intra organ crosstalk in general.   Cindy St. Hilaire:              So for our interview portion of the episode I have with me Dr Elizabeth Tarling and Dr Bethan Clifford. And Dr Tarling is an associate professor in the Department of Medicine in cardiology at UCLA, and Dr Clifford is a postdoctoral fellow with the Tarling lab. And today we're going to be discussing their manuscript that's titled, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels. So thank you both so much for joining me today.   Elizabeth Tarling:             Thank you for having us.   Bethan Clifford:               Yeah, thanks for having us. This is exciting.   Cindy St. Hilaire:              I guess first, Liz, how did you get into this line of research? I guess, before we get into that, I should disclose. Liz, we are friends and we've worked together in the ATVB Women's Leadership Committee. So full disclosure here, that being said, the editorial board votes on these articles, so it's not just me picking my friends. But it is great to have you here. So how did you enter this field, I guess, briefly?   Elizabeth Tarling:             Yeah, well briefly, I mean my training right from doing my PhD in the United Kingdom in the University of Nottingham has always been on lipid metabolism, lipoprotein biology with an interest in liver and cardiovascular disease. So broadly we've always been interested in this area and this line of research. And my postdoctoral research was on atherosclerosis and lipoprotein metabolism. And this project came about through a number of different unique avenues, but really because we were looking for regulators of LDL biology and plasma LDL cholesterol, that's sort of where the interest of the lab lies.   Cindy St. Hilaire:              Excellent. And Bethan, you came to UCLA from the UK. Was this a topic you were kind of dabbling in before or was it all new for you?   Bethan Clifford:               It was actually all completely new for me. So yeah, I did my PhD at the same university as Liz and when I started looking for postdocs, I was honestly pretty adamant that I wanted to stay clear away from lipids and lipid strategy. And then it wasn't until I started interviewing and meeting people and I spoke to Liz and she really sort of convinced me of the excitement and that the interest and all the possibilities of working with lipids and well now I won't go back, to be honest.   Cindy St. Hilaire:              And now here you are. Well-   Bethan Clifford:               Exactly.   Cindy St. Hilaire:              ... congrats on a wonderful study. So LDLR, so low density lipoprotein receptor, it's a major determinant of plasmid LDL cholesterol levels. And hopefully most of us know and appreciate that that is really a major contributor and a major risk for the development of atherosclerosis and coronary artery disease. And I think one thing people may not really appreciate, which your study kind of introduces and talks about nicely, is the role of the liver, right? And the role of receptor mediated endocytosis in regulating plasma cholesterol levels. And so before we kind of chat about the nitty-gritty of your study, could you just give us a brief summary of these key parts between plasma LDL, the LDL receptor and where it goes in your body?   Elizabeth Tarling:             Yeah. So the liver expresses 70% to 80% of the body's LDL receptor. So it's the major determinant of plasma lipoprotein plasma LDL cholesterol levels. And through groundbreaking work by Mike Brown and Joe Goldstein at the University of Texas, they really define this receptor mediated endocytosis by the liver and the LDL receptor by looking at patients with familial hypercholesterolemia. So those patients have mutations in the LDL receptor and they either express one functional copy or no functional copies of the LDL receptor and they have very, very large changes in plasma LDL cholesterol. And they have severe increases in cardiovascular disease risk and occurrence and diseases associated with elevated levels of cholesterol within the blood and within different tissues. And so that's sort of how the liver really controls plasma LDL cholesterol is through this receptor mediated endocytosis of the lipoprotein particle.   Cindy St. Hilaire:              There's several drugs now that can help regulate our cholesterol levels. So there's statins which block that rate limiting step of cholesterol biosynthesis, but there's this new generation of therapies, the PCSK9 inhibitors. And can you just give us a summary or a quick rundown of what are those key differences really? What is the key mechanism of action that these therapies are going after and is there room for more improvement?   Bethan Clifford:               Yeah, sure. So I mean I think you've touched on something that's really key about the LDR receptor is that it's regulated at so many different levels. So we have medications available that target the production of cholesterol and then as you mentioned this newer generation of things like PCSK9 inhibitors that sort of try and target LDL at the point of clearance from the plasma.   And in response to your question of is there room for more regulation, I would say that given the sort of continual rate of increased cholesterol in the general population and the huge risks associated with elevated cholesterol, there's always capacity for more to improve that and sort of generally improve the health of the population. And what we sort of found particularly exciting about RNF130 is that it's a distinct pathway from any of these regulatory mechanisms. So it doesn't regulate the level of transcription, it doesn't regulate PCSK9. Or in response to PCSK9, it's a completely independent pathway that could sort of improve or add to changes in cholesterol.   Cindy St. Hilaire:              So your study, it's focusing on the E3 ligase, RNF130. What is an E3 ligase, and why was this particular one of interest to you? How did you come across it?   Elizabeth Tarling:             is predTates Bethan joining the lab. This is, I think, again for the listeners and those people in training, I think it's really important to note this project has been going in the lab for a number of years and has really... Bethan was the one who came in and really took charge and helped us round it out. But it wasn't a quick find or a quick story. It had a lot of nuances to it. But we were interested in looking for new regulators of LDL cholesterol and actually through completely independent pathways we had found the RNF130 locus as being associated with LDL cholesterol in animals. And then it came out in a very specific genome-wide association study in the African American care study, the NHLBI care study. And so really what we started looking at, we didn't even know what it was.   Elizabeth Tarling:             So we asked ourselves, well what is this gene? What is this protein? And it's RNF, so that's ring finger containing protein 130 and ring stands for really interesting new gene. Somebody came up with the glorious name. But proteins that contain this ring domain are very characteristic and they are E3 ubiquitin ligases. And so they conjugate the addition of ubiquitin to a target protein and that signals for that protein to either be internalized and/or degraded through different decorative pathways within the cell. And so we didn't land on it because we were looking at E3 ligases, we really came at it from an LDL cholesterol perspective. And it was something that we hadn't worked on before and the study sort of blossomed from there.   Cindy St. Hilaire:              That's amazing and a beautiful, but also, I'm sure, heartbreaking story because these long projects are just... They're bears. So what does this RNF130 do to LDLR? What'd you guys find?   Bethan Clifford:               As Liz said, this is a long process, but one of the key factors of RNF130 is it's structurally characteristically looked like E3 ligase. So the first thing that Liz did and then I followed up with in the lab is to see is this E3 ligase ubiquitinating in vitro. And if it is going to ubiquitinate, what's it likely to regulate that might cause changes in plasma cholesterol that would explain these human genetic links that we saw published at the same time.   And so because the LDL cholesterol is predominantly regulated by the LDL receptor and the levels of it at the surface of the parasites in the liver, the first question we wanted to see is does RNF130 interact in any way with that pathway? And I'm giving you the brief view here of the LDL receptor. We obviously tested lots of different receptors. We tested lots of different endocytose receptors and lipid regulators, but the LDL receptor is the one that we saw could be ubiquitinated by RNF130 in vitro. And so then we wanted to sort of go on from there and establish, okay, if this E3 ubiquitin ligase, is it regulating LDL receptor? What does that mean in an animal context in terms of regulating LDL cholesterol?   Cindy St. Hilaire:              Yeah, and I guess we should also explain, ubiquitination, in terms of this receptor, and I guess related to Goldstein and Brown and receptor mediated endocytosis, like what does that actually mean for the liver cell and the cholesterol in the LDLR that is binding the receptor?   Bethan Clifford:               So yes, ubiquitination is a really common regulatory mechanism actually across all sorts of different cells, all sorts of different receptors and proteins. And basically what it does is it signals for degradation of a protein. So a ubiquitin molecule is conjugated to its target such as in our case the LDL receptor and that ubiquitin tells the cell that this protein is ready for proteasomal degradation. And that's just one of the many things ubiquitination can do. It can also signal for a trafficking event, it can signal for a protein to protein interaction, but it's most commonly associated with the proteasomal degradation.     Cindy St. Hilaire:              So in terms of... I guess I'm thinking in terms of PCSK9, right? So those drugs are stemming from observations in humans, right? There were humans with gain and loss of function mutations, which caused either more or less of this LDLR receptor internalization. How is this RNF130 pathway different from the PCSK9 activities?   Elizabeth Tarling:             Yeah, so PCSK9 is a secreted protein, so it's made by hepatocyte and actually other cells in the body and it's secreted and it binds to the LDL particle, LDL receptor complex, and signals for its internalization and degradation in the proteasome. So this is not ubiquitination event, this is a completely different trafficking event. And so the RNF130, actually what Bethan showed, is it directly ubiquitinates the LDL receptor itself, signaling for an internalization event and then ultimately degradation of the LDR receptor through a decorative pathway, which we also define in the study.   So these are two unique mechanisms and actually some key studies that we did in the paper were to modulate RNF130 in animals that do not have PCSK9. And so in that system where in the absence of PCSK9 you have a lot of LDR receptor in the liver that's internalizing cholesterol. What happens when you overexpress RNF130? Do you still regulate at the LDL receptor? And you absolutely do. And so that again suggests that they're two distinct mechanisms and two distinct pathways.   Cindy St. Hilaire:              That was one thing I really loved about your paper is every kind of figure or section, the question that would pop up in my head, even ones that didn't pop in my head were beautifully answered with some of these really nice animal models, which is never an easy thing, right? And so one of the things that you brought up was difficulty in making one of the animal models. And so I'm wondering if you could share a little bit for that challenge. I think one thing that we always tend to hide is just science is hard and a lot of what we do doesn't work. And I really think especially for the trainees and really everyone out there, if we kind of share these things more, it's better. So what was one of the most challenging things in this study? And I guess I'm thinking about that floxed animal.   Elizabeth Tarling:             Yeah, so I'll speak a bit about that and then I'll let Bethan address because she was really the one on the ground doing a lot of the struggles. But again, we actually weren't going to include this information in the paper. And upon discussion and actually prompted by the reviewers of the paper and some of the questions that they asked us, we realized, you know what? It's actually really important to show this and show that this happens and that there are ways around it.   And so the first story is before Bethan even arrived in the lab, we had purchased embryonic stem cells that were knockout first condition already. And so this is a knockout strategy in which the exon of interest is flanked with lots of P sites so that you can create a flox animal, but also so you can create a whole body knockout just by the insertion of this knockout first cassette.   Elizabeth Tarling:             And so we got those mice actually in the first year of Bethan joining the lab. We finally got the chimeric mice and we were able to stop reading those mice. And at the same time we tried to generate our flox animals so that we could move on to do tissue-specific studies. And Bethan can talk about the pain associated with this. But over two years of breeding, we never got the right genotypes from the different crosses that you need to do to generate the flox animal.   And it was actually in discussions with Bethan where we decided we need to go back. We need to go back to those ESLs that we purchased five years ago and we need to figure out if all of the elements that the quality control step had told us were in place are actually present. And so Bethan went back and sequenced the whole locus and the cassette to figure out what pieces were present and we found that one of the essential locks P sites that's required for every single cross from the initial animal was absent and therefore we could actually never make the mouse we wanted to make.   And so that's sort of just a lesson for people going down that route and making these tools that we need in the lab to answer these questions is that despite paying extra money and getting all of the sort of QCs that you can get before you receive the ESLs, we should have gone back and done our own housekeeping and sort of a long journey told us when we went back that we didn't have what we thought we had at the beginning. And that was a real sticking point as Bethan can-   Cindy St. Hilaire:              Yeah. And so you know you're not alone. My very first postdoc that I did, I went with a mouse that they had also bought and were guaranteed that it was a knockout and it was not. And it is a painful lesson, but it is critical to... You get over it.   So Bethan, maybe you can also tell us a little bit about what are the other kind of next things you tried? You pivoted and you pivoted beautifully because all the models you used I thought were quite elegant in terms of exactly asking the question you wanted to ask in the right cells. So can you maybe explain some of the in vivo models you used for this study?   Bethan Clifford:               Sure, there are definitely a lot. So I mean I think Liz sort of encapsulated the trouble we have with the knockout really succinctly, but actually I want to just take this moment to sort of shout out to another postdoc in the Tarling lab, Kelsey Jarrett, who was really instrumental in the pivoting to a different model. So for the knockouts when we sort of established we didn't have exactly what we thought we did and then to compound that we also weren't getting the DeLiAn ratios breeding this whole body knockout.   We wanted to sort of look at a more transient knockout model. And that's where Kelsey really stepped in and sort of led the way and she generated AAV-CRISPR for us to target RNF130 specifically in the liver. And that had the added beauty of, one, not requiring breeding to get over this hurdle of the knockout being somewhat detrimental to breeding. But it also allowed us to ask the question of what RNF130 is doing specifically in the liver where the liver regulates LDL receptor and LDL cholesterol.   And so that was one of the key models that really, really helped get this paper over the finish line. But we did a whole barrage of experiments, as you've seen. We wanted to make sure... One of the key facets of the Tarling lab is whenever you do anything, no matter what you show Liz, it will always be, "Okay, you showed it to me one way, now show it to me a different way." Can you get the same result coming at it from different ways? And if you can't, why is that? What is the regulation behind that? And so that's really what the paper is doing is asking the same question in as many ways as we can accurately and appropriately probe what RNF130 does to the LDR receptor.   So we tried gain of function studies without adenovirus overexpression. We tried transient knockdown with antisense oligonucleotides, and then we did, as I said, the AAV-CRISPR knockdown with the help of Kelsey and our whole body knockout. And then we also repeated some of these studies such as the adenovirus and the ASO in specific genetic backgrounds. So in the absence of PCSK9, can we still regulate the LDL receptor? And then we also, just to really confirm this, in the absence of the LDL receptor, do we see a difference? And the answer is no, because this effect was really dependent on that LDL receptor being present. So there was a big combination.   Cindy St. Hilaire:              It was really nice, really a beautiful step-wise progression of how to solidly answer this question. But a lot of, I think, almost all you did was in mice. And so what is the genetic evidence for relevancy in humans? Can you discuss a little bit about those databases that you then went to to investigate, is this relevant in humans?   Bethan Clifford:               I think Liz might be better off answering that question.   Elizabeth Tarling:             And I think this sort of pivots on what Bethan was saying. So when we had struggles in the lab, it was a team environment and a collaboration between people in the lab that allowed us to make that leap and make those next experiments possible to then really answer that question. And to be able to include the antisense oligonucleotides required a collaboration with industry. We were very lucky to have a longstanding collaboration with Ionis, who provided the antisense oligonucleotides.   And for the human genetics side of things, that also was a collaboration with Marcus Seldin, who was a former postdoc with Jake Lusis and is now our PI at UC Irvine. And what he helped us do is dive into those summary level databases and ask from that initial study in the NHLBI care population, do we see associations of RNF130 expression in humans with LDL cholesterol with cardiovascular outcomes. And so one database which I would recommend everybody use, it's publicly available, is the StarNet database. And it's in the paper and the website is there. And that allowed us to search for RNF130.   Elizabeth Tarling:             And what it does is it asks how RNF130 expression in different tissues is associated with cardiometabolic outcomes and actual in CAD cases and controls, so people with and without heart disease. And we found that expression of RNF130 in the liver was extremely strongly correlated with the occurrence of cardiovascular disease in people with CAD. So in cases versus controls. And then we were also able to find many other polymorphisms in the RNF130 locus that were associated with LDL cholesterol in multiple different studies.   And I think the other message from this paper is this, unlike PCSK9 and unlike LDR receptor itself, which are single gene mutations that cause cardiovascular disease, there are many sub genome-wide significant loci that contribute to this multifactorial disease, which is extremely complex. And I think RNF130 falls within that bracket that those sort of just on the borderline of being genome-wide significant still play significant biological roles in regulating these processes. And they don't come up as a single gene hit for a disease, but combinatorialy they are associated with increased risk of disease and they have a molecular mechanism that's associated with the disease. And so that's what Marcus helped us do in terms of the human genetics is really understand that and get down to that level of data.   Cindy St. Hilaire:              Yeah. Yeah, it really makes you want to go back and look at those. Everyone always focuses on that really high peak and those analyses, but what are all those other ones above the noise, right? So it's really important.   Elizabeth Tarling:             I think it's really hard to do that. I think that's one where people... Again, it comes down to team science and the group of people that we brought together allowed us to ask that molecular question about how that signal was associated with the phenotype. I think by ourselves we wouldn't have been able to do it.   Cindy St. Hilaire:              Yeah. So your antisense oligonucleotide experiments, they were really nice. They showed, I think it was a four-week therapy, they showed that when you injected them expression of RNF130 went down by 90%. I think cholesterol in the animals was lowered by 50 points or so. Is this kind of a next viable option? And I guess related to that, cholesterol's extremely important for everything, right? Cell membrane integrity, our neurons, all sorts of things. Is it possible with something that is perhaps really as powerful as this to make cholesterol too low?   Elizabeth Tarling:             I think that what we know from PCSK9 gain and loss of function mutations is that you can drop your plasma cholesterol to very low levels and still be okay because there are people walking around with mutations that do that. I think RNF130 is a little different in that it's clearly regulatory in a homeostatic function in that it's ubiquitously expressed and it has this role in the liver to regulate LDL receptor availability, but there are no homozygous loss of function mutants people walking around, which tells us something else about how important it is in potentially other tissues and in other pathways. And we've only just begun to uncover what those roles might be.   So I think that as a therapy, it has great potential. We need to do a lot more studies to sort of move from rodent models into more preclinical models. But I do think that the human data tell us that it's really important in other places too. And so yeah, we need to think about how best it might work as a therapy. If it's combinatorial, if it's dosed. Those are the types of things that we need to think about.   Cindy St. Hilaire:              Yeah, it's really exciting. Do you know, are there other protein targets of RNF130? Is that related to my next question of what is next?   Elizabeth Tarling:             I mean, so I should point out, so Bethan unfortunately left the lab last year for a position at Amgen where she's working on obesity and metabolic disease. But before she left, she did two very, very cool experiments searching for new targets or additional targets of RNF130. Starting in the liver, but hopefully we'll move those into other tissues. And so she did gain of function RNF130 versus what loss of function we have of RNF130, and she did specific mass spec analysis of proteins that are ubiquitinated in those different conditions. And by overlaying those data sets, we're hoping to carve out new additional targets of RNF130. And there are some, and they're in interesting pathways, which we have yet to completely test, but definitely there are additional pathways, at least when you overexpress and reduce expression. Now, whether they turn out to be, again, bonafide in vivo, actual targets that are biologically meaningful is sort of the next step.   Cindy St. Hilaire:              Yeah. Well, I'm sure with your very rigorous approach, you are going to find out and hopefully we'll see it here in the future. Dr Elizabeth Tarling and Dr Bethan Clifford, thank you so much for joining me today. I really enjoyed this paper. It's a beautiful study. I think it's a beautiful example, especially for trainees about kind of thoroughly and rigorously going through and trying to test your hypothesis. So thanks again.   Elizabeth Tarling:             Thank you.   Bethan Clifford:               Thank you very much.   Cindy St. Hilaire:              That's it for the highlights from the March 31st and April 14th issues of Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes, and #DiscoverCircRes. Thank you to our guests, Dr Liz Tarling and Dr Bethan Clifford.   This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.   This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.  

The Pinball Show Episode 125: Ranking The Big 5: FOO, TNA2, TGF, GTF, PF + TPS! 2.0   Hosts: Dennis Kriesel & Zach Meny   - Back In The Best Way - A Kriesel Easter - The Official Pinball Show Club  - Ranking The Big 5: Foo Fighters, Final Resistance, The Godfather, Pulp Fiction, Galactic Tank Force - MEMBER'S ONLY: GTF?! - The Other 5: Bond 60th, Scooby Doo, Fathom Revisited, Queen, Ninja Eclipse - Stern Pinball Production Updates - Pinball Market Trends   EXCLUSIVE CONTENT AND TPS MEMBERSHIP CAN BE FOUND AT Patreon.com/thepinballshow   Follow, like, and subscribe to The Pinball Show (TPS), the industry's most popular podcast!   email: thepinballshow@gmail.com website: thepinball.network youtube: youtube.com/thepinballshow instagram: @thepinballshowpodcast tik tok: @thepinballshow review: thisweekinpinball.com/the-pinball-show/ store: flipnoutpinball.com membership/support: patreon.com/thepinballshow  

A new research paper was published in Oncotarget's Volume 14 on March 24, 2023, entitled, “Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells.” Abnormal expression of bicellular tight junction claudins, including claudin-2 are observed during carcinogenesis in human lung adenocarcinoma. However, little is known about the role of tricellular tight junction molecule angulin-1/lipolysis-stimulated lipoprotein receptor (LSR). In the present study, researchers Wataru Arai, Takumi Konno, Takayuki Kohno, Yuki Kodera, Mitsuhiro Tsujiwaki, Yuma Shindo, Hirofumi Chiba, Masahiro Miyajima, Yuji Sakuma, Atsushi Watanabe, and Takashi Kojima from Sapporo Medical University School of Medicine examined expression of claudin-2 in the lung adenocarcinoma tissues and found it was higher than in normal lung tissues, while angulin-1/LSR was poorly or faintly expressed. “We investigated how loss of angulin-1/LSR affects the malignancy of lung adenocarcinoma cell line A549 and normal human lung epithelial (HLE) cells.” The researchers found that the EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. Knockdown of LSR induced expression of claudin-2 at the protein and mRNA levels and AG1478 prevented the upregulation of claudin-2 in A549 cells. Knockdown of LSR induced cell proliferation, cell migration and cell metabolism in A549 cells. Knockdown of claudin-2 inhibited the cell proliferation but did not affect the cell migration or cell metabolism of A549 cells. The TGF-β type I receptor inhibitor EW-7197 prevented the decrease of LSR and claudin-2 induced by TGF-β1 in A549 cells and 2D culture of normal HLE cells. EW-7197 prevented the increase of cell migration and cell metabolism induced by TGF-β1 in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma. “In conclusion, AG1478 and EW-7197 demonstrated potent in vitro anti-lung adenocarcinoma therapeutic activities via LSR/CLDN-2 and the cell metabolism. The use of both AG1478 and EW-7197 may provide a clinical therapeutic approach for lung adenocarcinoma caused by loss of angulin-1/LSR.” Full research paper: DOI: https://doi.org/10.18632/oncotarget.27728 Correspondence to: Takashi Kojima - ktakashi@sapmed.ac.jp Keywords: angulin-1/LSR, claudin-2, cell metabolism, malignancy, lung adenocarcinoma About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

On this week's episode of The Garden Faithful, Arthur and Vally discuss the Rangers coming off a 3-2 loss to the Carolina Hurricanes at The Garden Tuesday night, and what the Blueshirts need to do differently tonight against the Canes in Raleigh, how a potential playoff series between the two teams would go, the 3 games since the last TGF including the Rangers outscoring the Pittsburgh Penguins and Nashville Predators 13-0 in back-to-back shutouts, head coach Gerard Gallant loading up the first power play unit, and more. Plus, to close things out, Producer Chris joins the show for a roundtable discussion about whether Mika Zibanejad deserves Hart Trophy votes this season or not.  Get a 1-year subscription to The Athletic for just $1 a month when you visit http://theathletic.com/tgf

A new research paper was published in Oncotarget's Volume 14 on March 21, 2023, entitled, “Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior.” Glypicans (GPC1-6) are associated with tumorigenic processes and their involvement in neoplastic behavior has been discussed in different cancer types. In this recent cancer-wide GPC expression study, researchers Fang Cheng, Victor Chérouvrier Hansson, Grigorios Georgolopoulos, and Katrin Mani from Lund University and Genevia Technologies used clinical cancer patient data in The Cancer Genome Atlas to reveal net upregulation of GPC1 and GPC2 in primary solid tumors. On the other hand, GPC3, GPC5 and GPC6 displayed lowered expression patterns compared to normal tissues. “[...] we identify and propose a mechanism where GPC1 interacts with extracellular matrix mediating signal transduction by mitogenic molecules involving TGF-β and p38 MAPK.” Focusing on GPC1, the researchers conducted survival analyses of the clinical cancer patient data that revealed a statistically significant correlation between high expression of GPC1 and poor prognosis in 10 particular cancer types: bladder urothelial carcinoma, brain lower grade glioma, liver hepatocellular carcinoma, colon adenocarcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, mesothelioma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, and uveal melanoma. In vitro studies targeting GPC1 expression by CRISPR/Cas9 or siRNA or treatment with an anti-GPC1 antibody resulted in attenuation of proliferation of cancer cells from bladder carcinoma, glioma and hepatocellular carcinoma patients (T24, U87 and HepG2 cells). Further, GPC1 overexpression exhibited a significant and negative correlation between GPC1 expression and proliferation of T24 cells. Their attempt to reveal the mechanism through which downregulation of GPC1 leads to attenuation of tumor growth using systematic Ingenuity Pathway Analysis indicated that suppression of GPC1 results in ECM-mediated inhibition of specific pro-cancer signaling pathways involving TGF-β and p38 MAPK. The team also identified differential expression and pleiotropic effects of GPCs in specific cancer types. This emphasizes their potential as novel diagnostic tools and prognostic factors, and open doors for future GPC targeted therapy. “It is plausible to measure circulating GPCs in serum, plasma or urine using a variety of methods including ELISA, urine cell sediments or exosome isolation [13, 24]. Further, detection and quantification of GPC1 by histopathological and immunohistochemical methods in tumor biopsies could be a new way to predict the biological outcome. The results of this investigation would also emphasize the potential of GPCs as novel tumor antigens, and open for GPC targeted immunotherapy. GPC targeted immunotherapy would be of high value, especially as we move into an era of precision and personalized cancer therapy.” DOI: https://doi.org/10.18632/oncotarget.28388 Correspondence to: Katrin Mani - katrin.mani@med.lu.se Keywords: Glypican-1, TCGA, bladder carcinoma, hepatocellular carcinoma, glioma About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget MEDIA@IMPACTJOURNALS.COM

Cal & Chip are back! The Fellas discuss all things Misfits 005 ahead of this weekend's big event in Telford. The card is headlined by TGF member Jay Swingler This waffle comes with a side of podcast, discussing everything from abusive autistic brothers, deep fakes ruining the world & much much more! Want to call into the podcast LIVE? Join the Discord: https://discord.gg/dZK7T58AmS Join the discussion: https://www.reddit.com/r/FellasPodcast/ All Links: https://linktr.ee/thefellaspod Learn more about your ad choices. Visit podcastchoices.com/adchoices

In this episode we explore ways in which the extracellular matrix can be manipulated, including the story of doxycycline, TGF-beta in Marfan syndrome and whether beta blockers can reduce vascular events in vascular EDS. ·        Intro 0:12 ·        Review of previous episode 0:28 ·        In this episode 2:26 ·        The pressure against the vessels 4:06 ·        The pressure against the wall 8:44 ·        Matrix metalloproteinases 10:16 ·        Tadpole study – collagen breakdown 10:35 ·        Tetracycline antibiotics 14:05 ·        Rat model – periodontal disease and hydroxyproline 14:24 ·        Chemically modified tetracyclines 20:14 ·        Mouse model – tetracycline use 22:00 ·        Tetracyclines and other autoimmune conditions 23:22 ·        Marfan syndrome 24:45 ·        Fibrillin and Marfan syndrome 28:48 ·        TGF-beta 29:36 ·        Mouse model – Marfan syndrome and fibrillin 31:14 ·        ARBs and TGF-beta 33:51 ·        TGF-beta and vascular EDS 37:25 ·        Back to the mouse model 38:38 ·        Protein kinase C 39:56 ·        Summary 40:26 Disclosures: Brown reports no relevant financial disclosures. We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Bowen CJ, et al. J Clin Invest. 2020;130:686-698. Brooke BS. Lancet. 2010;doi:10.1016/S0140-6736(10)61155-5 Dietz HC, et al. Am J Med Genet C Semin Med Genet. 2005;doi:10.1002/ajmg.c.30068. Dubacher N, et al. Cardiovasc Res. 2020;116:457-465. Golub LM, et al. SAGE. 1998;doi:10.1177/08959374980120010501. Gross J, et al. PNAS. 1962;doi:10.1073/pnas.48.6.1014 Habashi JP, et al. Science. 2006;312:117-121. Morissette R, et al. Circ Cardiovasc Genet. 2014;7:80-88. Mullen M, et al. Lancet. 2019;394:2263-2270. Neptune ER, et al. Nat Genet. 2003;33:407-411.

Please join author Petr Ostadal and Associate Editor Dharam Kumbhani as they discuss the article "Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor from Akershus University Hospital and University of Oslo in Norway. And today Carolyn will have such an interesting feature discussion. We are going to look into the use of ECMO to treat patients with cardiogenic shock, the results of the ECMO-CS randomized clinical trial. Isn't that interesting? Dr. Carolyn Lam: Awesome. Can't wait. But I suppose you're going to tell us about some papers in the issue first. I'm getting my coffee. Dr. Peder Myhre: Yeah, go ahead. Because first we're going to talk about a very interesting paper that relates to diabetes and the progression of coronary artery disease. So as you know, Carolyn, diabetes remains associated with an increased risk of cardiovascular morbidity and mortality. And although the absolute risk difference between patients with and without diabetes have declined over the past 20 years, we still don't know what is the diabetes associated differences in coronary plaque morphology and lipid content. Dr. Carolyn Lam: It's true. That's a very interesting question. And will you tell us more? Dr. Peder Myhre: Yeah. So the investigators in the prospect two study who enrolled patients exclusively from Denmark, Norway in Sweden who presented with biomarker positive MI and assessed both culprit lesions and untreated non-culprit lesions in these patients. And then they stratified the patients by diabetes status and examined with three vessel quantitative coronary angiography and near infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Dr. Carolyn Lam: Okay, that's deep investigation. And what did they find? Dr. Peder Myhre: So diabetes was present in about 12% of patients and during a median or 3.7 year follow up, MACE occurred almost twice as free frequently in patients with versus without diabetes. And that was primarily due to an increased risk of MI related to culprit lesion stenosis and non-culprit relation related spontaneous MI. However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes, concerning culprit and the non-culprit lesions and in multi-variable models, diabetes was associated with MACE in lesions but not with prevalence of high-risk plaque characteristics. So Carolyn, the authors conclude that diabetes related plaque characteristics that might underlie the increased risk were not identified by multimodal imaging. Dr. Carolyn Lam: Oh, I just love studies like that so elegant with just a really, really intriguing results that make us ask more important questions. Love it. Thank you. Well, the next paper is also about myocardial infarction, but this time looking at the fibrotic remodeling after myocardial infarction because we know that MI induces a repair response that ultimately generates a stable fibrotic scar. And although the scar is important to prevent cardiac rupture, excessive pro-fibrotic response impairs optimal recovery because it promotes a development of non-contractual fibrotic areas. So would it be possible to regulate the expansion of cardiac fibroblast after MI through a paracrine action on the cardiac stromal cells? So the authors led by corresponding author Dr. Hulot from University of Paris performed a bioinformatic secretome analysis of cardiac stromal PW1 positive cells isolated from normal and post MI mouse hearts to identify novel secreted proteins. And they found that first cardiac PW1 positive stromal cells responded to myocardial infarction by secreting factors that promoted the proliferation and activation of resident fibroblasts and one such factor growth differentiation factor three or GDF3 was highly upregulated in the ischemic hearts and promoted a high induction of fibroblast proliferation via interaction with TGF beta receptors and activation of SMAD1/5 and SMAD2/3 signaling cascades. The upregulation of GDF3 was detected in the plasma of mice and humans following MI and high levels of plasma GDF3 in the days following MI predicted adverse outcomes measured six months later including cardiac dilation and limited recovery of contractile function in humans. Dr. Peder Myhre: Oh, that's so interesting. We already know GDF15 were very well, but now we hear about GDF3 in predicting fibrotic remodeling post myocardial infarction. So Carolyn, what are the clinical implications of these findings? Dr. Carolyn Lam: Exactly, Peder, in fact you said it. So the detection of high circulating GDF3 in plasma may serve as a novel biomarker of adverse fibrotic remodeling in heart tissue. That's one. And next the measurement of GDF3 plasma levels in the early post MI phase may allow for the identification of patients within an increased risk of severe myocardial fibrosis and heart failure and therefore could guide specific disease management. Dr. Peder Myhre: Thank you. That was an excellent summary of the paper, Carolyn. And now I'm going to look into a paper that relates to the important issue of arteriosclerosis following heart transplantation because as you know, transplant arteriosclerosis characterized by concentric and diffuse narrowing of vastly lumen is a major complication in long-term survivors of heart transplant patients. And increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis. But how lymphangiogenesis affects this process is unknown. The authors of this paper, which comes to us from corresponding author Sue from Sejong University, transplanted vascular allografts between various combinations of mice including mice with severe combined immune deficiency and studied the lymphatic vessels within the grafted arteries. Dr. Carolyn Lam: Wow, that is really cool. Studying lymphatics and lymphangiogenesis in atherosclerosis. Interesting. What did they find, and what are the clinical implications? Dr. Peder Myhre: So Carolyn, lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 were associated with these immune structures. Fibroblasts in the vascular allografts released VEGFC, which stimulated lymphangiogenesis into the grafts and inhibition of VEGFC signaling inhibited lymphangiogenesis, neointima formation and adventitial fibrosis of vascular allografts. And these studies identified VEGFC released from fibroblasts as signal stimulating lymphangiogenesis extending from the host into the vascular allografts. So, Carolyn, the authors conclude that the formation of lymphatic vessels play a key role in the immune response to vascular transplantation and inhibition of lymphangiogenesis may be a novel approach to prevent transplant atherosclerosis. Dr. Carolyn Lam: Wow, that is super interesting. Thanks, Peder. While also in this issue, there's an exchange of letters between Drs. Tanaka and Schulze regarding SGLT2 inhibitor treatment in acute decompensated heart failure. Why do we initiate it early? There's also a really nice On My Mind paper by Dr. Schiattarella on Cardiometabolic HFpEF. Is it the NASH of the heart? Dr. Peder Myhre: Oh, that's interesting. We also have some cardiology news by our own ‪Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing Over Morning Dosing for Antihypertensive Medications.” And this is a summary of the time trial, which was presented at European Society of Cardiology Congress in 2022. And finally, Carolyn, we have a Research Letter entitled “Stepwise Generation of Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from Stanford University School of Medicine. Dr. Carolyn Lam: While cool, Peder. But now I'm so excited to hear about the ECMO-CS randomized trial. Let's go. Dr. Greg Hundley: Welcome listeners to this February 7th feature discussion and we have with us today Dr. Petr Ostadal from Na Homolce Hospital in Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome, gentlemen. Well, Petr, we'll start with you. Can you describe for us some of the background information that really led you to perform this study, and what was the hypothesis that you wanted to address? Dr. Petr Ostadal: According to the current guidelines from the management for the management of cariogenic shock, it should be considered administration of inotropes and vasopressor for hemodynamic stabilization, or it may be considered administration of inotropes and vasopressors and it should be considered the use of short-term mechanical circulatory support. And the aim of the ECMO-CS trial was to compare early conservative therapy with inotropes and vasopressors and immediate implementation of ECMO in patients with the rapidly deteriorating or severe cardiogenic shock. The hypothesis of the ECMO-CS trial was that immediate implantation of ECMO in patients with cardiogenic shock and critical hemodynamic condition will be associated with improved outcomes. Dr. Greg Hundley: Very nice. Can you describe for us this study population and then also what study design did you use to address your hypothesis? Dr. Petr Ostadal: We try to select patients who can really profit from the early ECMO implantation, and we define two categories of patients. First category where the patients with rapidly deteriorating cardiogenic shock corresponding to current sky stage D or E. This patient should have evidence of left ventricle pump failure as left ventricle ejection fraction below 35% or ejection fraction 35 to 55 in case of severe mitral regurgitation or aortic stenosis. And this patient also should require a repeated both of vasopressors to maintain mean arterial pressure about 50 millimeters of mercury. The second category where the patients with severe cardiogenic shock corresponding to current sky stage D and this patient should have the criterion of a hemodynamic conditions which was cardiac index less than 2.2 or systemic blood pressure below 100 millimeters of mercury in both situation with higher doses of inotropes and vasopressors. And in case of a low systolic blood pressure, also the evidence of left ventricle pump failure based on ejection fractional below 35 or ejection fraction 35 to 55 in case of severe mitral regurgitation of aortic stenosis. The second criteria for the metabolic criteria, that was the evidence of tissue hypoperfusion and this was defined as a higher lactate above three millimeters per litter or low ScvO2 below 50%. And the third criterion was exclusion of hypovolemia, and this was based on central venous pressure or pulmonary artery wedge pressure. So this was the major inclusion criteria in the ECMO trial. The study population was not defined based on theology of cardiogenic shock, but just on severity of cardiogenic shock. Dr. Greg Hundley: Very nice. And so your design, did you have a one-to-one randomization, or how did that work? And then also how many subjects did you include in this important trial? Dr. Petr Ostadal: The patients were randomized in one-to-one ratio to immediate implementation of ECMO or to early conservative therapy. But it is important to point out that in the early conservative therapy downstream use of ECMO was allowed in case of further hemodynamic worsening defined as increase of what lactate by three millimeters per litter. We enrolled 122 patients, 61 were randomized to early ECMO and 61 to early conservative strategy. Five patients were excluded due to absence of informed consent and finally 58 patients were analyzed in the early ECMO or immediate ECMO arm and 59 patients were analyzed in the early conservative arm. Dr. Greg Hundley: Sounds great Petr. And then tell us and describe your study results. Dr. Petr Ostadal: The primary endpoint was composite of death from any cause, resuscitated circulatory RS and implementation of another mechanical circulatory support including ECMO in the early conservative arm at 30 days. And there was no difference in the primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95% confidence in interval 0.46 to 1.12. There was also no difference in the incidence of death from any cause. 50% in the immediate ECMO arm and 28%, 47.5% in the early conservative arm. There was no difference in the incidence of resuscitated circulatory arrest, 10.3 in the immediate ECMO arm and 13.6 in the early conservative arm. Less patient required another mechanical circulatory support in the early ECMO arm through 17.2 in comparison with 42.4% in the early conservative arm and downstream ECMO was used in 39% of patients in the early conservative arm. Dr. Greg Hundley: Very nice. So similar results both immediately and then 30 days later for both arms. And I think that last point that you make is very interesting. 39% of the individuals randomized to the conservative arm went on to receive VA-ECMO. Well, listeners next, we're going to turn to one of our associate editors and Dharam, you have many papers that you see. How do we put the results that Petr has just described really in the context of management of shock and results that have been published previously? Dr. Dharam Kumbhani: Yeah, Greg, thank you. And Petr, thank you for this important paper and again, I'm really honored to be here on behalf of Circulation on the Run. So again, want to congratulate the authors for really an important study. I think in terms of context, what is really interesting is the use of ECMO, particularly VA-ECMO for patients with shock has really skyrocketed. And it is interesting that this expansion has occurred in the absence despite, I guess high quality clinical trials, this trial certainly fills an important void. Although it is a small patient population, it is randomized, it is a largest randomized trial to date on this important population. And so I think most of the studies that have been done so far have been done using observational data sets which have sort of inherent limitations. So I certainly want to congratulate you on trying to study this very challenging population because in sort of that acute setting, it's frequently very hard to get patients randomized. So just broadly in that context, I think at the same time this study does sort of pose some important questions and sort of perhaps leads, just given the limitations of the sample size does sort of leave a few unanswered questions. So one question I have is, Petr, in addition to the 40% crossover rate is obviously important as Greg pointed out. The other thing is it appears that the use of other mechanical support during the conduct of this trial was also close to 40%, about 42%. So pretty much everybody in the conservative arm ended up with some kind of mechanical support. Now, at least in the last few years, a concept that has gained a lot of traction is a concept of a shock team where a number of providers with particular expertise from different disciplines would get together and sort of decide next steps was a shock team sort of part of the decision-making, especially for the conservative arm. Dr. Petr Ostadal: Thank you for this question. The situation is maybe a little bit more simple in the Czech Republic here, the cardiologist are responsible for the acute cardiac care, usually competent and experience not only for the diagnosis and examinations and monitoring of patients in cardiogenic shock, but also experience in insertion and management of the mechanical circulatory support. So here this attending cardiologist competent to manage this patient from different sites from the manage not only the conservative therapy but also the mechanical circulatory support therapy in these patients. So in this respect, this is more simple situation in the Czech Republic. Dr. Dharam Kumbhani: I just had a very quick question about, and I don't know if you want to include this, but Petr, I was curious, were patients with cardiac arrest, I know you mentioned sky shocks in were patients with cardiac arrest on the field or in the hospital included? Dr. Petr Ostadal: Thank you for this excellent question. And in comparison, with other trials comparing the or focusing on patients with cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors were excluded. And the reason was that the brain damage, which is the major cause of death in these patients cannot be influenced by ECMO insertion. And second, in majority of patients after cardiac arrest, if there is a presence of shock, there is frequently combined shock with important peripheral component. And again, it cannot be assumed that this peripheral component can be reversed by ECMO implantation. So in the ECMO-CS trial, the cardiac arrest survivors were excluded from that enrollment. Dr. Greg Hundley: Well, thank you so much Petr. Petr, what do you think is the next study to be performed really in this area of research? Dr. Petr Ostadal: I think that we are happy because several other clinical trials focusing on the mechanical circulatory support in patients with cardiogenic shock underway. And there are other trials focused on ECMO and trials a bit focused on combination of ECMO with balloon pump and trials focused on Impella. So I think in the very close time we will be able to see the results of these current running trials1. Dr. Greg Hundley: And Dharam, do you have anything to add? Dr. Dharam Kumbhani: No, I agree completely with Petr. I think this is a very exciting field. I know there's a lot of interest in doing well conducted clinical trials in this space. And so certainly, I think the future is bright for investigation in this field. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Petr Ostadal from Prague in the Czech Republic and our own associate editor, Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study highlighting that immediate implementation of VA-ECMO in patients with rapidly deteriorating, or severe cardiogenic shock did not improve clinical outcomes compared to an early conservative strategy that permitted downstream use of VA-ECMO in the case when the patient's hemodynamic status worsened. Well, on behalf of Carolyn, and Peder, and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

My guest this week is Kent Holtorf, M.D. of Holtorf Medical. In this episode, Dr. Holtorf and I discuss how his clinic treats complex conditions such as lyme, mold, shingles and other chronic illnesses. Could it be that there is a more simple way of treating them than we think? What to treat first with chronically ill people, especially when they are incredibly sensitive? Dr. Holtorf addresses the importance of the immune system from a different perspective than most, specifically the thymus gland. Can you be sick if your thymus is working at an optimal level? How does the immune system get out of balance? How does mitochondrial dysfunction fit into chronic conditions? What is human transforming growth factor beta (TGF-β) and why is it important? What peptides are the best for various conditions? These are just a few of the many topics we discuss. And stay to the end where Dr. Holtorf shares which peptide he thinks might become the next superstar over BPC-157!   Learn more about Integrative Peptides and try them for yourself at IntegrativePeptides.com. Use code Longevity10 to get 10% off.   Follow Dr. Holtorf: https://holtorfmed.com/ https://integrativepeptides.com/ https://www.nahypothyroidism.org/ https://mybettermedicine.com/ https://www.instagram.com/integrativepeptides/ https://www.instagram.com/holtorfmedicalgroup/       ------     Episode Sponsors Timelinenutrition make Mitopure, a scientific breakthrough formula for your cells! Ten years of research led to the discovery of Urolithin A; a mitochondrial powerhouse that assists in mitophagy, protecting cells from cellular decline. Mitopure is clinically proven to enhance muscle health and performance. It comes in a whey protein powder, capsules or a berry (or ginger) powder. Learn more here and use code NAT10 for 10% off! Young Goose:  YG's products are designed to rewind cells to their youthful state and visibly improve the appearance of fine lines, hyperpigmentation, and improve skin radiance. These products are the best skincare I have ever experienced. My top 3 products are Bio-Retinol, NAD Boosting EyeCARE and Hyperbaric Mask. Visit Young Goose and use code SUPERHUMAN20 for 20% off first purchases or code NAT5 for future orders.       ------     Episode Takeways [05:00] Lyme and mold illness and how to treat it FAST… [20:30] Dysfunctional mitochondria and illness… [23:00] Senescent cells and what to do about them?.. [28:00] There is a bioregulator for that… [31:50] TA1, can you take too much too quickly?.. [35:00] TB4 and the fragments… [38:00] Where does epitalon fit into an immune protocol? [43:00] 5-Amino-1MQ for OCD? [52:00] What are our favorite thymus peptides?.. [54:00] What is human transforming growth factor beta (TGF-β)?..     ------     Follow Nat Facebook Facebook Group  Instagram Mighty Networks BSP Community Work with Nat: Book Your 20 Minute Optimization Consult

This month on Episode 44 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the January 6th and January 20th issue of Circulation Research. This episode also features an interview with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart.   Article highlights:   Prasad, et al. ACE2 in Gut Integrity and Diabetic Retinopathy   Cui, et al. Epsins Regulate Lipid Metabolism and Transport   Li, et al. Endothelial H2S modulates EndoMT in HF   Luo, et al. F. plautii Attenuates Arterial Stiffness   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh. And today I'm going to be highlighting articles from our January 6th and January 20th issues of Circulation Research. I'm also going to have a chat with Dr Timothy McKinsey and Dr Marcello Rubino about their study, Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. But before the interview, I want to get to a few articles to highlight.   Cindy St. Hilaire:        The first article is titled, Maintenance of Enteral ACE2 Prevents Diabetic Retinopathy in Type 1 Diabetes. The first authors are Ram Prasad and Jason Floyd, and the corresponding author is Maria Grant, and they are from the University of Alabama.   Type 1 Diabetes has a complex etiology and pathology that are not entirely understood. In addition to the destruction of insulin-producing cells, a recently discovered feature of the disease in both humans and in rodent models is that the levels of angiotensin converting enzyme 2 or ACE2 can be unusually low in certain tissues. ACE2 is a component of the renin angiotensin system controlling hemodynamics and interestingly, genetic deficiency of ACE2 in rodents exacerbates aspects of diabetes such as gut permeability, systemic inflammation and diabetic retinopathy, while boosting ACE2 has been shown to ameliorate diabetic retinopathy in mice. This study shows that ACE2 treatment also improves gut integrity and systemic inflammation as well as retinopathy. Six months after the onset of diabetes in a mouse model, oral doses of a bacteria engineered to express humanized ACE2 led to a reversal of the animal's gut barrier dysfunction and its retinopathy. Humans with diabetic retinopathy also displayed evidence of increased gut permeability in low levels of ACE2. This study suggests they may benefit from a similar probiotic treatment.   Cindy St. Hilaire:        The next article I want to highlight is titled, Epsin Nanotherapy Regulates Cholesterol Transport to Fortify Atheroma Regression. The first authors are Kui Cui, Xinlei Gao and Beibei Wang, and the corresponding authors are Hong Chen and Kaifu Chen and they're from Boston Children's Hospital. Epsins are a family of plasma membrane proteins that drive endocytosis. They're expressed at varying levels throughout the tissues of the body, and recent research shows that they are unusually abundant on macrophages within atherosclerotic lesions. In mice, macrophage specific Epsin loss results in a reduction in foam cell formation and atherosclerotic plaque development. This study now shows that this effect on foam cells is because Epsins normally promote the internalization of lipids into macrophages through their endosytic activity.   But that's not all. The proteins also impede cholesterol efflux from macrophages to further exacerbate lipid retention. It turns out out Epsins regulate the endocytosis and the degradation of a cholesterol efflux factor called ABCG1. Importantly, these pro atrogenic activities of Epsins can be stopped. Using macrophage targeted nanoparticles carrying Epson specific silencing RNA, the team could suppress reduction of the protein in cultured macrophages and could reduce the size and number of plaques in atherosclerosis prone mice. Together these results suggest blocking Epsins via nanotherapy or other means could be a therapeutic approach to stopping or slowing atherosclerotic plaque progression.   Cindy St. Hilaire:        The third article I want to highlight is coming from our January 20th issue of Circ Res and is titled, Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure. The first author is Zhen Li, and the corresponding author is David Lefer and they're from Cedars-Sinai. Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine γ-lyase, or CSE, is one of the three hydrogen sulfide producing enzymes, and it's predominantly localized in the vascular endothelium. Genetic deletion of CSE, specifically in the endothelium, leads to reduced nitric oxide bioavailability, impaired vascular relaxation and impaired exercise capacity, while genetic over-expression of PSE in endothelial cells improves endothelial cell dysfunction, and attenuates myocardial infarction following myocardial ischemia-reperfusion injury.   In this study, endothelial cell specific CSE knockout mice and endothelial cell specific CSE overexpressing transgenic mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. And the goal was to investigate the contribution of the CSE hydrogen sulfide access in heart failure. Endothelial specific CSE knockout mice exhibited increased endothelial to mesenchymal transition and reduced nitric oxide bioavailability in the myocardium. And this was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and it worsened the vascular performance of these animals. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased EndoMT and decreased cardiac fibrosis. It also improved exercise capacity. These data demonstrate that endothelial CSE modulates endothelial mesenchymal transition and ameliorated the severity of pressure overload induced heart failure , in part through nitric oxide related mechanisms. This data further suggests that endothelium derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.   Cindy St. Hilaire         The last article I want to highlight is titled, Flavonifractor plautii Protects Against Elevated Arterial Stiffness. The first authors are Shiyun Luo and Yawen Zhao, and the corresponding author is Min Xia, and they are at Sun Yat-sen University. Dysbiosis of gut microbiota contributes to vascular dysfunction and gut microbial diversity has been reported to be inversely correlated with arterial stiffness. However, the causal role of gut microbiota in the progression of arterial stiffness and the specific species along with the molecular mechanisms underlying this change remain largely unknown. In this study, the microbial composition in metabolic capacities were compared in participants with elevated arterial stiffness and in normal controls free of medication. And these groups were age and sex match.   Human fecal metagenomic sequencing identified a significant presence of Flavonifractor plautii or F. plautii in normal controls, which was absent in the subjects with elevated arterial stiffness. The microbiome of normal controls exhibited an enhanced capacity for glycolysis and polysaccharide degradation, whereas individuals with increased arterial stiffness exhibited increased biosynthesis of fatty acids and aromatic amino acids. Additionally, experiments in the angiotensin II induced and humanized mouse model show that replenishment with F. plautii or its main effector cis-aconitic acid or CCA improved elastic fiber network and reversed increased pulse wave velocity through the suppression of matrix metalloproteinase-2 and through the inhibition of monocyte chemoattractant protein-1. And this was seen in both the angiotensin II induced and humanized models of arterial stiffness. This study now identifies a novel link between F. plautii and arterial function and raises the possibility of sustaining vascular health by targeting the gut microbiota.   Cindy St. Hilaire:        Today with me I have Dr Tim McKinsey and Dr Marcello Rubino from the University of Colorado Anschutz Medical Campus, and we're here to talk about their paper Inhibition of Eicosanoid Degradati`on Mitigates Fibrosis of the Heart. And this article is in our January 6th issue of Circulation Research, so thank you both so much for joining me today.   Timothy McKinsey:    Thank you for inviting us.   Marcello Rubino:        Yeah, thank you for the opportunity.   Cindy St. Hilaire:        And so Dr McKinsey, you're a professor at the University of Colorado. How long have you been investigating cardiac fibrosis?   Timothy McKinsey:    Oh, a long time. Before I started the lab here in 2010, I was in industry working in biotech with Myogenic Gilead, and we were very interested in cardiac fibrosis all the way back then.   Cindy St. Hilaire:        Oh wow, so you actually made an industry to academia transfer.   Timothy McKinsey:    Yes.   Cindy St. Hilaire:        Good topic for another podcast. That is really great.   Timothy McKinsey:    Yeah, it's of interest to a lot of people, including trainees.   Cindy St. Hilaire:        Yeah, I bet. Dr Rubino, you were or are a postdoc in the McKinsey lab? Marcello Rubino:        Yeah, I was a postdoc in Timothy McKinsey lab. I spent four years in Tim's lab. It was my first time studying cardio fibrosis, so it was a little bit difficult at the end, but I think I was right choosing Tim, so I'm really happy now.   Cindy St. Hilaire:        Nice and are you sticking with fibrosis or are you moving on?   Marcello Rubino:        Yeah, so now I'm back in Milan where I did my PhD student and postdoc. I am like an independent researcher, but it's still not a principal investigator, so I want to become one of the that, studying cardiac fibrosis. Yeah. And inflammation and epigenetics, so yeah, I'm going try to go to my way, thanks to Tim, I think that I find my own way.   Cindy St. Hilaire:        I'm sure you will. I mean, based on the great work in this study, right. Building upon that, I'm sure you'll be a success.   Timothy McKinsey:    No doubt about it.   Cindy St. Hilaire:        So your manuscript, this study, it's investigating whether eicosanoid availability can attenuate fibrosis in the heart. But before we kind of jump into this study, why is fibrosis in the heart a bad thing? Is it always detrimental? Is there some level of fibrosis that's necessary or even helpful?   Timothy McKinsey:    I mean, a certain level of extracellular matrix is deposited in your heart and that maintains the structure of the heart. Fibrosis can also be good after you have a myocardial infarction and a big piece of the muscle of your heart has died, it needs to be replaced with a fibrotic scar, essentially to prevent rupture of the ventricle. So fibrosis isn't always bad, but chronic fibrosis can be really deleterious to the heart and contribute to stiffening of the heart and cause diastolic dysfunction. It can create substrates for arrhythmias and sudden cardiac death. So we're really trying to block the maladaptive fibrosis that occurs in response to chronic stress.   Cindy St. Hilaire:        Yeah, yeah. And what about eicosanoids? What are they and what role do they play in cardiac fibrosis or what was known about their role in this process before your study?   Timothy McKinsey:    Eicosanoids are lipids, they're basically fatty acids, 20 carbon in length and a lot is known about them. It's a very complex system. There are many different eicosanoids, but they're produced from arachidonic acid through the action of cyclooxygenase enzymes like COX-2. And so you're probably familiar with the literature showing that non-steroidal anti-inflammatory drugs that target the COX enzymes can actually increase the risk of cardiac disease, so there was a lot known about what produces eicosanoids in the heart, but our study is really the first to address how they're degraded and how that controls cardiac fibrosis.   Cindy St. Hilaire:        What I thought you did really well in the introduction and what I guess I didn't really fully appreciate until I had read your study, was that your goal was to identify compounds that could attenuate fibrosis. And you spent some time emphasizing the differences between a targeted small molecule screen and a phenotype based screen. And I was wondering if you could just expand on this difference for the audience and maybe just explain why in your case you went with the latter.   Timothy McKinsey:    Well, we wanted to use an unbiased approach and some people call this a chemical biology approach where we took a targeted library, meaning we took compounds with known activities, meaning compounds that with known targets and we screened that library using a phenotypic assays that we developed in the lab. And the phenotypic assay is an unbiased assay, right? We're just screening for compounds that have the ability to block the activation of fibroblasts. And we monitor activation by looking at markers of fibroblast activation such as alpha smooth muscle Actin. And we can do this in a very quantitative and high throughput manner using this imaging system, high content imaging system that we have in the lab.   It was an unbiased screen looking for inhibitors of fibroblasts activation across organ systems. We not only studied cardiac fibroblasts, but we also studied lung and renal fibroblasts looking for compounds with a common ability to block the activation state of each of those cell types.   One of the things that I get asked frequently is how do we maintain the cardiac fibroblasts in a quiescent state? Because you may know this, but when fibroblasts are plated on cell culture plastic, which has a very high 10 cell strength, they tend to spontaneously activate, so we actually spent a couple of years working out the conditions to maintain the cells in quiescent state, and I think that will also be of great interest to the field.   Cindy St. Hilaire:        Probably even the smooth muscle cell biology field where I hang out and even valve interstitial cells that we study. All of those, I guess basic things related to cell culture, we have taken for granted that plastic is not physiological.   Timothy McKinsey:    Right.   Cindy St. Hilaire:        And so I think with this really nice phenotypic or chemical screen that you conducted, you first identified nine compounds, but what made you zero in on this one, SW033291?   Timothy McKinsey:    When we got the hits, we were intrigued by the SW compound SW033291 because there was only one paper describing its action and there was a paper published in Science showing that SW or inhibition of this enzyme 15-PGDH could enhance organ regeneration.   Cindy St. Hilaire:        Oh, okay.   Timothy McKinsey:    And there's a very interesting interplay between fibrosis and organ regeneration where fibrosis inhibits regeneration and if you can stimulate regenerative pathways, they can actually block fibrosis, so there's this back and forth. And so that's really the main reason we were interested in pursuing SW just because of the novelty and the potential. And also it was a compound that behaved beautifully in our cell culture models with beautiful dose-dependent inhibition of each of the fibroblast types.   Cindy St. Hilaire:        It's kind of like the cleanest thing to start with. Also, if there's nothing known, it's ripe for investigation, so that's great. You just said this SW compound acts on 15-PGDH, so what is the role of that protein in fibroblasts and what if any known effects are there on this protein's inhibition in other cell types or disease states?   Marcello Rubino:        In fibroblasts team, I would like to say that this was really the first article that was published. Maybe there was just one published in Pulmonary Fibrosis, but like last year, but I didn't really talk about 15-PGDH, so you need to consider that 15-PGDH is an inhibitor, an enzyme that degrades prostaglandin, so if you inhibit the inhibitor, the release increase production, a lot of prostaglandin. And so a lot of paper were talking about this effect, so they will see we are just using SW in order to increase Prostaglandin E2 level and that was why we had this like anti-inflammatory or whatever effect. I would like to say that until now, maybe this can be the first really paper talking about no more than not just prostaglandin but 15-PGDH. Its action total level, a global level at particularly on fibroblasts.   To answer your question, I would like to say that this was also our question first and we checked by level other browser to try to find the answer to your question. We figured out that it was known that 15-PGDH was increasing a pathology condition in different organ, not just related by fibroblasts, not just related to cardiac disease, about the function with discover a function in macrophage that interested us because it can regulate maybe the polarization macrophage, so still involving the prostaglandin production inflammation, so that's why also we decide to take a look because it was still novel in fibrolbasts and we still know that it was doing something important and we were trying not to put the piece together and find something new in that we were lucky for this.   Timothy McKinsey:    15-PGDH is actually expressed at very low levels in fibroblasts. It's much more highly expressed in macrophage, just as Marcello pointed out, so in the future we're very interested in knocking out or inhibiting 15-PGDH in different cell types to see how that contributes to inhibition of cardiac fibrosis.   Cindy St. Hilaire:        Really interesting. Related to that, you used a couple different animal models for fibrosis. They're all different or special in their own way. How well did these recapitulate what we observe in humans. Are there any limitations of benefits?   Timothy McKinsey:    They're always limitations to animal models. We started out with a very robust commonly used model of cardiac fibrosis, which relies on Angiotensin II infusion in mice. We like that model because it's robust and quick so we can get answers quickly. And then we transitioned into a model of diastolic dysfunction that we've been working with in a lab where we remove a kidney from a mouse and we implant something called DOCA, which is an aldosterone memetic. And so the animals develop hypertension that leads to a mild but significant diastolic dysfunction with preserved ejection fraction.   And that's a model that we like a lot. It has something that we call hidden fibrosis, so if you just do standard histochemical staining of the hearts from the DOCA unit, nephrectomy model, that diastolic dysfunction model, you really can't see robust fibrosis. It's only when you dive more deeply with more sensitive assays like mass spectrometry or atomic force microscopy that you can detect this fibrosis and stiffening of the heart, so we usually lead with a robust model of fibrosis, cardiac fibrosis, and then transition into a slightly more complex model but more physiologically relevant model or disease relevant model.   Cindy St. Hilaire:        Obviously you showed some really nice robust results with this SW compound. So in the continuum of heart failure in human, what do you think or what would you speculate would be the ideal timeframe for administration of this compound?   Timothy McKinsey:    Wouldn't want to give it immediately after someone's had a heart attack. As we discussed earlier, you need that reparative scar to form so you don't want to block that fibrotic remodeling. We believe that there's kind of smoldering fibroblast activation in the heart, even in someone who's had heart disease for many, many years. And if we can dampen that, we can either prevent further progression of heart failure or perhaps reverse it. We don't really know if we can reverse really established fibrosis in the heart yet. But I would want to try to catch fibrosis fairly early on in the disease process in someone who has chronic hypertension or obesity or a variety of different comorbidities and then start delivering an antifibrotic therapy at that point.   Marcello Rubino:        I would like to add that, so it is really tricky when we talk about clinical trials because a lot of molecules that maybe they can work hopefully in a preclinical model don't work at the end in the clinical model. That's because can be some off target also like you just asked what is really important is when you do the administration of the molecule and talk about this in SW, like things say we don't want to prevent the fibrosis because there is something like called a kneeling at the beginning, so it is the good fibrosis we like to say, but the good thing of SW compound is that is affecting in a good way the proliferation of fibroblast that is different for all the other. I would like to say all the other inhibitor that we saw so far, because I remember the first time that I presented this work, there was an expert told me that he didn't believe that all my data because the compound was inhibiting fibrosis, it was inhibiting proliferation.   And I show him, no, this is contrary, so oh okay, I like it. We need to consider this that the action seems to be not like the retire for the cell, so because the cells continue to proliferate, they can proliferate more. But the good thing and we need to investigate more is that SW action seems to increase when the cell are more fibrotic, because we show just few human fibroblasts isolating from a human patient and we saw a higher positive effect of SW compound when the cell were more fibrotic. That can be interesting. I think that it's worth to try to test in the future like in different preclinical models and maybe in patients at the end because if we really can find something like maybe SW that can be specific for the state of pathology, that will be wonderful. I don't really know if we can really do it, but we need some therapy like this, so that's why we were really excited about what we discovered for this compound.   Timothy McKinsey:    We have a lot more to learn about this pathway and about fibrosis in general.   Cindy St. Hilaire:        Yeah.   Timothy McKinsey:    It's a very exciting time to be doing science because of the amazing technologies that we have at our disposal to address detailed mechanisms of disease.   Cindy St. Hilaire:        What was the most challenging aspect of the study?   Timothy McKinsey:    This was an incredibly difficult study. I can't even stress to you how much work went into this. Spearheaded by Marcello's awesome leadership. There was huge input from a big team. Keith Cook and I worked together in industry and we were able to recruit him over here for a few years as part of our fibrosis center called the CFReT. It's an advertisement. And Keith was able to implement some of the drug discovery approaches that we used in biotech and create this imaging system that we initially employed for the screens. That was challenging. Maintaining the cells in a quiescent state was very challenging as I mentioned. That took a couple of years and then just following up on SW and trying to figure out its mechanism of action was really challenging as well because as Marcello mentioned, most people have attributed SW's effects to an increase in PGE2 levels, so PGE2 is an eicosanoid that is degraded by 15-PGDH.   And definitely when you inhibit 15-PGDH with SW, you see increased PGE2. But surprisingly we couldn't find that PGE2 was doing anything in our cell culture systems, meaning when we added it exogenously it was not blocking fibroblast activation, so then Marcello set out to identify which eicosanoid that is regulated by 15-PGDH is actually the antifibrotic eicosanoid. And that led him to something called 12(S)-HETE. That was challenging. And then just determining at the molecular level what was going on was also challenging. And that led Marcello to this kind of paradoxical discovery that it activating ERK signaling was actually blocking fibroblast activation.   Cindy St. Hilaire:        And of course ERK does everything right?   Marcello Rubino:        It does. Everything.   Timothy McKinsey:    And sort of the dogma is that ERK is promoting fibrosis in the heart, but Marcello's data suggests otherwise.   Timothy McKinsey:    And then other shout outs, Josh Travers, who's the second author of the paper provided huge input, especially after Marcello left. Josh helped get this across the finish line. We have an amazing in vivo team conducting the animal model studies. Maria Cavasin and Elizabeth Hardy. I could go on and on. There are a lot of authors and if I didn't mention one of them, it doesn't mean that they weren't key contributors. I just wanted to throw that out there. We also had great collaborators. I think another component of this paper that is of great interest to us, and initially I was against doing any of this, is that Marcello and Josh created this biobank of human cardiac fibroblasts that we obtained from explanted hearts from individuals undergoing heart transplantation.   And initially I thought it was going to be a waste of time and money for Marcello and Josh to do that, but they were persistent and they started isolating these cells. And the cells are really fascinating because even after you take them out of that failed human heart and culture them, they maintain this constituently active state, which is different than the cells we were using for screening where we kept them quiescent and then we stimulated them with TGF-β to activate them. These human cardiac fibroblasts from the failed human hearts are just on all the time.   Cindy St. Hilaire:        Wow.   Timothy McKinsey:    And SW does a really amazing job of reversing that activated state.   Cindy St. Hilaire:        Very cool and excellent resource I'm sure for future studies. So my last question is what's next? You know, you discovered a lot in this paper. What's the next thing you want to tackle?   Timothy McKinsey:    Cell type specific roles for 15-PGDH in the heart, in the control of cardiac homeostasis and disease. Basically we want to knock it out in fibroblasts. We want to knock it out in our macrophages and see what the consequences are. That's one thing. We want to really pursue the whole GPR31 12(S)-HETE pathway in the heart. That's something that has never been studied. And so GPR31 is a G protein coupled receptor that is bound by this eicosanoid called 12(S)-HETE. And that seems to be blocking fibroblast activation, so we're going to further pursue that pathway. And then we think that this paradoxical finding related to ERK signaling in the heart is also worthy of pursuit. Why is it that stimulating ERK in a cardiac fibroblast is actually blocking the activation state of that cell?   Marcello Rubino:        I'm interested in this like Tim says, but also interested in the role of the interaction of the cell because it's important to study like a specific gene inhibitor, whatever role in a specific cell, but what happened to the other cell, the interaction the other cell when you do knocking in some specific cell, so that's what I'm trying to do in general. Now I move back in Italy, like I told you, I'm like a kind of independent research and I'm studying a lot single cell sequencing right now. Try to do also try to see what happened to interaction, understand during pathology.   The idea is to study like inhibitor treatment and to see what really happened because gene expression is important, but we need to consider also of course the protein shape, the protein interaction, the cell interaction, so I try to grow in this field and see what really happened because the problem of the cell, they're just cell in vitro. They can mimic what happened, but it's not what really happened in vivo, so can we use this novel technology to improve our knowledge, that's what I want to try to do.   Cindy St. Hilaire:        Well that's great. Dr McKinsey, Dr Rubino, thank you so much for taking the time to speak with me today. Title of their article was Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart. It's in our January 6th issue of Circ Res. And thank you both so much for joining me today and thank you to you and all of your colleagues who worked so hard on this for this amazing study.   Timothy McKinsey:    Thank you. We really enjoyed this visit and we're grateful to have our work published in Circulation Research.   Cindy St. Hilaire:        That's it for highlights from the January 6th and 20th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes or #DiscoverCircRes. Thank you to our guests, Dr Tim McKinsey and Dr Marcello Rubino. This podcast is produced by Ishara Rantayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

A new research paper was published in Oncotarget's Volume 13 on December 20, 2022, entitled, “Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression.” One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune-tolerant microenvironment. In this new study, researchers Hongyan Yuan, Lu Jin, Handan Xiang, Anannya Bhattacharya, Philip E. Brandish, Gretchen Baltus, Alexander Tong, Changyan Zhou, and Robert I. Glazer from Georgetown University Medical Center, Merck Research Institute and Bicycle Therapeutics aimed to determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1). A conditional model of mammary fibrosis recently developed by this team, NeuT/ATTAC mice, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab. The researchers monitored drug response by tumor development, imaging mass cytometry, immunohistochemistry, and tumor gene expression by RNAseq. “Utilizing this more stringent tumor model to test its susceptibility to anti-PD-1 immunotherapy, we report the signaling processes associated with its lack of responsiveness.” Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1, and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors. “Overall, the immune tolerant TME in NeuT/ATTAC mice was associated with tumor-infiltrating macrophages, Foxp3+/PD-1- Treg cells as well as upregulation of the Wnt signaling pathway, which may provide further insights into the therapeutic options that may enhance immune checkpoint therapy.” DOI: https://doi.org/10.18632/oncotarget.28330 Correspondence to: Robert I. Glazer - glazerr@georgetown.edu Keywords: PD-1, NeuT, Wnt, macrophages, mammary tumorigenesis About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter - https://twitter.com/Oncotarget Facebook - https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram - https://www.instagram.com/oncotargetjrnl/ LinkedIn - https://www.linkedin.com/company/oncotarget/ Pinterest - https://www.pinterest.com/oncotarget/ LabTube - https://www.labtube.tv/channel/MTY5OA SoundCloud - https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com.

In this short, off-the-cuff video with the very first details on The Good Future Project. To quote Jane Goodall "What you do makes a difference, and you have to decide what kind of difference you want to make” More here: https://www.thegoodfutureproject.com #peopleplanetpurposeprosperity #goodfutureproject #thegoodfuture Check out our new Project YT page: https://www.youtube.com/channel/UCVsE3gQYHLffapbpbDqjaaA or https://thegoodfutureproject.com/ The Good Future Project, initiated by Futurist Gerd Leonhard and supported by the Futures Agency, is a global, non-profit network of like-minded individuals and supporters who focus on making ‘The Good Future' (TGF) a reality. TGF's concept is based on Gerd's 2021 film ‘The Good Future' see https://youtu.be/yHC5n7G5SeI

Happy New Year and here we go with Season 2 on the Dirty Side of the Track!!Not a huge amount of #F1 news around but we dig deep to kick off 2023 with with the news and social media that caught our eye over our holiday break.Episode running order is:1) News & SocialVideos from the world of #Formula1 Marriott Bonvoy Good Travel Talk With Lewis Hamilton. Marriott Bonvoy channel https://youtu.be/wyfW3Iu7NqMLewis Reacts To Fan Comments https://youtu.be/yTHaR7w00a0The 2022 F1 Drivers And Team Principals' Hilarious Studio Outtakes https://www.youtube.com/watch?v=35NlL2OdTkYBest Cooldown Room Moments Of 2022 https://www.youtube.com/watch?v=FQflRuLSHT4Best of McLaren Unboxed 2022 https://www.youtube.com/watch?v=e9oFCqFdNmwPierre Gasly & Yuki Tsunoda's Italian Christmas https://www.youtube.com/watch?v=p3ldh83xpTUMcLaren Racing | Bad Lip Reading https://www.youtube.com/watch?v=h0aL2_Jc62IWatch Charles Leclerc & Carlos Sainz Prepare Gingerbreads for the Shell Track Lab Team https://www.youtube.com/watch?v=Zt44U_VGWTkFunniest F1 Moments Of 2022 https://www.youtube.com/watch?v=YSZ3J2d_kSk&t=143sF1 Grid Does Secret Santa 2022 https://www.youtube.com/watch?v=H7eFj_fZphoLollipopman 12 Days https://youtu.be/AM-7p3bu75QLollipopman Jingle Bells https://youtu.be/tgF_ik7redw2) #100SecondsofDRS with Brian3) #100SecondsofDRS with Rob4) Ramblings about what might be coming next weekIf you want to sign up then get in touch via our social channels all of which can be found over at our website https://www.dirtysideofthetrack.comWe are excited to launch our Discord server so use this invite link to join us https://discord.gg/XCyemDdzGB

Arthur and guest cohost Steve Valiquette break down the recent 3-games-in-4-nights stretch for the Rangers, with the Blueshirts going 1-1-1 against the Senators, Blackhawks, and Blues, and discuss whether head coach Gerard Gallant's coaching style is working for this group right now, captain Jacob Trouba's attempts to jolt his team to life with his physical play, Alexis Lafrenière and Kaapo Kakko playing on a line with Mika Zibanejad, and a make-or-break stretch with games against the Vegas Golden Knights tonight, the defending Stanley Cup champion Colorado Avalanche on Friday, the league-leading New Jersey Devils Monday at the Garden, and the surging Toronto Maple Leafs at MSG on Thursday. And, right now, get a one year subscription to The Athletic for $2 a month when you visit theathletic.com/TGF

This month on JHLT The Podcast, JHLT Digital Media Editor Marty Tam, MD, takes over hosting duties to present two papers from the December issue of The Journal of Heart and Lung Transplantation. Listen now to hear study authors discuss their work, their studies, and next steps for their research. First, we welcome first author Jorge V. López-Ibor, MD, and senior author Javier Segovia-Cubero, MD, PhD, about their team's study from Hospital Universitario Puerto de Hierro Majadahonda entitled “Role of TGF-β1 +869T>C polymorphism in renal dysfunction one year after heart transplantation.” Drs. López-Ibor and Segovia-Cubero share some background on their work and their areas of research before diving into the study. The study analyzed 355 adult patients for renal dysfunction a year post-heart transplant and suggested a protective role for the TGF- β1 + 869CC genotypes in the development of chronic kidney disease (CKD) in heart transplant patients on calcineurin inhibitors (CNIs). Next, Tsuyoshi Takahashi, MD, PhD, from Washington University, shares details on the study “A comparison of outcomes after lung transplantation between European and North American centers.” Dr. Takahashi begins by discussing his global journey in thoracic surgery, including some of the differences between being a surgeon in the United States and Japan. The study used the ISHLT Thoracic Organ Registry to complete a retrospective, comparative cohort analysis of adult patients undergoing deceased donor lung transplant in North America and Europe between January 2006 and December 2016. It compared overall survival between North American and European transplant centers in a propensity score matched analysis, suggesting a higher 5-year survival for European centers. Dr. Takahashi answers questions about the many factors contributing to these variances. Follow along in the December issue at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org. This episode of JHLT: The Podcast, but not the studies within, is sponsored by Enzyvant.

Arthur and guest cohost Steve Valiquette break down the Rangers much-needed 3-1 win over the Ottawa Senators on Wednesday night and discuss Jaroslav Halak's first win as a Ranger, the play of Jimmy Vesey, Vitali Kravstov, and Barclay Goodrow throughout a reshuffled lineup, Jacob Trouba playing with an upper-body injury, Igor Shesterkin's struggles, upcoming must-wins against the Sens and Blackhawks this weekend, and Vally tries to name the 10 goalies to win games for both the Rangers and Islanders to close things out. And, right now, get a one year subscription to The Athletic for $2 a month when you visit theathletic.com/TGF

This week, please author Jung-Minh Ahn and Associate Editor Emmanouil Brilakis as they discuss the article "Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial." Dr. Greg Hundley: Welcome, listeners to this November 22 issue of Circulation on the Run. And I am Dr. Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway, and also a social media editor interpolation. Dr. Greg Hundley: Well Peder, our feature this week, we are reviewing a comparison between drug eluting stents and bypass surgery for multi vessel coronary artery disease. Really an extended follow up from the Vest trial. Dr. Peder Myhre: I can't wait, Greg. Dr. Greg Hundley: Right. But before we get onto that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Would you like to go first? Dr. Peder Myhre: Sure, I'd love to. And the first paper today is a clinical one and it is entitled, “Efficacy of a Drug Eluting Stent Versus Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the Eminent Randomized Trial.” And it comes to us from the corresponding author Yann Gouëffic from Groupe Hospitalier Paris St. Joseph in France. So Greg, a clear patency benefit of a drug eluting stent over bare metal stents for treating peripheral artery disease of the femoropopliteal segment has not been definitely demonstrated. But today's paper publishes the primary results of the eminent randomized trials, which was designed to evaluate the patency of the Eluvia drug eluting stent. And this stent is a polymer based paclitaxel eluting stent and it was compared with bare metal stents for the treatment of femoropopliteal artery lesions. In fact, with 775 patients, Eminent is the largest randomized trial of drug eluting stent treatment for symptomatic femoropopliteal arterial disease to report patency to dates. Dr. Greg Hundley: Very nice, Peder. So describe for us, what were the results of this very large randomized clinical trial? Dr. Peder Myhre: Sure, Greg. So the primary effectivity outcome was primary patency at 12 months, defined as independent core laboratory assessed duplex ultrasound peak systolic velocity ratio less than or equal to 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesions. And primary effectiveness analysis from the Eminent randomized study demonstrated superior one year primary patency for the Eluvia drug eluting stent versus bare metal stent. And that is 83.2% versus 74.3% with a P value less than 0.01. And this treatment was associated with a greater incident of Rutherford classification improvement without the need for re-intervention, and functional parameters demonstrated improvements in both groups, and there were no statistical difference observed in one year mortality between patients treated with the Eluvia drug eluting stents and bare metal stents. So in summary, this high level evidence supports the one year benefit of polymer based paclitaxel elusion over bare metal stents to treat superficial femoral artery and/or proximal popliteal artery lesions. What'd you think of that, Greg? Dr. Greg Hundley: Very nice. So sounds like for peripheral arterial interventions, a benefit from the polymer based paclitaxel eluting stents. Dr. Peder Myhre: Exactly. And there's also an editorial putting these results in context from Doctors Mosarla and Secemsky entitled, “From Imperialism to Eminence: The Noble Rise of the Second Generation Peripheral Drug Eluting Stents.” Dr. Greg Hundley: Excellent, Peder. Well, my article comes to us, Peder, from the world of preclinical science. And Peder, these investigators led by Professor Volker Spindler from University of Basel evaluated arrhythmogenic cardiomyopathy. And as you know, arrhythmogenic cardiomyopathy is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life threatening arrhythmias. So a substantial proportion of arrhythmogenic cardiomyopathy is caused by mutations in genes of the desmosomal cell to cell adhesion complex, but the underlying mechanisms are not well understood. So to address this, the team mutated the binding site of desmoglein two, a crucial desmosomal adhesion molecule in cardiomyocytes. This desmoglein two W2A mutation abrogates the tryptophan swab, a central interaction mechanism of desmogenin two based on structural data. Now, the impaired adhesive function of this DSG2W2A was confirmed by cell to cell dissociation assays and for spectroscopy measurements by atomic force microscopy. Dr. Peder Myhre: Wow. We continue to learn more about this disease, arrhythmogenic cardiomyopathy. And this sounds so interesting. Greg, please tell me what did they find? Dr. Greg Hundley: Right, Peder. So they found that the DSG2W2A mutation impaired binding on the molecular level and compromised intercellular adhesive function. Now, mice bearing this mutation, developed a severe cardiac phenotype recalling the characteristics of arrhythmogenic cardiomyopathy including cardiac fibrosis, impaired systolic function, and arrhythmia. Now, a comparison of the transcriptome of the mutant mice with arrhythmogenic cardiomyopathy patient data suggested deregulated integrin alpha V beta six and subsequent TGF beta signaling as a driver of cardiac fibrosis. Now accordingly, blocking integrin alpha V beta six led to reduced expression of pro-fibrotic markers and reduced fibrosis formation in the mutant animals in vivo. Dr. Peder Myhre: Oh, this is so important mechanistically. And Greg, can you please tell us something about the clinical importance of these findings? Dr. Greg Hundley: Right Peder, just like Carolyn always driving at that clinical significance. So these authors show now that disruption of desmosomal adhesion is sufficient to induce a phenotype which fulfills the clinical criteria to establish the diagnosis of arrhythmogenic cardiomyopathy confirming the dysfunctional adhesion hypothesis. Now mechanistically, deregulation of integrin alpha V beta six and TGF beta signaling was identified as a central step in the process toward developing fibrosis. And then finally, a pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. So perhaps, new information leading to future therapeutic strategies to halt myocardial fibrosis in patients with arrhythmogenic cardiomyopathy. Dr. Peder Myhre: Oh wow. What an amazing issue this is, Greg, and we actually have even more in the mail bag. We have a Perspective piece by Dr. Prystowsky entitled “Rate versus Rhythm Control for Atrial Fibrillation, Has the Debate Been Settled?” And we have some Cardiology News by Bridget Kuehn entitled, “Fitness Rather than BMI Appears to be Better Predictor of Survival for Women with Heart Disease.” I'm sure Carolyn would love to read that one. And in this paper, Bridget Kuehn discusses a new study published in European Journal of Preventive Cardiology. Dr. Greg Hundley: Very nice, Peder. Well, I've got a couple other articles in the issue. First, Dr. Tonelli has a Primer entitled, “Increasing Societal Benefit from Cardiovascular Drugs.” And then Professor Januzzi has a Research Letter entitled, “Association Between Sacubitril/Valsartan Initiation in Mitral Regurgitation Severity and Heart Failure with Reduced Ejection Fraction: The PROVE HF Study.” Well, now let's get on to that feature discussion in this issue to discuss PCI versus CABG for multi vessel coronary artery disease. Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this November 22nd feature discussion and we have with us today Dr. Jung-Min Ahn from Seoul, South Korea and our own associate editor, Dr. Manos Brilakis from Minneapolis, Minnesota. Welcome gentlemen. Jung-Min, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Jung-Min Ahn: Thank you, Greg. So the everolimus-eluting stent Freedom trial, showed a higher mortality after PCI than after bypass surgery in multi vessel disease. However, these findings maybe delimited predictability in the contemporary practice because such trials use the first generation drug stent which may have higher rate of stent thrombosis. The Press trial is the first randomized trial using the second-generation drug eluting stent. The initial approach was published in New England Journal of Medicine five years ago. So they showed that the 4.6 years of follow the PCI with everolimus-eluting stents showed a significantly higher rate of prime endpoint deaths, MI, the target revascularization, but overall mortality, there was no significant difference. So the hypothesis that, in a long term follow, more than 10 years follow, so we want to see the mortality difference between the PCI with the second generation everolimus-eluting stent versus bypass surgery. So we designed this extended follow trial best studies. Dr. Greg Hundley: Very nice, Jung-Min. And can you describe for us the study design, and who was your study population, and how many subjects did you enroll? Dr. Jung-Min Ahn: Actually, this study is the extended follow original Press trial, enrolled 880 patients from mostly Korea, China, Malaysia, and Thailand. So the study population was Asian population with a symptomatic or symptomatic coronary artery disease with angiopathy confirming the multi vessel coronary artery disease population. One additional criteria is the patient with coronary artery disease should report PCI and bypass surgery decided by the attending physicians and surgeons. Dr. Greg Hundley: Thank you, Jung-Min. And so, can you describe for us your study results? Dr. Jung-Min Ahn: Yes. During the extended follow-up study we found that there is no significant difference between the PCI with everolimus-eluting stent and bypass surgery regarding prime endpoint deaths, MI, vascularization. In addition, more importantly, we reduced the compost endpoint of death, MI, stroke. There was no significant difference in addition regarding the mortality. Also, there is no significant difference during the long term follow. Dr. Greg Hundley: Really interesting results, Jung-Min. Did you notice any differences in men versus women or in younger versus older individuals? Dr. Jung-Min Ahn: In our sub-group analysis, there is no interaction according to the sub-groups except the diabetic sub-groups. In diabetics and long term outcomes, have interaction with the treatment assignment regarding the primary endpoint, prime endpoints, death, MI, target vascularization. Even though contrary to the Freedom trial, the overall mortality rate, there is no significant difference between the PCI versus the bypass surgery even in diabetic populations. Dr. Greg Hundley: Well thank you so much, Jung-Min. And now listeners, we're going to turn to our Associate Editor, our expert in the area of advanced percutaneous coronary artery interventions, Dr. Manos Brilakis from Minneapolis, Minnesota. Manos, you have many papers come across your desk. What attracted you to this particular paper and how do you put its results in the context of other studies that have been performed to compare multi vessel percutaneous coronary artery intervention versus coronary artery bypass grafting? Dr. Manos Brilakis: Yeah, thank you, Greg. And again, congratulations to Jung-Min for a great paper. And the reason we were very interested in this paper is because it is an area that is still debated clinically quite extensively. As Jung-Minh mentioned, there is the Syndex trial showing that there was higher mortality amongst the PCI group over long term, but that was done a long time ago with previous generation drug diluting stents, and the data, the contemporary data with recently the currently used DS, is much more limited. So I think the appeal for us, and I think frankly for the practicing interventionalist, is that this paper provides long term outcomes with contemporary drug eluting stents over a fairly large patient population, and it does so fairly well, but there are plus and minuses. There was no difference in mortality, which continues to be debated. But this paper is fairly equivalent on this respect. And if we see the coupled myo curves, they also look very similar. And there was some differences in death in myocardial infarction to be taken into consideration. But all this information is important for deciding for each patient we treat right now, which is the best way to go in terms of coronary devascularization. Dr. Greg Hundley: Very nice. And so, let's circle back next to Jung-Min. What do you see as the next research study really to be performed in this sphere of investigation? Dr. Jung-Min Ahn: Thank you, Greg. So I'd like to talk about the future study, but I'd like to say something about the how to do PCI. So what is the difference between the Press trial and previous randomized trial? In the Pres trial, we used the intracoronary imaging in 72% of PCI population. This is a huge higher rate than what was used compared with the previous randomized trial. Only 10% or less than 10% PCI population used intracoronary imaging. So I think to get the comparable research to the bypass surgery, I think we have to optimize the PCR region. What is the best way shortcut to get optimizing PCR region? It could be intracoronary imaging guided PCI, could be one important way to get optimized PCR region. I think this is very important to take a message from the first trial. Dr. Greg Hundley: Well, Jung-Min, it sounds like from your description that the application of intracoronary imaging was very important in this study. Do you want to expand on that for our listeners? You know, what were maybe some subgroup analysis results of using intracoronary ultrasound? And then, how would you recommend to our listening audience that that particular technique be applied? Dr. Jung-Min Ahn: Thank you, Greg. So I mentioned that the Press trial used the intravascular ultrasound in 72% of PCI. So we analyzed the the PCI with I, without I. PCI with I showed a very comparable primary endpoint and overall mortality rate to the bypass surgery group. But PCI without I showed a significantly higher rate of primary endpoint and overall mortalities. So intravascular ultrasound guided PCI may improve the PCI outcomes and we can compare our clinical outcomes to the bypass surgery. Dr. Greg Hundley: Very nice. And Manos, do you have anything to add? Dr. Manos Brilakis: Yeah, I think the era of doing multiple huge mega trials may be tough to find these days. I think we may not have big trials comparing those two modalities, but I do agree with Junh Minh. I think the conclusion from this study as well as the previous studies is that you can choose which way to go. But if you're going to go with PCI for example, you do want to make sure that you do the best possible outcome so that you use intravascular imaging, you use physiology. We know from phase three, that use of intravascular imaging was very limited. So if you're going to go with PCI for a specific patient, the decision of course depends on the study's results and the previous studies and the patients' specific preferences. But if you're going to do PCI, you want to take your time to get the best possible result, make sure you can get as complete revascularization as possible because that will translate into better clinical outcomes as well. Dr. Greg Hundley: Very nice. Well listeners, we want to thank our main author today, Dr. Jung-Min Anh, and our own associate editor, Dr. Manos Brilakis, for bringing us this important study highlighting that in patients with multi vessel coronary artery disease, there were no significant differences between PCI and coronary artery bypass grafting in the incidence of major adverse cardiac events, the safety composite endpoint, and all cause mortality during an extended follow up period. Well, on behalf of Peder, Carolyn, and myself, we want to wish you a great week and we will catch you next week On the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Join us this week as we sit with the one and only, Tacticool Girlfriend. In this episode we discuss how she began creating content, why it's so beneficial to the community and how we can improve gun culture ourselves. TGF schools us on the nitty gritty of getting into NODs and the benefits of doing so. We also chat about community-based prepping and the realistic scenario of self-defense against an endless mob of rabid children.If you like what we do and want to support The A Better Way 2A Podcast, check us out on Patreon where you can gain access to exclusive clips, get free merch, discount codes, and more.https://www.patreon.com/abetterway2a

This week the TGF team catches up with Chicago's own, singer and songwriter, Morgan Gold. In this episode, the team discusses Morgan Gold's latest project "MIDAS" and gets her first-hand opinion on what is the true meaning of "Ethereal R&B". Tune in to hear about how this project came to be and learn a little more about Gold's path to get to where she is today. We dive into topics ranging from the definition of an "industry plant", Gold's time at Columbia Chicago, and how she transitioned from screenplay and comedy to singing and songwriting. The Fresh Flower Podcast is The Ghetto Flower's bi-weekly underground talk and debate show featuring co-hosts Michael “Trill” Tayo, Quinton “Q” Coleman, and Josue “Sway” Roman. Apple: https://podcasts.apple.com/us/podcast/tgf-project-podcast/id1435114130 Spotify: https://open.spotify.com/show/1jaqB6RKffpzCvKHOC84GE?si=8UzvJTSgSHaI-tXn1RFLRg Check out more of The Ghetto Flower here: https://www.theghettoflower.com https://www.twitter.com/TheGhettoFlower https://www.instagram.com/TheGhettoFlower The Ghetto Flower was founded in 2017. It is a leading online publication and marketing agency that deepens into the underground arts surrounding them. On The Ghetto Flower, you'll find the latest music news, in-depth interviews, and up-to-date content marketing focused on the subculture niche. Michael “Trill” Tayo instagram.com/trilltayo twitter.com/trilltayo Quinton “Q” Coleman instagram.com/qguapo_ twitter.com/iGot_That_Kudi Josue “Sway” Roman instagram.com/tgf_sway twitter.com/TGF_Sway --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

This week the TGF team CHOPS IT UP with, FLEX for a deep conversation on his rise into the for front of Chicago's underground scene, and authenticity in today's rap game, and his latest trip to Los Angeles. We dive into topics ranging from the having courage to chase your dreams, Flex's team and their visions, and how he changed his plans to take over the city in years to come. The Fresh Flower Podcast is The Ghetto Flower's bi-weekly underground talk and debate show featuring co-hosts Michael “Trill” Tayo, Quinton “Q” Coleman, and Josue “Sway” Roman. Apple: https://podcasts.apple.com/us/podcast/tgf-project-podcast/id1435114130 Spotify: https://open.spotify.com/show/1jaqB6RKffpzCvKHOC84GE?si=8UzvJTSgSHaI-tXn1RFLRg Subscribe to The Ghetto Flower on YouTube: Check out more of The Ghetto Flower here: https://www.theghettoflower.com https://www.twitter.com/TheGhettoFlower https://www.instagram.com/TheGhettoFlower The Ghetto Flower was founded in 2017. It is a leading online publication and marketing agency that dives deep into the underground arts surrounding them. On The Ghetto Flower, you'll find the latest in music news, in-depth interviews, and up-to-date content marketing focused on the subculture niche. Michael “Trill” Tayo instagram.com/trilltayo twitter.com/trilltayo Quinton “Q” Coleman instagram.com/qguapo_ twitter.com/iGot_That_Kudi Josue “Sway” Roman instagram.com/tgf_sway twitter.com/TGF_Sway --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

NEWS: Sugar-studded protein is key to an Alzheimer's cure | The Brighter Side (01:38) In a bit of “reverse engineering” research using brain tissues from five people who died with Alzheimer's disease, Johns Hopkins Medicine researchers say they discovered that a special sugar molecule could play a key role in the development of Alzheimer's disease. This could indicate the molecule, known as a glycan, to be used as an early diagnostic test. And opens a way to perhaps prevention of the disease Cleaning up the disease-causing forms of amyloid and tau is the job of the brain's immune cells, called microglia. Earlier studies found that when cleanup is impaired, Alzheimer's disease is more likely to occur.  Thought to be caused by an overabundance of a receptor on the microglia cells, called CD33. Past studies by the researchers showed that for CD33, these “connector” molecules are special sugars.These molecules are ferried around the cell by specialized proteins that help them find their appropriate receptors.  The protein-glycan combination is called a glycoprotein.  The researchers, to find out more about the glycoproteins, obtained brain tissue from five people who died of Alzheimer's disease and from five people.Among the many thousands of glycoproteins they gathered from the brain tissues, only one connected to CD33. What was this mysterious glycoprotein?The researchers determined the protein component's identity by taking its “fingerprint” using mass spectroscopy, which identifies protein building blocks. Then they compared the molecular makeup of the protein with a database of known protein structures. The research team was able to conclude the protein portion of the glycoprotein was receptor tyrosine phosphatase (RPTP) zeta. Further experiments showed that the brain tissue of the five people who died with Alzheimer's disease had more than twice as much RPTP zeta S3L as the donors who did not have the disease. Implying that this glycoprotein may be connecting with more CD33 receptors than a healthy brain, limiting the brain's ability to clean up harmful proteins. Gonzalez-Gil Alvarenga, Ph.D., first author on the study stated:“Identifying this unique glycoprotein provides a step toward finding new drug targets and potentially early diagnostics for Alzheimer's disease.”   A Surprising Link Between Immune System and Hair Growth | Neuroscience News (07:36) Salk scientists have uncovered an unexpected molecular target of a common treatment for alopecia, a condition in which a person's immune system attacks their own hair follicles, causing hair loss. Corresponding author of the study, Ye Zheng, associate professor in Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis, stated:“For the longest time, regulatory T cells have been studied for how they decrease excessive immune reactions in autoimmune diseases … Now we've identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration completely separate from suppressing immune response.” Initially the researchers were interested in researching the roles of regulatory T cells and glucocorticoid hormones in autoimmune diseases.They did not function together to play a significant role in any of these conditions.  Thought they'd have more luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The scientists induced hair loss in normal mice and mice lacking glucocorticoid receptors in their regulatory T cells.After two weeks, the researchers saw the normal mice grew their hair back, while the ones lacking the receptors struggled to grow it back The findings suggested that some sort of communication must be occurring between regulatory T cells and hair follicle stem cells to allow for hair regeneration.They continued to investigate how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples. They found that glucocorticoids instruct the regulatory T cells to activate hair follicle stem cells, which leads to hair growth. Depends on a mechanism whereby glucocorticoid receptors induce production of the protein TGF-beta3, all within the regulatory T cells. TGF-beta3 then activates the hair follicle stem cells to differentiate into new hair follicles, promoting hair growth.  This study revealed that regulatory T cells and glucocorticoid hormones are not just immunosuppressants but also have a regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.     Engineers devise clever system for EVs to share charge—while driving | Anthropocene (13:34) The charging station expansion isn't keeping up with the growing number of EVs on the road.The number of EVs on the road per public charging point globally rose to 9.2 at the end of last year, from 7.4 at the end of 2020, according to a study by BloombergNEF analyst Ryan Fisher on the state of public charging infrastructure. In a new study, engineers propose a way around this conundrum: EVs that share charge with each other while driving. In their vision, cars with low batteries could buy some charge from others with extra to spare, all without stopping. Could be orchestrated via a cloud-based control system Electrical and computer engineer Prabuddha Chakraborty the University of Florida and his colleagues propose a two-battery system for EVs.A large, slow-charging lithium-ion battery would drive the car,  A smaller, fast-charging battery would be used for on-the-go charging.  Once powered up, the small battery would transfer its charge to the car's main battery.  “Just like in your computer you have fast cache memory—but it's expensive—so you have other type of high-capacity memories that are slower,” said Tamzidul Hoque, a professor of electrical engineering and computer science at the University of Kansas The cloud-based system idea:Monitor charge levels of electric cars.  If a car's power is starting to run low, the network would alert it to other cars nearby with enough charge to sell.  Once two cars are matched with owner consent, cables would connect them for charging and they would be locked at the same speed until the power transfer is complete. Yet even in a well-planned, dynamic peer charging network, the researchers found in simulations that the total charge of the network will slowly deplete.To try to get around this idea, they propose the concept of mobile charging stations: large battery-loaded trucks that would recharge multiple vehicles at once.  Like military jets being refueled in-flight by tanker aircraft.  Using popular traffic modeling software they were able to simulate their idea somewhat.They found that it would eliminate range anxiety and re-charging wait time, and reduce EV cost by eliminating the need to have big batteries.   Scientists Use Vegetable Oil Byproduct to Remove Heavy Metals From Contaminated Water | EcoWatch (20:27) Scientists from Nanyang Technological University, Singapore, collaborating with ETH Zurich, Switzerland (ETHZ), have discovered a way to turn byproduct from vegetable oil production into a membrane that filters out heavy metals from water. Ali Miserez, study author and professor at Nanyang Technological University, stated:“Water pollution remains a major global issue in many parts of the world…Heavy metals represent a large group of water pollutants that can accumulate in the human body, causing cancer and mutagenic diseases. Current technologies to remove them are energy-intensive, requiring power to operate, or are highly selective in what they filter.” The researchers noticed that proteins in peanut and sunflower oil waste byproducts, called oilseed meals, were useful in attracting heavy metal ions.Turned the oilseed meals' proteins into nano-sized protein amyloid fibrils, which strongly attract heavy metal ions.  Combined these amyloid fibrils with activated carbon and tested the filters on three types of metal: platinum, chromium and lead. The membranes were 99.89% effective at filtering out all of the heavy metals from water, with the best results for platinum and lead. The membrane made from waste byproduct proteins is a low-cost option that requires little energy for decontamination, and the researchers say this innovation could work all over the world for water purification.  “Recovering precious platinum, which costs US$33,000/kg, only requires 32 kg of protein, while recovering gold, which is worth almost US$60,000/kg, only requires 16 kg of protein. Considering that these proteins are obtained from industrial waste that is worth less than US$1/kg, there are large cost benefits,” Miserez explained. Because of the simple technology, this filtration membrane is readily scalable, according to the researchers.   Tesla launches new virtual power plant that pays Powerwall owners to help end brownouts | Electrek (25:30) Tesla has launched a new virtual power plant in partnership with PG&E in California that will pay Powerwalls owners to help stabilize the electric grid and end brownouts in California. What is a virtual power plant?Consists of distributed energy storage systems, like Tesla Powerwalls, used in concert to provide grid services and avoid the use of polluting and expensive peaker power plants. Tesla has partnered with PG&E to launch a new version of its virtual power plant that will actually compensate people participating:The company's statement: “Become a part of the largest distributed battery in the world and help keep California's energy clean and reliable. Opt-in to the Tesla Virtual Power Plant (VPP) with PG&E and your Powerwall will be dispatched when the grid needs emergency support. Through the Emergency Load Reduction Program (ELRP) pilot, you will receive $2 for every additional kWh your Powerwall delivers during an event. Adjust your Backup Reserve to set your contribution, while maintaining backup energy for outages.” Depending on the events and the number of Powerwalls homeowners have, they could earn anywhere from $10 to $60 per event or even more for bigger systems. The extra capacity your Powerwall provides could help avoid or reduce blackouts in a severe emergency. This way, Powerwall can keep the lights on for both you and your community. Tesla said that it has about 50,000 Powerwalls that could be eligible for this VPP, which add up to a significant 500 MWh of energy capacity than can be distributed in any event.

This week the TGF team sits down with, DJ DRIP for a fun conversation that really paints the picture of Drip's rise to stardom in the booming Party and Night Club scene of Chicago and its neighboring cities. We dive into topics ranging from the best clubs to play at in the city, Drip's opinion on breaking artists at his hosted nights, and how he changed his military plans to pursue his real dreams. The Fresh Flower Podcast is The Ghetto Flower's bi-weekly underground talk and debate show featuring co-hosts Michael “Trill” Tayo, Quinton “Q” Coleman, and Josue “Sway” Roman. Apple: https://podcasts.apple.com/us/podcast/tgf-project-podcast/id1435114130 Spotify: https://open.spotify.com/show/1jaqB6RKffpzCvKHOC84GE?si=8UzvJTSgSHaI-tXn1RFLRg Subscribe to The Ghetto Flower on YouTube: https://www.youtube.com/channel/UC_LSl0OB8zzkL-dJ3ZKqDvA KHALIYAH X https://twitter.com/Khaliyah_X https://www.instagram.com/khaliyah_x/ Check out more of The Ghetto Flower here: https://www.theghettoflower.com https://www.twitter.com/TheGhettoFlower https://www.instagram.com/TheGhettoFlower The Ghetto Flower was founded in 2017. It is a leading online publication and marketing agency that dives deep into the underground arts surrounding them. On The Ghetto Flower, you'll find the latest in music news, in-depth interviews, and up-to-date content marketing focused on the subculture niche. Michael “Trill” Tayo instagram.com/trilltayo twitter.com/trilltayo Quinton “Q” Coleman instagram.com/qguapo_ twitter.com/iGot_That_Kudi Josue “Sway” Roman instagram.com/tgf_sway twitter.com/TGF_Sway --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, share the latest news on immunotherapy trials KEYNOTE-A10, LIBRETTO-001, and other key IO studies across tumor types featured at the 2022 ASCO Annual Meeting.  Transcript Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology in phase 1 therapeutics, at the University of Pittsburgh's Hillman Cancer Center, and the guest host of today's podcast. I'm delighted to welcome Dr. Jason Luke to this podcast. He's the director of the Cancer Immunotherapeutic Center at the Hillman Cancer Center, University of Pittsburgh, and a great colleague and friend.  Today we'll be discussing some key posters that highlight some advances in immunotherapy that will be featured and the 2022 ASCO Annual Meeting. You will find our collective disclosures in the show notes and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  So, Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Well, thanks very much for the invitation. I always love doing these podcasts for ASCO, and never love anything more than hanging out with my friend Diwakar Davar.  Dr. Diwakar Davar: Well, thank you! Below are the abstracts we've selected. We will start with Abstract 2504. This is a phase 1 trial of the TIM-3 inhibitor cobolimab monotherapy, singly and in combination with the PD-1 inhibitors nivolumab or dostarlimab. Phase 1 data from the AMBER trial with the presenting author being Dr. Gerald Falchook. And this is a trial that initially started several years ago. And I know Jason, that you were involved with the inception of this agent, that TIM-3 inhibitor. So, walk us through, TIM-3. It's a third-generation checkpoint, we now have TIGIT LAG coming into the landscape. Definitely a first indication for LAG-3 melanoma with a positive trial, RELATIVITY 047. So, where are we with TIM-3? Why should we be excited about TIM in general, and this data in particular?  Dr. Jason Luke: It is quite exciting, especially building off the recent data that we saw for relatlimab or LAG-3 because it's becoming clearer that a number of these other immune checkpoints that we have been talking about for many years, actually really can be effective when used in the right setting.  So, this drug, this anti-TIM-3 antibody cobolimab monotherapy, as you mentioned, started out in a phase 1 clinical trial dating all the way back to I think about 2015. And that was at the time in immuno-oncology when everybody was so excited, [and] they thought everything was going to work immediately.  Subsequent to that, obviously, we've had some hurdles that we've had to come over. But we're coming back to some of these agents now, which are looking very exciting. So, just in the same way we think about blocking PD-1 or now blocking LAG-3 to reinvigorate T cells in the tumor microenvironment, there's a good chance and a high probability based on preclinical data that blocking TIM-3 could be just as effective as blocking LAG-3, so to say.  Now, one thing that I note in this abstract is really the safety finding and early PK analysis. And so, this is the important work we do early on to understand the drug. It's important to be aware that in a study like this, it's very hard to seek efficacy signals.  So, when you see this poster, really, you probably shouldn't be thinking, ‘Oh, this is a frontline phase 3 trial,' but rather that the efficacy is going to be a secondary consideration. Rather, what's quite important is looking at the properties of the drug and looking at the safety signals around that. And what we can see here is that TIM-3 appears to be quite safe when blocking it in conjunction with anti-PD-1 across several different tumor types. And that really sets the stage then to think about moving this into earlier lines of therapy across many different cancers.  And so, here we see advanced solid tumors but focused on lung cancer and melanoma and kind of the usual tumors we think about, and people can keep their eyes open because there are other posters of this molecule with PD-1 in some of the other sections outside of developmental therapeutics.  Now, one thing I would like to get your opinion on because your group has focused a lot on TIM-3, as I described it as this T cell centric mechanism to reinvigorate exhausted T cells. But it's possible that TIM-3 does other things as well. And I don't know if you want to comment on that or give any other feedback that you've had when thinking about this AMBER Trial.  Dr. Diwakar Davar: That was an excellent summary, Jason, of really what is a truncated 8-year track record of developing this agent all the way from 2015. But you bring up a very interesting point, which is: exactly what does this drug does in the non-T-cell compartment?  Some very interesting data from Brian Ruffell in a paper that was published about 3 years ago now suggested that TIM-3 was actually potentially a myeloid checkpoint, meaning that, in a tumor model in which Dr. Ruffell was studying this in the context of breast cancer, the drug primarily appeared to work on the effect of antigen-presenting cells and augment the presentation of antigen to T cells suggesting that it may be, in addition to being a chronicle T cell exhaustion marker, it may also be reinvigorating antigen-presenting cells. And the question of whether or not the role of TIM-3 on APCs as well as the role of TIM-3 on T cells, and which of these compartments are more important, and how these compartments segregate in any given cancer across many different lines of therapy will hopefully be something that we disengage, and understand a little bit better as we look at biomarkers of this drug across different settings.  And especially to that point, Jason, the biomarker question, you'll notice that very interestingly, that was a signal in which that drug had a certain response rate. Again, as you correctly point out, we cannot read too much into response rates in very small patient numbers. But very interestingly, there was a slightly higher response rate at the 300 milligrams, which is not the top dose level of the drug, and a slightly lower response rate at the ceiling dose of the drug that was tested, 900 milligrams, leading the investigators to conclude that the RP2D, was actually 300 milligrams every 3 weeks and not 900 milligrams.  What are your thoughts on dose in the context of immunotherapy (IO) drug development? And why might it be that 300 is the optimal dose as opposed to 900?  Dr. Jason Luke: That's a complicated question. I mean, when we think about checkpoint blockade, we classically think about it as only blocking on T cells. But to your point, if there are multiple mechanisms in play, sort of modulating other cell compartments actually may start to do different things at different doses that maybe weren't our primary intent as we went into the trial.  That's a little bit of hand waving, immunologic hand waving, but I think the data are the data and once we hit an effective dose level, there's really no need to really push the dose that much further. But that really emphasizes the importance of these kinds of early phase clinical trials.  So, I'm really looking forward to seeing this data. For disclosure, obviously, we have both been investigators on this trial. But we're very excited about the idea that there may be hope for a fourth checkpoint to come forward in the field beyond just PD-1 CTLA-4, and LAG-3, maybe now here with TIM-3.  Dr. Diwakar Davar: So, with that we'll go to the next abstract and that is Abstract 2516, “Phase I trial of adjuvant autogene cevumeran, an individualized mRNA neoantigen vaccine, for pancreatic ductal adenocarcinoma.”  So, this is an mRNA vaccine from our good friend, BioNTech. And that's been essentially evaluated in the context of highly lethal cancer, pancreatic ductal cancer, and specifically in the context of adjuvant vaccines, specifically in the setting of patients who had followed definitive pancreatic cancer surgery.  So, Jason, you know a lot of neoantigen vaccines, you've led some of these trials, really, the neoantigen vaccine is really the primary reason we are actually having an in-person meeting this year, because if not for this company and others like this, really this pandemic would not be behind us.  What are your thoughts on the role of neoantigen vaccines in cancer therapeutics, and also, particularly this particular trial in the data, the immunological data, and the clinical data regarding the development of neoantigen-specific T cells in this setting, and what this means for you?  Dr. Jason Luke: Right. So, the idea of targeting neoantigens as cancer immunotherapy was really all the rage a few years back, and it was thought based on preclinical animal models that this was just going to be the secret sauce, and this would be the new targeted therapy for immunotherapy. And it isn't to say that that's not true, but the first generation of neoantigen, peptide-based vaccines for the most part, unfortunately, just kind of didn't end up moving the needle the way we had hoped.  The question then was raised: is that because targeting neoantigens isn't reasonable, or is that because the setting where we were trying to do it in the refractory disease area was not the optimal way to leverage this?  And so, a couple of different companies and trials now are coming forward looking at targeting neoantigen in a minimal residual disease setting where the idea could be that immunologic responses that you could generate wouldn't be hampered by all the immunosuppression associated with the tumor microenvironment.  And so, here we have this molecule, which you eloquently pronounced, ‘autogene cevumeran.' It's an RNA-lipoplex neoantigen vaccine. So, it's not a peptide. It's more like the COVID-19 vaccines actually. And it's being given after surgery, followed by anti-PD-L1 followed by chemotherapy.  So, it's a complicated regimen, but it's very intriguing these early data, which do show that the patients who got the vaccine seemed to have better and longer-term outcomes. But then as you emphasize, really, I think probably what's at the heart of this that really makes it exciting is their ability to immune monitor the patients, meaning to look for antigen-specific immune cells from the peripheral blood in these patients to be able to identify those immune responses as being specific to cancer. Because this kind of a clinical trial, it's still signal seeking and proof of concept kind of trial.  In order to actually establish that a vaccine approach in a post-surgical setting would have efficacy, we need to do a large randomized trial. And so, this is not that yet. But I think these data really point in the direction that that could be a reasonable thing to try. And when you think about pancreatic cancer, where we've made no success with immunotherapy, really in a meaningful way in terms of checkpoint blockade, at least, that's pretty exciting actually to think about.  I would actually marry this dataset with another that we actually saw at the American Association for Cancer Research (AACR) meeting that also looked at neoantigen targeting and antigen-specific responses in colorectal cancer, again, and in a similar setting with the minimal residual disease setting.  And so, I think this highlights that we may need to start thinking about using immunotherapy in different ways than we had before. Obviously, everybody knows about using PD-1 blockade in lots of different cancer types that are really for metastatic disease, or maybe even for adjuvant now in melanoma a little bit. But maybe there's this space, which is the minimal residual disease setting where you might be able to detect by ctDNA after surgery, the patients are still positive. And maybe you could treat that before there's visible cancer, and maybe certain immunotherapies could be more valuable in that setting than others. And that's where I think maybe some of these mRNA technologies really might find their sweet spot.  So, coming back to this abstract, I think really, the emphasis point here is the novelty of generating patient-specific neoantigen vaccines, and then being able to track linearly over time the immune response against those vaccines.  I think with that kind of technology and being able to leverage that, I think we're really headed towards a real shift in the way we think about managing cancer in a post-surgical setting, again, thinking about MRD, or minimal residual disease, maybe in a way that our leukemia colleagues have been thinking it about for a long time.  Dr. Diwakar Davar: That's an excellent summary of a very, very complicated, both setting, and in this case, a therapeutic landscape. So, well said, well summarized, and we'll now pivot to Abstract 2514. So, this is ‘Efficacy and safety of NT-I7, long-acting interleukin-7, plus pembrolizumab in patients with advanced solid tumors: Results from the phase 2a study' [and] the presenting author is Dr. Aung Naing from [The University of Texas] MD Anderson [Cancer Center].  So, Jason, you know, with checkpoints, we've got so many thoughts about checkpoints, particularly given the rather unfortunate failure of BEMPEG in the context of melanoma.  So, we've got lots of interesting cytokines that we think of as important in the context of immuno-oncology 2, certainly 12, 15. You've been very involved with IO-15. We've got a lot of clinical trials studying IL-12. And now we've got one studying IL-7. So, tell us what do you think of this IL-7 targeting approach in the context of cytokine-based therapeutics?  Dr. Jason Luke: I think it's really important to emphasize on first principles, for those that are listening, who don't think about immunology all the time that not all cytokines are the same thing.  So, interleukin 2 that many people have heard of is very different actually than interferon. And that's very different from many of the other cytokines, the ILs, and everything, right?  So, IL-7 is a very potent cytokine that's associated with the expansion of immune responses, and that can drive interferon gamma-dependent effects. And you should hear whenever I say interferon-gamma is sort of a link through to PD-1 responsiveness. Because we think the mechanism that underpins anti-PD-1 effectiveness in patients really is interferon gamma biology.  So, IL-7 has been a molecule, it's been of a lot of interest but really was too toxic to try to deliver. But now we have novel drug delivery sorts of approaches that are being developed to try to bring the drug in, in a way that doesn't cause such systemic toxicity.  So, in this clinical trial, this NT-I7 molecule is given intramuscularly, every 6 weeks in conjunction with pembrolizumab, and very interestingly, in a small number of patients, but there were resist responses observed across a series of tumors that you really wouldn't expect should be responsive in any way to pembrolizumab alone. And so, we're talking about microsatellite stable colorectal cancer, pancreatic cancer, and some others as well.  And in conjunction with that, they were able to identify some of the biomarker effects we would think we would see with IL-7, such as expansion of peripheral immune compartments. And the toxicity profile was really consistent with what we've seen with fevers and chills, but manageable in a way that previous approaches really weren't.  So, I think this is really exciting because I think the idea here then is with this IL-7 approach, we might expand the kinds of cancers that we could go after, in conjunction with anti-PD-1 again, pancreas, colorectal cancer. I think that's really where the unmet need lies in oncology.  So, I really applaud these kinds of approaches and several of these cytokine approaches, and what we're going to talk about them, I think, have the potential to do that over the next couple of years.  Dr. Diwakar Davar: Excellent! Pivoting now to a different cytokine, but one that was alluded to before IL-12. So, Abstract 2518 is ‘Phase II evaluation of the combination of PDS0101, M9241, and bintrafusp alfa in patients with HPV 16+ malignancies,' and the presenting author here is Dr. Julius Strauss of the NCI Cancer Center and the Clinical Center of the National Cancer Institute at the National Institutes of Health.  So, what do you think, Jason, about the role of the HPV targeting vaccine, in this case, that was added to IL-12 immune-cytokine and bintrafusp alpha contextualizing the recent data that we have of bintra along with what is a very interesting result here?  Dr. Jason Luke: Yes, I think building on the last abstract where we talked about IL-7 as some novel biology now we move to IL-12, which again introduces other biology. So, interleukin-12 is a complicated cytokine, but one that's strongly associated with initial immune responses or immune priming, as well as enhancement of anti-tumor effects in the tumor microenvironment.  So, here we have sort of a 3-legged approach. So, the vaccination approach against HPV really can generate a strong immune response initially, and that can be supported with the IL-12. And then you come in with anti-PD-L1 and to whatever extent the TGF data is relevant here. And so, you have this cocktail where you're generating tumor-specific responses with a vaccine, you're supporting them with IL-12, and then blocking PD-L1.  And as we go back even a couple of abstracts we talked about, now we sort of have a cocktail right of approaches. And so, I think this is very exciting. It's unique in that, in these tumors, obviously, HPV is the driving force of cancer. So, developing a vaccine against that is fairly straightforward. But I really like this concept of bringing forward sort of a multi-dimensional immunotherapy approach. And we'll note they have previously presented data on this trial, I think last year at ASCO, actually. But what they see are pretty strong response rates, almost 30% range in PD-1 refractory tumors.  Again, that's our area of really high unmet need. It's hard to read through how useful a PD-1 naive treated patient here, although the response rates were high. But to me, it's really those patients who had progressed on PD-1 where they're getting these responses that tells me that this really could be something that's useful and potentially could be expanded beyond just say head neck cancer to any HPV relevant malignancy.  Dr. Diwakar Davar: Excellent! Now on to our last abstract. Abstract 2520, ‘Effect of intratumoral INT230-6 on tumor necrosis and promotion of a systemic immune response: Results from a multicenter phase 1/2 study of solid tumors with and without pembrolizumab (PEM) [Intensity IT-01; Merck KEYNOTE-A10].' The first author is Dr. Jacob Thomas.  Jason, we've seen a lot of interesting intratumoral therapies. You and I have both done a lot of studies in looking at intratumoral agents from toll-like receptor agonists, TLR-9, TLR 7-8, and more recently, oncolytic viruses.  So, contextualizing IT230-6 in the spectrum of intratumoral therapies, how do you feel about this drug, which is actually a very interesting novel drug. It's not just a TLR agonist, or for that matter, an OV, very interestingly, it's an intratumoral therapy that has actually got chemotherapy in it. So, how do you feel about this drug? How do you feel about the responses that we've seen? And particularly how do you feel about the setting in neoadjuvant breast cancer?  Dr. Jason Luke: Yeah. I would pick up where you said that this drug INT230-6 is just a really interesting concoction. So, it's cisplatin mixed with vinblastine, in a specific amphiphilic molecule that allows it to diffuse in through the cancer.  And so, if you had said that to me a few years ago, I would have looked at you and been like, ‘What are you talking about?' But I think the data that's been emerging for this is just really interesting because something about this chemotherapy cocktail actually drives immune responses. And really what the focus of this abstract is on is showing that you get an influx of CD foreign CDTa cells into the tumor microenvironment that's associated with a therapeutic benefit.  I think that's just really, really interesting to think about. It sort of makes one wonder when we're doing these intratumoral injections, how much of it is just the injection, and how much of it is the therapeutic agent, but I think it's a really novel therapy, and one that appears to be very well tolerated as well. And that's also the exciting part. When you hear cisplatin and vinblastine, you think, ‘Oh, well, that's not going to work.'  But apparently, it stays right in the tumor and generates these immune effects. I think it's very exciting. I think their approach here—going after what we usually call cold tumors, ones that don't respond to immunotherapy, you mentioned breast cancer—I think it's really interesting. I'm really looking forward to seeing the actual data from this abstract because, on first pass, it wouldn't have been what I thought about in terms of driving immune responses, but maybe it just goes to show that there's a lot more to understand there about immunogenic cell death and some of these other concepts that we bandy about. But I think this will be one of the most interesting abstracts actually to see the data for once it's available.  Dr. Diwakar Davar: Great! Taking a slight pivot from that. You've been involved in the development of novel response endpoints. One of the issues that we have with intratumoral therapies is that you're measuring a lesion that you inject, so now you inject something and it gets a little bigger. Is it getting bigger because it's growing? Is it getting bigger because the drug is working? We don't know. We have now itRECIST, which you have been working on.  What's very interesting is that whether you look at itRECIST, or RECIST, irRECIST, or imRECIST, when you have the monopoly of different response endpoints we have to deal with these days, these patients have monotherapy responses in non-injected tumors. How do you feel about that as a drug developer and somebody who's giving patients drugs like that? What is your impression of having shrinkage in the non-injected tumor?  Dr. Jason Luke: I think it's really exciting about this concept of the abscopal effect that we've bandied about for years. Despite being an investigator in this space, I'm really excited to actually see the data and to understand what these out of field responses are. If it's really true that this is robust, I mean, it could potentially be like a game-changer kind of thing. But I'll reserve judgment until I see the actual scans of the tumors that actually shrank that weren't injected.  Dr. Diwakar Davar: Fantastic insights, Jason. So, thank you for taking the time to join us on this podcast and to highlight these extraordinarily important advances in immunotherapy.  Dr. Jason Luke: I appreciate the opportunity to participate today.  Dr. Diwakar Davar: So, thank you, and thank you to our listeners for your time today, you will find the links to the abstracts that we discussed today in the transcript of the episode.  Finally, if you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate review and subscribe wherever you get your podcasts.  So, thank you, Jason. And thank you to the team for putting this together.      Disclosures:   Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Shionogi (Immediate Family Member), Vedanta Biosciences  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, Zucero Therapeutics (Inst), GSK, Merck, Arcus Biosciences  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231, and Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, Stipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences , Hotspot Therapeutics, SERVIER , STINGthera, Synthekine  Research Funding (Inst): Merck, Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  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. 

The Fresh Flower Podcast is The Ghetto Flower's bi-weekly underground talk and debate show featuring co-hosts Michael “Trill” Tayo, Quinton “Q” Coleman, and Josue “Sway” Roman. This week the TGF team sits down with Chicago's own, singer, songwriter, and entertainer, artist Khaliyah X for a deep conversation that really tells the story of her upbringing and shines a light on her musical family background. We flow into topics ranging from the purpose of her stage name, to her inspirations early on growing up in Chicago, how her family influenced her musical talents, and even down to the topic of Kanye West and the Chicago music scene back in the late 80s and early 90s. Apple: https://podcasts.apple.com/us/podcast/tgf-project-podcast/id1435114130 Spotify: https://open.spotify.com/show/1jaqB6RKffpzCvKHOC84GE?si=8UzvJTSgSHaI-tXn1RFLRg Subscribe to The Ghetto Flower on YouTube: https://www.youtube.com/channel/UC_LSl0OB8zzkL-dJ3ZKqDvA KHALIYAH X https://twitter.com/Khaliyah_X https://www.instagram.com/khaliyah_x/ Check out more of The Ghetto Flower here: https://www.theghettoflower.com https://www.twitter.com/TheGhettoFlower https://www.instagram.com/TheGhettoFlower The Ghetto Flower was founded in 2017. It is a leading online publication and marketing agency that dives deep into the underground arts surrounding them. On The Ghetto Flower, you'll find the latest in music news, in-depth interviews, and up-to-date content marketing focused on the subculture niche. Michael “Trill” Tayo instagram.com/trilltayo twitter.com/trilltayo Quinton “Q” Coleman instagram.com/qguapo_ twitter.com/iGot_That_Kudi Josue “Sway” Roman instagram.com/tgf_sway twitter.com/TGF_Sway --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app

We are BACK! This is the first show in the new time era of P.M. (Post-Myke) so I had to bring in some solid folks to begin our next phase of TGF. Ana Mendoza and Greg Mucino joined to share their toughts on HBO's Euphoria Season 2. This is a spoiler filled review so if you haven't seen Euphoria stop at (23:40) but jump back in at (1:01:45). We talk what other shows that keep our butts on the couch.