Podcasts about micrornas

Send a textGene regulation through RNAs, the neurobiology of opioid addiction, and how psychedelics affect drug-seeking by modulating inflammation and plasticity. Not medical advice.TOPICS DISCUSSED:Gene regulation basics: DNA transcribes to RNAs, including non-coding types like microRNAs that inhibit mRNA translation into proteins, influencing up to 60% of the proteome.Non-coding RNAs in neuroplasticity: MicroRNAs and circular RNAs regulate synaptic changes, with activity-induced ones like miR-485-5p linked to rapid responses in drug cue memory and addiction reinforcement.Opioid addiction models: Rats self-administer heroin or fentanyl via levers, showing compulsive seeking; fentanyl's higher potency drives faster learning but similar long-term effects to heroin when doses are equated.Differences between opioids: Heroin and fentanyl both activate mu-opioid receptors for euphoria and dopamine release, but fentanyl lingers longer; no major behavioral differences in seeking once potency is matched.Psilocybin's effects on addiction: A single psilocybin dose post-abstinence reduces heroin-seeking in rats by dampening neuroinflammation in brain regions like the nucleus accumbens and prefrontal cortex.Brain Inflammation: Opioids induce pro-inflammatory changes via cytokines like IL-17A and pathways like TNF-alpha, leading to glial activation and blood-brain barrier leaks; psilocybin counters this.MicroRNA biomarkers: Blood microRNAs reflect gene expression patterns tied to disease states, with potential to predict opioid relapse risk, treatment response, or neonatal withdrawal severity non-invasively.Future research: Ongoing work links psilocybin's serotonin 2A activation to anti-inflammatory gene changes, plus human studies on microRNAs for personalized addiction treatments.ABOUT THE GUEST: Stephanie Daws, PhD is an associate professor at Temple University in the Center for Substance Abuse Research and Department of Neurosciences, where she researches mechanisms of drug-seeking behavior with a focus on opioids and psychedelics.RELATED EPISODE:M&M 2 | Psilocybin, LSD, Ketamine, InflamSupport the showHealth Products by M&M Partners: SporesMD: Premium mushrooms products (gourmet mushrooms, nootropics, research). Use code 'nickjikomes' for 20% off. Lumen device: Optimize your metabolism for weight loss or athletic performance. MINDMATTER gets you 15% off. AquaTru: Water filtration devices that remove microplastics, metals, bacteria, and more from your drinking water. Through link, $100 off AquaTru Carafe, Classic & Under Sink Units; $300 off Freestanding models. Seed Oil Scout: Find restaurants with seed oil-free options, scan food products to see what they're hiding, with this easy-to-use mobile app. KetoCitra—Ketone body BHB + electrolytes formulated for kidney health. Use code MIND20 for 20% off any subscription (cancel anytime) For all the ways you can support my efforts

How do breakthroughs in the lab become real-world treatments that save lives? In this episode, Professor Stephen Maher of Trinity College Dublin joins us to discuss the rapidly evolving field of translational oncology and how cutting-edge research is shaping the future of cancer therapy. As a leading expert in radiation research and Director of Postgraduate Studies for the School of Medicine at Trinity, Stephen focuses on a critical question: why do some cancers respond to treatment while others resist it? His work examines the role of microRNAs, tumor hypoxia, and DNA damage response in shaping how cancers react to chemotherapy and radiotherapy — with particular attention to oesophageal and pancreatic cancers. In this episode, we explore: ·       Where anti-cancer therapeutics are headed in the coming years ·       How radiation research is evolving to improve treatment precision ·       Why translational oncology is essential for turning discovery into patient care ·       How treatment resistance forms — and what researchers are doing to overcome it After earning his Ph.D. in Oncology at RCSI and completing a fellowship at the National Cancer Institute in Maryland, Professor Maher has dedicated his career to bridging the gap between scientific discovery and clinical impact. He leads major national and international collaborations and has helped build advanced radiotherapy and hypoxia research programs at Trinity's Translational Medicine Institute. Learn more about Professor Maher and his work here. Episode also available on Apple Podcasts: https://apple.co/38oMlMr 

Host Parag Mallick chats with Professor Afshin Beheshti who is a Professor of Surgery, Director of the Center for Space Biomedicine, and Associate Director of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh. In addition, Professor Beheshti has a visiting researcher appointment at the Broad Institute of MIT and Harvard and is president of two non-profits – the COVID-19 International Research Team and Kwaai. The latter aims to democratize access to artificial intelligence through the design, construction, and maintenance of a free personal AI called Kwaai.Professor Beheshti's research covers a range of topics focused on how circulating mirco RNAs and mitochondria impact health, but this conversation focuses primarily on Professor Beheshti's work advancing our understanding of how spaceflight impacts biology. We cover:How research on spaceflight and biology is doneGaps that remain in our understanding of spaceflight and biologyOmics studies of spaceflight and biologyHow studying spaceflight and biology enhances our understanding of human health more broadlyResourcesTrivedi Institute for Space and Global BiomedicineNew Institute at the University of Pittsburgh focused on “advancing human health through space-driven innovation”NASA Open Science Data Repository"Provides open access to biological and physical science datasets from spaceflight and ground studies, enabling data reuse for discovery and innovation."Camera et al., 2024. Agining and putative frailty biomarkers are altered by spaceflightStudy on molecular biomarkers and frailty phenotypes in spaceOverbey et al., 2024. The Space Omics and Medical Atlas (SOMA) and international astronaut biobankAn “integrated data and sample repository for clinical, cellular, and multi-omic research profiles” from a variety of space missionsSpace Omics and Medical Atlas (SOMA) websiteCorti et al., 2024. To boldly go where no microRNAs have gone before: spaceflight impact on risk for small-for-gestational-age infantsExplores how miRNA signatures of “small-for-gestational-age” are impacted by the space environmentBeheshti et al., 2013. Age and space irradiation modulate tumor progression: implications for carcinogenesis riskSome of Professor Beheshti's early...

Many listeners asked us to go deeper into exosomes, and this episode expands on everything that most brands avoid talking about: count, consistency, purity, and microRNA composition. We explain why exosomes on a label don't mean much without verified numbers, and how dose shapes whether the skin actually receives a biologically meaningful message.We walk through why platelet-derived exosomes offer the clearest communication to human skin, why microRNAs matter more than growth factors alone, and how publishing full sequencing data creates a new standard for transparency in longevity skincare. We also explore the synergy between exosomes and NAD+, how cellular energy drives repair, and why combining messenger and fuel creates a regenerative loop the skin can sustain.This episode gives listeners a clear, science-driven understanding of how exosome formulas should be evaluated and what truly defines high-performance regenerative skincare.As founders of Young Goose Skincare, we focus on bringing advanced longevity science into daily routines through transparency, validated potency, and clinically guided innovation.We Also Discuss:(00:19) Why “Exosomes on the Label” Tells You Almost Nothing(01:48) The Dose Problem: How Most Exosome Serums Miss Biological Activity(03:11) Why microRNA is the Real Engine Behind Skin Repair(05:16) The Transparency Gap in Skincare, and How We're Closing It(09:21) Exosomes as Messages, NAD+ as the Battery(12:21) Clearing Senescent Cells and Restoring Youthful FunctionFind more from Young Goose:VAMPIRE EXOSOMES → Professional Exosome Serum for Regeneration and Post-Treatment Recovery → Vampire ExosomesUse code PODCAST10 to get 10% off your first purchase, and if you're a returning customer use the code PODCAST5 to get 5% off at https://www.younggoose.com/ Instagram: @young_goose_skincare

BUFFALO, NY - December 17, 2025 – A new #research paper was #published in Oncotarget (Volume 16) on December 15, 2025, titled “Machine learning-based survival prediction in colorectal cancer combining clinical and biological features.” In this study, led by Lucas M. Vieira from the University of Brasília and the University of California San Diego, researchers used machine learning to predict survival in patients with colorectal cancer. They built a model by combining biological markers with clinical data. This approach could help improve prognosis and guide treatment strategies for one of the world's most common and deadly cancers. The team analyzed data from over 500 patients, using clinical details such as age, chemotherapy status, and cancer stage, along with molecular features like gene expression and microRNAs. Their goal was to improve how clinicians identify high-risk patients and make outcome predictions more precise. Researchers evaluated three different patient data scenarios using different machine learning techniques. The best-performing was an adaptive boosting model, which achieved 89.58% accuracy. This approach showed that integrating clinical and biological data led to significantly better predictions than using either data type alone. Among the biological markers, the gene E2F8 was consistently influential in all patient groups and is known to play a role in tumor growth. Other important markers included WDR77 and hsa-miR-495-3p, which are also associated with cancer development. Key clinical predictors included cancer stage, patient age, lymph node involvement, and whether chemotherapy was administered. “The proposed method combines biological and clinical features to predict patient survival, using as input data from patients from the United States, available in the TCGA database.” Unlike earlier models that relied on either clinical or molecular data alone, this study demonstrates the added value of combining both. Ensemble methods, which merge multiple learning algorithms, provided more stable and consistent results across all patient groups tested. These research findings could lead to new tools that help clinicians better predict how a patient's disease might progress or respond to treatment. The study also highlights the importance of collecting complete clinical information, such as lifestyle factors, which were missing from the dataset but could enhance future predictions. Overall, the study demonstrated how machine learning can support more accurate and personalized survival predictions in colorectal cancer. It also points to potential future research on markers like E2F8, which may be useful for monitoring or targeted therapy. DOI - https://doi.org/10.18632/oncotarget.28783 Correspondence to - Lucas M. Vieira - lvieira@health.ucsd.edu Abstract video - https://www.youtube.com/watch?v=cy7UL5ZUKuI Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28783 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, colorectal cancer, machine learning, feature selection, non-coding RNAs, genes To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us on social media: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Send us a textIn this episode of Vet Life Reimagined, Dr. Eve Hanks, BVM&S, CertAVP (EM), PhD, FRCVS, takes us inside the emerging world of microRNA diagnostics, a technology that could transform how veterinarians detect and manage disease across species.Dr. Hanks' journey is remarkable: from becoming a single mom at 19, to mixed animal practice, to discovering a passion for research, and ultimately founding MiRNA, a biotech company advancing early-detection diagnostics in animals.Eve explains what microRNAs are, why they represent a major leap forward in precision medicine, and how this technology may allow veterinarians to identify chronic disease earlier and improve outcomes for both companion and production animals. She also shares honest insights about leadership, resilience, and what it really takes to build a mission-driven company from the ground up.This conversation blends science, innovation, and career inspiration — a must-listen for anyone curious about the future of veterinary medicine.Resources:Episode on YouTubeMiRNA websiteMiRNA on LinkedInGet your gift guide here. Support the showMore Vet Life Reimagined?

Dr. Pedro Barata and Dr. Aditya Bagrodia discuss the evolving landscape of testicular cancer survivorship, the impact of treatment-related complications, and management strategies to optimize long-term outcomes and quality of life. TRANSCRIPT:  Dr. Pedro Barata: Hello and welcome to By the Book, a podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book. I'm Dr. Pedro Barata. I'm a medical oncologist at University Hospitals Seidman Cancer Center and associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also an associate editor of the ASCO Educational Book. We all know that testicular cancer is a rare but highly curable malignancy that mainly affects young men. Multimodal advances in therapy have resulted in excellent cancer specific survival, but testicular cancer survivors face significant long term treatment related toxicities which affect their quality of life and require surveillance and management. With that, I'm very happy today to be joined by Dr. Aditya Bagrodia, a urologic oncologist, professor, and the GU Disease Team lead at UC San Diego[KI1]  Health, and also the lead author of the recently published paper in the ASCO Educational Book titled, "Key Updates in Testicular Cancer: Optimizing Survivorship and Survival." And he's also the host of the world-renowned BackTable Urology Podcast. Dr. Bagrodia, I'm so happy that you're joining us today. Welcome. Dr. Aditya Bagrodia: Thanks, Pedro. Absolutely a pleasure to be here. Really appreciate the opportunity. Dr. Pedro Barata: Absolutely.  So, just to say that our full disclosures are available in the transcript of this episode.  Let's get things started. I'm really excited to talk about this. I'm biased, I do treat testicular cancer among other GU malignancies and so it's a really, really important topic that we face every day, right? Fortunately, for most of these patients, we're able to cure them. But it always comes up the question, "What now? You know, scans, management, cardio oncology, what survivorship programs we have in place? Are we addressing the different survivorship piece, psychology, fertility, et cetera?" So, we'll try to capture all of that today. Aditya, congrats again, you did a fantastic job putting together the insights and thoughts and what we know today about this important topic. And so, let's get focused specifically about what happens when patients get cured. So, many of us, in many centers, were fortunate enough to have these survivorship programs together, but I find that sometimes from talking to colleagues, they're not exactly the same thing and they don't mean the same thing to different people, to different institutions, right? So, first things first. What do you tell a patient perhaps when they ask you, "What can happen to me now that I'm done with treatment for testicular cancer?" Whether it's chemotherapy or just surgery or even radiation therapy? "So, what about the long term? What should I expect, Doctor, that might happen to me in the long run?" Dr. Aditya Bagrodia: Totally. I mean, I think that question's really front and center, Pedro, and really appreciate you all highlighting this topic. It was an absolute honor to work with true thought leaders and the survivorship bit of it is front and center, in my opinion. It's really the focus, you know, we, generally speaking should be able to cure these young men, but it's the 10, 15, 20 years down the way that they're going to largely contend with. The conversation really begins at diagnosis, pre-education. Fortunately, the bulk of patients that present are those with stage one disease, and even very basic things like before orchiectomy, talking about a prosthetic; we know that that can impact body image and self esteem, whether or not they decide to receive it or not. Actually, just being offered a prosthetic is important and this is something, you know, for any urologist, it's kind of critical. To discussing fertility elements to this, taking your time to examine the contralateral testicle, ask about fertility problems, issues, concerns, offer sperm banking, even in the context of a completely normal contralateral testicle, I think these things are quite important.  So if it's somebody with stage one disease, you know, without going too far down discussing adjuvant therapy and so forth, I will start the conversation with, "You know, the testes do largely two things. They make testosterone and they make sperm." By and large, patients are going to be able to have acceptable levels of testosterone, adequate sperm parameters to maintain kind of a normal gonadal state and to naturally conceive, should that be something they're interested in. However, there's still going to be, depending on what resource you look at, somewhere in the order of 10-30% that are going to have issues. Where I think for the stage one patients, it's really incumbent upon us is actually to not wait for them to discuss their concerns, particularly with testosterone, which many times can be a little bit vague, but to proactively ask about it every time. Libido, erectile quality, muscle mass maintenance, energy, fatigue. All of these are kind of associated symptoms of hypogonadism. But for a lot of kids 18-20 years old, it's going to be something insidious that they don't think about. So, for the stage one patients, it absolutely starts with gonadal function. If they are stage two getting surgery, I think the counseling really needs to center around a possibility for ejaculatory dysfunction. Now, for a chemotherapy-naive, nerve-sparing RPLND, generally these days we should be able to preserve ejaculatory function at high volume centers, but you still want to bring that up and again kind of touch base on thinking about sperm banking and so forth before the operation, scars, those are things I think worth talking about, small risk of ascites. Then, I think the intensity of potential long term adverse effects really ramps up when we're talking about systemic therapy, chemotherapy. And then there's of course some radiation therapy specific elements that come up. So, for the chemotherapy bits of it, I really think this is going to be something that can be a complete multi-system affected intervention. So, anxiety, depression, our group has actually shown using some population resources that even suicidality can be increased among patients that have been treated for germ cell tumor. You know, really from the top down, tinnitus, hearing changes, those are things that we need to ask about at every appointment. Neuropathy, sexual health, that we kind of talked about, including ED (erectile dysfunction), vertigo, dizziness, Raynaud's phenomenon, these are kind of more the symptoms that I think we need to inquire about every time. And what we do here and I think at a lot of survivorship programs is use kind of a battery of validated instruments, germ cell tumor specific, platinum treated patient specific. So we use a combination of EORTC questions and PROMIS questions, which actually serves as like a review of systems for the patient, also as a research element. We review that and then depending on what might be going on, we can dig into that further, get them over to colleagues in audiology or psychology, et cetera.  And then of course, screening for the hypertension, hyperlipidemia, metabolic syndrome with basically you or myself or somebody kind of like us serving, many times it's the role of the PCP, just making sure we're checking out, you know, CBC, CMP, et cetera, lipid parameters to screen for those kind of cardiac associated issues along with secondary malignancies. Dr. Pedro Barata: So that's super comprehensive and thorough. Thank you so much. Actually, I love how you break it down in a simple way. Two functions of the testes, produce testosterone and then, you know, the problem related to that is the hypogonadism, and then the second, as you mentioned, produce sperm and of course related to the fertility issues with that.  So, let's start with the first one that you mentioned. So, you do cite that in your paper, around 5-10% of men end up getting, developing hypogonadism, maybe clinical when they present with symptoms, maybe subclinical. So, I'm wondering, for our audience, what kind of recommendations we would give for addressing that or kind of thinking of that? How often are you ordering those tests? And then, when you're thinking about testosterone replacement therapy, is that something you do immediately or are there any guidelines into context that? How do you approach that? Dr. Aditya Bagrodia: So, just a bit more on digging into it even in terms of the questions to ask, you know, "Do you have any decrease in sexual drive? Any erectile dysfunction? Are your morning erections still taking place? Has the ejaculate volume changed? Physically, muscle mass, strength? Have you been putting on weight? Have you noticed increase in body fat?" And sometimes this is complicated because there's some anxiety that comes along with a cancer diagnosis when you're 20, 30 years old, multifactorial, hair loss, hot flashes, irritability. Sometimes they'll, you know, literally they'll say, "You know, my significant other or partners noticed that I'm really just a little bit labile." So I think, you know, there's the symptoms and then checking, usually kind of a gonadal panel, FSH, LH, free and total testosterone, sex hormone binding globulin, that's going to be typically pretty comprehensive. So if you've got symptoms plus some laboratory work, and ideally that pre-orchiectomy testosterone gives you some delta. If they started out at an 800, 900, now they're 400, that might be a big change for them. And then, when you talk about TRT (Testosterone Replacement Therapy) recommendations, you know, Pedro, yourself, myself, we're kind of lucky to be at academic centers and we've got men's health colleagues that are ultra experts, but at a high level, I would say that a lot of the TRT options center around fertility goals. Exogenous testosterone treats the low T, but it does suppress gonadal function, including spermatogenesis. So if that's not a priority, they can just get TRT. It should be done under the care of a urologist, a men's health, an endocrinologist, where we're checking liver chemistries and CBCs and a PSA and so forth. If they're interested in fertility preservation, then I would say engaging an endocrinologist, men's health expert is important. There's medications even like hCG, Clomid, which works centrally and stimulate the gonadal access. Niche scenarios where they might want standard TRT now, and then down the way, 5, 7 years, they're thinking about coming off of that for fertility purposes, I think that's really where you want to have an expert involved because there's quite a bit of nuance there in recovery of actual spermatogenesis and so forth.  To kind of summarize, you got to ask about it. Checking it is, is not overly complicated. We do a baseline pre-orchiectomy and at least once annually, you can tag it in with the tumor markers, so it's not an extra blood draw. And if they have symptoms of course, kind of developed, then we'll move that up in the evaluation. Dr. Pedro Barata: Got it. And you also touch base on the fertility angle, which is truly important. And I'm just curious, you know, a lot of times many of us might see one, two patients a year, right, and we forget these protocols and what we've got to do about that.  And so I'm interested to hear your thoughts about when you think about fertility, and how proactive you get. In other words, who do you refer for the fertility clinic, for a fertility preservation program? You know, do all cases despite getting through orchiectomy or just the cases that you're going to, you know you're going to seek chemotherapy at some point? What kind of selection or it depends on the chemo, like how do you do that assessment about the referral for preservation program that you might have available at UCSD? Dr. Aditya Bagrodia: Yeah, I mean I feel really fortunate to sit on the NCCN Testis Cancer Guidelines. It's in there that fertility counseling should be discussed prior to orchiectomy. So 100% bring it up. If there are risk factors, undescended testicles, previous history of fertility concerns, atrophic contralateral testicle, anything on the ultrasound like microlithiasis in the contralateral testicle, you kind of wanna get it there. And then again, there's kind of niche scenarios where you're really worried, maybe get a semen analysis and it doesn't look that good, arrange for the time of orchiectomy to have onco-testicular sperm extraction from the, quote unquote, "normal" testis parenchyma. You know, I think you have to be kind of prepared to go that route and really make sure you're doing this completely comprehensively.  So pre-orchiectomy all patients. Don't really push for it too hard if they've got a contralateral testicle, if they've had no issues having children. There's some cost associated with this, sperm banking still isn't kind of covered even in the context of men with cancer. If they've got risk factors, absolutely pre-orchiectomy. Pre-RPLND, even though the rates of ejaculatory dysfunction at a high-volume center should be low single digits, I'll still offer it. That'd be a real catastrophe if they were in that small proportion of patients and now they're going to be reliant on things like intrauterine insemination, where it becomes quite expensive.  Pre-chemo, everybody. That's basically a standard these days where it should be discussed and it's kind of amazing currently, even if you don't have an accessible men's health fertility clinic, there are actually companies, I have no vested interest, Fellow is one such company where you can actually create an account, receive a FedEx semen analysis and cryopreservation kit, send it back in, and all CLIA certified, it's based out of California. The gentleman that runs it, is a urologist and very, very bright guy who's done a lot of great stuff for testis cancer. So, even for patients that are kind of in extremis at the hospital that kind of need to get going like yesterday, we still discuss it. We've got some mechanisms in place to either have them take a semen analysis over to our Men's Health clinic or send it off to Fellow, which I think is pretty cool and that even extends to some of our younger adolescent patients where going to a clinic and providing a sample might be tricky.  So, I think bringing it up every stage, anytime there's an intervention that might be offered, orchiectomy, chemo, surgery, radiation, it's kind of incumbent on us to discuss it. Dr. Pedro Barata: Gotcha. That's super helpful. And you also touch base on another angle, which is the psychosocial angle around this. You mentioned suicidal rates, you mentioned anxiety, perhaps depression in some cases as well as chronic fatigue, not necessarily just because of the low testosterone that you can get, but also from a psychological perspective. I'm curious, what do the recommendations look like for that? Do these patients need to see a social worker or a psychologist, or do they need to answer a screening test every time they come to see us and then based on that, we kind of escalate, take the next steps according to that? Do they see a psychologist perhaps every so often? How should that be managed and addressed? Dr. Aditya Bagrodia: It's an excellent question and again, these can be rather insidious symptoms where if you don't really dig in and inquire, they can be glossed over. I mean, how easy to say, "Your markers look okay, your scans look okay. See you in six months," and keep it kind of brief. First off, I think bringing it up proactively and normalizing it, that, "This may be something that you experience. Many people do, you're not alone, there's nothing kind of wrong with you." I also think that this is an area where support groups can be incredibly useful. We host the Testicular Cancer Awareness Foundation support group here. They'll talk about chemo brain or just like a little bit of an adjustment disorder after their diagnosis. Support groups, I think are critical. As I mentioned, we have a survivorship program that's led by a combination of our med oncs, myself on the uro-onc side, as well as APPs, where we are systematically asking about essentially the whole litany of issues that may arise, including psychosocial, anxiety, depression, suicidality. And we've got a nice kind of fast path into our cancer center support services for these young men to meet with a psychologist. If that isn't going to be sufficient, they can actually see a psychiatrist to discuss medications and so forth. I do think that we've got to screen for these because, as anticipated from diagnosis, those first 2 years, we see a rise. But even 10, 15 years out, we note, compared to controls, that there is an increased level of anxiety, depression, suicidality that might not just take place at that initial acute period of diagnosis and treatment. Dr. Pedro Barata: Really well said. Super important.  So I guess if I were to put all these together, with these really amazing advances in technology, we all know AI, some of us might be more or less aware of biomarkers coming up, including microRNA for example, and others, like as I think of all these potential long term complications for these patients, look at the future, I guess, can we use this as a way to deescalate treatment where it's not really necessary, as a way to actually prevent some of these complications? Like, how do we see where we're heading? As we manage testicular cancer, let's say, within the next 5 or 10 years, do you think there's something coming up that's going to be different from what we're doing things today? Dr. Aditya Bagrodia: Totally. I mean, I think it's as exciting as a time as there's ever been, you know, maybe notwithstanding circa 1970s when platinum was discovered. So microRNAs, which you mentioned, you know, there's a new candidate biomarker, microRNA-371. We are super excited here at UCSD. We actually have it CLIA-certified available in our lab and are ordering these tests for patients kind of in their acute stage, you know, stage one and surveillance, stage two, post-RPLND, receiving chemotherapy. And essentially this is a universal germ cell tumor specific biomarker, except for teratoma, suffice it to say 90% sensitive and specific. And I think it's going to change the way that we diagnose and manage patients. You know, pre-orchiectomy, that's pretty straightforward. Post-orchiectomy, maybe we can really decrease the number of CT scans that are done. Maybe we can identify those patients that basically have occult disease where we can intervene early, either with RPLND or single cycle chemo. Post-RPLND, identify the patients who are at higher risk of relapse that may benefit from some adjuvant therapy. In the advanced setting, look at marker decline for patients in addition to standard tumor markers. Can we modulate their systemic therapy?  So, the international interest is largely on modifying things. There's really cool clinical trials that we have for stage one patients, that treatment would be prescribed based on a post-orchiectomy microRNA. I think the microRNAs are really exciting. Teratoma remains an outstanding question. I think this is where maybe ctDNA, perhaps some radiomics and advanced imaging processing and incorporating AI may allow us to safely avoid a lot of these post-chemo RPLNDs. And then identification using SNPs and so forth of who might be most susceptible to some of the cardiac toxicity, autotoxicity and personalizing things in that way as well. Dr. Pedro Barata: Super exciting, right, what's about to come? And I agree with you, I think it's going to change dramatically how we manage this disease.  This has been a pleasure sitting down with you. I guess before letting you go, anything else you'd like to add before we wrap it up? Dr. Aditya Bagrodia: Yeah, first off, again, just want to thank you and ASCO for the opportunity. And it's easy enough to, I think, approach a patient with the testicular germ cell tumor as, "This is an easy case. We're just going to do whatever we've done. Go to the guidelines that says do X, Y, or Z." But there's so much more nuance to it than that. Getting it done perfectly, I think, is mandatory. Whatever we do is an impact on them for the next 50, 60, 70 years of their life. And I found the germ cell tumor community, people are really passionate about it. If you're ever uncertain, there's experts throughout the country and internationally. Ask somebody before you do something that you can't undo. I think we owe it to them to get it perfect so that we can really maximize the survivorship and the survival like we've been talking about. Dr. Pedro Barata: Aditya, thanks for sharing your fantastic insights with us on this podcast. Dr. Aditya Bagrodia: All right, Pedro. Fantastic. Appreciate the opportunity. Dr. Pedro Barata: And also, thank you to our listeners for your time today. I actually encourage you to check out Dr. Bagrodia's article in the 2025 ASCO Educational Book. We'll post a link to the paper in the show notes. Remember, it's free access online, and you can actually download it as well as a PDF. You can also find on the website a wealth of other great papers from the ASCO Educational Book on key advances and novel approaches that are shaping modern oncology.  So with that, thank you everyone. Thank you, Aditya, one more time, for joining us. Thank you, have a good day. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:         Dr. Pedro Barata  @PBarataMD   Dr. Aditya Bagrodia @AdityaBagrodia Follow ASCO on social media:         @ASCO on X (formerly Twitter)         ASCO on Bluesky        ASCO on Facebook         ASCO on LinkedIn         Disclosures:      Dr. Pedro Barata:  Stock and Other Ownership Interests: Luminate Medical  Honoraria: UroToday  Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon  Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas  Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck   Dr. Aditya Bagrodia: Consulting or Advisory Role: Veracyte, Ferring  

In today's episode, we are joined by Professor Stephen Maher, an expert in translational oncology and radiation research at Trinity College Dublin, where he also serves as the Director of Postgraduate Studies for the School of Medicine. Stephen's work focuses on understanding why some cancers respond to treatment while others resist it — particularly in relation to chemotherapy and radiotherapy. His research explores how factors like microRNAs, the DNA damage response, and tumor hypoxia influence treatment sensitivity, with a strong emphasis on oesophageal and pancreatic cancers. Hit play to explore: The future of anti-cancer therapeutics. The ways that radiation research is evolving. Why translational oncology is so important for improving patient outcomes. After completing his Ph.D. in Oncology at RCSI and a fellowship at the National Cancer Institute in Maryland, Stephen has built a career dedicated to bridging lab-based discovery with patient-focused care. He leads national and international collaborations in cancer biology and has helped develop cutting-edge radiotherapy and hypoxia research cores at Trinity's Translational Medicine Institute. Click here to learn more about Stephen and his important work!

BUFFALO, NY — October 7, 2025 — A new #research paper was #published in Volume 17, Issue 9 of Aging-US on August 27, 2025, titled, “Deregulated miR-145 and miR-27b in Hutchinson-Gilford progeria syndrome: implications for adipogenesis.” In this study, led by first author Felix Quirin Fenzl and corresponding author Karima Djabali from the Technical University of Munich (TUM), researchers identified that miR-145-5p and miR-27b-3p interfere with the formation of fat cells in children with Hutchinson-Gilford progeria syndrome (HGPS), a rare and fatal premature aging disorder. Their findings help explain why patients often experience fat loss and related metabolic complications and suggest new potential therapeutic strategies. Hutchinson-Gilford progeria syndrome is a genetic condition that causes rapid aging in children, often leading to early death due to heart disease. Although affected children appear healthy at birth, they soon develop signs of accelerated aging, including hair loss, stiff joints, and a significant reduction in fat tissue. While certain treatments can slow disease progression, many aspects, such as the loss of fat tissue, remain poorly understood. “Overall, this study provides the first comprehensive miRNA profiling of HGPS and control fibroblasts across different stages of cellular senescence.” This study focused on how microRNAs—tiny molecules that help regulate gene expression—contribute to the disease. To explore this, the researchers used skin-derived stem cells from both healthy individuals and HGPS patients. When they transformed these cells into fat cells, the HGPS-derived stem cells formed significantly fewer fat cells. This difference was linked to unusually high levels of miR-145-5p and miR-27b-3p. These molecules were found to silence important genes required for fat cell growth and function. When the researchers blocked these microRNAs, fat cell formation improved. The team also examined fat tissue from a mouse model of HGPS. Similar to the human cells, these mice showed increased levels of miR-145-5p and miR-27b-3p and impaired fat development. These results confirm that these two microRNAs play a central role in the loss of fat tissue seen in the disease. Importantly, reducing their activity could become a promising therapeutic strategy for restoring fat tissue in affected individuals. Although further research is needed before developing treatments, this study represents a step forward in understanding the molecular causes of lipodystrophy, a condition in which the body cannot form healthy fat tissue, in HGPS. It also opens the door for future therapies that could improve quality of life and health outcomes for patients. In the long term, similar approaches might benefit people with other metabolic diseases, such as obesity or diabetes, where fat cell function is also disrupted. DOI - https://doi.org/10.18632/aging.206309 Corresponding authors - Karima Djabali — djabali@tum.de Abstract video - https://www.youtube.com/watch?v=b0ksC3cvdZ0 Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206309 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, Hutchinson-Gilford progeria syndrome (HGPS), progerin, microRNAs, adipogenesis To learn more about the journal, please visit our website at https://www.Aging-US.com​​ and connect with us on social media at: 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/ Bluesky - https://bsky.app/profile/aging-us.bsky.social Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY — September 2, 2025 — A new #research paper featured on the #cover of Volume 17, Issue 8 of Aging (Aging-US) was #published on July 30, 2025, titled “Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures.” In this study, led by first authors Sandip Kumar Patel and Joanna Bons, along with corresponding author Birgit Schilling from The Buck Institute for Research on Aging, researchers found that exosomes—tiny particles released by cells—carry molecular signatures that indicate both biological aging and cellular senescence. These signatures include proteins, lipids, and microRNAs associated with inflammation, oxidative stress, and tissue remodeling. The findings could enhance our understanding of biological aging and help in developing future anti-aging therapies. Senescence is a state in which cells stop dividing but remain metabolically active. These cells often release harmful substances, known collectively as the senescence-associated secretory phenotype (SASP), that can affect nearby tissues. This study shows that exosomes are an important component of this secretory profile. The researchers analyzed exosomes from senescent human lung cells and from the blood plasma of both young and older adults. They identified over 1,300 proteins and 247 lipids within these particles. Many of these molecules were significantly altered with age. “In parallel, a small human plasma cohort from young (20–26 years) and old (65–74 years) individuals revealed 1,350 exosome proteins and 171 plasma exosome proteins were altered in old individuals.” Exosomes from older individuals contained more inflammation-related proteins and fewer antioxidants, while those from senescent cells showed lipid changes associated with membrane integrity and cellular stress. These changes suggest that exosomes may play a role in spreading senescence to nearby cells, a process known as secondary senescence. The study also identified distinct patterns in microRNAs—small molecules that regulate gene expression—found in the blood of older adults. Some of these, including miR-27a and miR-874, have previously been associated with cognitive decline and chronic illnesses, highlighting their potential as biomarkers for biological aging. Although the study involved a limited number of samples, it provides strong early evidence that exosomes reflect the molecular changes associated with aging. By showing how these particles carry and possibly spread aging-related signals throughout the body, the research opens new possibilities for diagnosing and treating age-related diseases. DOI - https://doi.org/10.18632/aging.206292 Corresponding author - Birgit Schilling – bschilling@buckinstitute.org Video short - https://www.youtube.com/watch?v=tcyAZahw-g8 Keywords - aging, proteomics, senescence, exosomes, data-independent acquisitions Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts To learn more about the journal, 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/ Bluesky - https://bsky.app/profile/aging-us.bsky.social Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - July 18, 2025 – A new #editorial was #published in Volume 16 of Oncotarget on July 16, 2025, titled “microRNAs in soft tissue sarcoma: State of the art and barriers to translation.” In this article, Elizaveta K. Titerina, Alessandro La Ferlita, and Joal D. Beane from Ohio State University discuss the role of microRNAs in soft tissue sarcomas (STS), a rare and diverse group of cancers that begin in connective tissues, like bone or fat. The authors explain how these small molecules regulate cancer-related processes and highlight their potential as non-invasive biomarkers for diagnosis and monitoring. They also outline the main challenges that need to be addressed before microRNA-based strategies can be used in clinical settings. Soft tissue sarcomas include over 50 subtypes, making precise diagnosis and effective treatment difficult. The editorial describes how microRNAs influence cancer growth, spread, and response to therapies. Because microRNAs are stable in body fluids like blood and saliva, they could be used for early detection and to help guide treatment decisions. Such as, certain groups of microRNAs are linked to how patients respond to specific drugs, showing their potential as tools for precision medicine. “For example, miR-17-92 and miR-106b-25 clusters have been associated with sensitivity or resistance to eribulin in STS.” The authors also explain that microRNAs could help distinguish between tumor types that are often difficult to differentiate, such as benign lipomas and malignant liposarcomas. Recognizing these differences is crucial for guiding treatment decisions. Specific patterns of microRNA expression in blood samples may enable clinicians to make quicker and more reliable diagnoses without the need for invasive procedures. Beyond their diagnostic role, microRNAs are also being explored as therapeutic tools, but applying microRNA-based therapies to patients remains challenging. These molecules can act as either cancer promoters or suppressors, depending on the environment, which complicates the development of safe and targeted treatments. However, new delivery methods such as lipid nanoparticles show promise in improving precision and safety. Overall, microRNAs are emerging as an important focus in STS research, offering new possibilities for advancing diagnosis, prognosis, and treatment. As researchers continue to address the current challenges, these small molecules could become valuable tools in improving cancer care. DOI - https://doi.org/10.18632/oncotarget.28754 Correspondence to - Joal D. Beane, joal.beane@osumc.edu Video short - https://www.youtube.com/watch?v=MlLGA8BObPQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28754 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, soft tissue sarcoma, liposarcoma, microRNA, small non-coding RNA, cancer biomarkers To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

I denne episoden er hovedtema okklusjonstrening og gjesten vår heter Thomas Bjørnsen. Thomas jobber som førsteamanuensis for Universitetet i Stavanger. Dagens tema omhandler hans doktorgrad der han skrev om okklusjonstrening og hvilke virkninger denne type trening gir i form av muskelstyrke og muskelmasse. For de av dere som har prøvd slik type trening der den venøse blodtilstrømning til begrenset har nok kjent på en smerte under eller etter endt treningsøkt. Vedvarer smerten under/etter alle øktene? Er smerten verdt effekten, og hva slags effekt gir det egentlig? God lytting!Kontaktinformasjon:⁠https://www.researchgate.net/profile/Thomas_Bjornsen⁠⁠https://twitter.com/thomasbjornsen⁠Relevante artikler:D'Souza, R. F., Bjørnsen, T., Zeng, N., Aasen, K. M., Raastad, T., Cameron-Smith, D., & Mitchell, C. J. (2017). MicroRNAs in muscle: characterizing the powerlifter phenotype. Frontiers in physiology, 8, 383.Bjørnsen, T., Wernbom, M., Kirketeig, A., Paulsen, G., Samnøy, L. E., Bækken, L. V., ... & Raastad, T. (2018). Type 1 Muscle Fiber Hypertrophy after Blood Flow–restricted Training in Powerlifter.Bjørnsen, T., Wernbom, M., Løvstad, A., Paulsen, G., D'Souza, R. F., Cameron-Smith, D., ... & Raastad, T. (2019). Delayed myonuclear addition, myofiber hypertrophy, and increases in strength with high-frequency low-load blood flow restricted training to volitional failure. Journal of Applied Physiology, 126(3), 578-592.Wernbom, M., Schoenfeld, B. J., Paulsen, G., Bjørnsen, T., Cumming, K. T., Aagaard, P., ... & Raastad, T. (2020). Commentary: Can Blood Flow Restricted Exercise Cause Muscle Damage? Commentary on Blood Flow Restriction Exercise: Considerations of Methodology, Application, and Safety. Frontiers in Physiology, 11.Wernbom, M., Paulsen, G., Bjørnsen, T., Cumming, K., & Raastad, T. (2019). Risk of Muscle Damage With Blood Flow–Restricted Exercise Should Not Be Overlooked.

Früher bezeichnete man die Pest als „Geißel der Menschheit“. Unter allen heutigen Erkrankungen dürfte Krebs zweifelsohne diesen Rang einnehmen. Keine andere Diagnose wird von so vielen Menschen als die schrecklichste empfunden, an keiner anderen Krankheit wird so intensiv geforscht. In der heutigen Folge von „Medizin für Mitdenker“ fragt Volker Pietzsch Dr. med. Sybille Freund, was Krebs eigentlich ist, wie er entsteht, was man über die Prozesse im Körper weiß und natürlich auch: was man tun kann, um einer Krebserkrankung vorzubeugen. Eine lange Folge, voll gepackt mit Informationen, Erklärungen und Hinweisen. Studie: Seneff S, Nigh G, Kyriakopoulos AM, McCullough PA. Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs. Food Chem Toxicol. 2022 Jun;164:113008. doi: 10.1016/j.fct.2022.113008. Epub 2022 Apr 15. PMID: 35436552; PMCID: PMC9012513 Alle Podcastfolgen und ein ausführliches Stichwortverzeichnis finden Sie auf: doktorfreund.de/podcast

On this episode of Careers in Discovery, we spoke with Riccardo Panella, Founder and Chief Scientific Officer of Resalis Therapeutics, and Associate Professor at the Center of RNA Medicine in Copenhagen. Riccardo shared his journey from academia to Biotech entrepreneurship, discussing how a serendipitous discovery during his postdoctoral research at Harvard led him to explore the role of microRNAs in metabolism. He delved into the challenges and rewards of founding Resalis Therapeutics, highlighting the importance of resilience in securing funding and the differences between academic and commercial science. We also explored his perspectives on leadership, the value of collaboration, and the advice he would give to early-career scientists. A compelling conversation about adaptability, perseverance, and the pursuit of translational science.

Dr. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan. Our full disclosures are available in the transcript of this episode.  Dr. Wang, thanks for coming on the podcast today. Dr. David Wang: Well, thank you. It's a pleasure to be here. Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting? Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years' themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz's wonderful lecture.  We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings. Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study? Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024. This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic. Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of? Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care. And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines. Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there? Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients.  Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference.  Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away. Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge. Dr. David Wang: Yes, I agree. Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present? Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned.  So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago. Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results. Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8. Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space? Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting.  What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo.  So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here. Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States? Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial. Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study? Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors.  But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination. If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype. Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year. Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode.  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. Shaalan Beg @ShaalanBeg  Dr. David Wang Follow ASCO on social media:   @ASCO on Twitter  @ASCO on BlueSky ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg:  Employment: Science 37  Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine  Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals  Dr. David Wang: Honoraria:  Novartis Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai  

******Support the channel****** Patreon: https://www.patreon.com/thedissenter PayPal: paypal.me/thedissenter PayPal Subscription 1 Dollar: https://tinyurl.com/yb3acuuy PayPal Subscription 3 Dollars: https://tinyurl.com/ybn6bg9l PayPal Subscription 5 Dollars: https://tinyurl.com/ycmr9gpz PayPal Subscription 10 Dollars: https://tinyurl.com/y9r3fc9m PayPal Subscription 20 Dollars: https://tinyurl.com/y95uvkao   ******Follow me on****** Website: https://www.thedissenter.net/ The Dissenter Goodreads list: https://shorturl.at/7BMoB Facebook: https://www.facebook.com/thedissenteryt/ Twitter: https://x.com/TheDissenterYT   This show is sponsored by Enlites, Learning & Development done differently. Check the website here: http://enlites.com/   Dr. David Henshall is Professor of Physiology and Medical Physics at the Royal College of Surgeons in Ireland. His laboratory is studying cell and molecular mechanisms of epilepsy. His research team combines cell and molecular biology techniques, data science and bioinformatics, pharmacology, neuroscience and behavior, imaging and histology, and employs a range of experimental and human models. He is the author of Fine-Tuning Life: A Guide to MicroRNAs, Your Genome's Master Regulators.   In this episode, we focus on Fine-Tuning Life. We start by covering some basics of DNA and RNA. We talk about microRNAs: how they were discovered and how we learn about them; how they evolved; how they are produced in cells; their functions and role in fine-tuning life; how they work; and their role in evolution and speciation. We then get specifically into how they work in human development, their role in brain physiology and brain cell structure, cognition and intelligence, and brain disease. Finally, we discuss a new picture of genetics coming from gene regulation and the role of microRNAs. -- A HUGE THANK YOU TO MY PATRONS/SUPPORTERS: PER HELGE LARSEN, JERRY MULLER, BERNARDO SEIXAS, ADAM KESSEL, MATTHEW WHITINGBIRD, ARNAUD WOLFF, TIM HOLLOSY, HENRIK AHLENIUS, FILIP FORS CONNOLLY, DAN DEMETRIOU, ROBERT WINDHAGER, RUI INACIO, ZOOP, MARCO NEVES, COLIN HOLBROOK, PHIL KAVANAGH, SAMUEL ANDREEFF, FRANCIS FORDE, TIAGO NUNES, FERGAL CUSSEN, HAL HERZOG, NUNO MACHADO, JONATHAN LEIBRANT, JOÃO LINHARES, STANTON T, SAMUEL CORREA, ERIK HAINES, MARK SMITH, JOÃO EIRA, TOM HUMMEL, SARDUS FRANCE, DAVID SLOAN WILSON, YACILA DEZA-ARAUJO, ROMAIN ROCH, DIEGO LONDOÑO CORREA, YANICK PUNTER, CHARLOTTE BLEASE, NICOLE BARBARO, ADAM HUNT, PAWEL OSTASZEWSKI, NELLEKE BAK, GUY MADISON, GARY G HELLMANN, SAIMA AFZAL, ADRIAN JAEGGI, PAULO TOLENTINO, JOÃO BARBOSA, JULIAN PRICE, EDWARD HALL, HEDIN BRØNNER, DOUGLAS FRY, FRANCA BORTOLOTTI, GABRIEL PONS CORTÈS, URSULA LITZCKE, SCOTT, ZACHARY FISH, TIM DUFFY, SUNNY SMITH, JON WISMAN, WILLIAM BUCKNER, PAUL-GEORGE ARNAUD, LUKE GLOWACKI, GEORGIOS THEOPHANOUS, CHRIS WILLIAMSON, PETER WOLOSZYN, DAVID WILLIAMS, DIOGO COSTA, ALEX CHAU, AMAURI MARTÍNEZ, CORALIE CHEVALLIER, BANGALORE ATHEISTS, LARRY D. LEE JR., OLD HERRINGBONE, MICHAEL BAILEY, DAN SPERBER, ROBERT GRESSIS, IGOR N, JEFF MCMAHAN, JAKE ZUEHL, BARNABAS RADICS, MARK CAMPBELL, TOMAS DAUBNER, LUKE NISSEN, KIMBERLY JOHNSON, JESSICA NOWICKI, LINDA BRANDIN, NIKLAS CARLSSON, GEORGE CHORIATIS, VALENTIN STEINMANN, PER KRAULIS, ALEXANDER HUBBARD, BR, MASOUD ALIMOHAMMADI, JONAS HERTNER, URSULA GOODENOUGH, DAVID PINSOF, SEAN NELSON, MIKE LAVIGNE, JOS KNECHT, ERIK ENGMAN, LUCY, MANVIR SINGH, PETRA WEIMANN, CAROLA FEEST, STARRY, MAURO JÚNIOR, 航 豊川, TONY BARRETT, BENJAMIN GELBART, AND NIKOLAI VISHNEVSKY! A SPECIAL THANKS TO MY PRODUCERS, YZAR WEHBE, JIM FRANK, ŁUKASZ STAFINIAK, TOM VANEGDOM, BERNARD HUGUENEY, CURTIS DIXON, BENEDIKT MUELLER, THOMAS TRUMBLE, KATHRINE AND PATRICK TOBIN, JONCARLO MONTENEGRO, AL NICK ORTIZ, NICK GOLDEN, CHRISTINE GLASS, AND KOMOMO! AND TO MY EXECUTIVE PRODUCERS, MATTHEW LAVENDER, SERGIU CODREANU, BOGDAN KANIVETS, ROSEY, AND GREGORY HASTINGS!

Send us a textThis week we spoke to Dr. Colm Collins! Dr. Collins is an Associate Professor at the Conway Institute of Biomolecular and Biomedical Research at University College Dublin. He shares his journey from the world of pharmacology to pioneering research in inflammatory bowel disease (IBD). You'll learn about the innovative approaches his team is exploring to revolutionize treatment options for IBD patients. With a blend of humor and expertise, Dr. Collins offers a rare glimpse into the challenges and triumphs of translating scientific breakthroughs into real-world health solutions.Our conversation unravels the intricate relationship between the immune system and gut bacteria, as Dr. Collins explains how retinoic acid and microRNAs play crucial roles in managing IBD. We delve into the promising possibilities of replacing lost proteins and the therapeutic potential of cannabinoids, exploring their implications on both the immune system and the digestive tract. Amidst the science, we tackle the ethical and legal complexities of cannabis research, particularly in adolescents, as Dr. Collins shares his experiences navigating these challenges with integrity and humor.Join us for an enlightening discussion that balances serious scientific inquiry with light-hearted anecdotes, as Dr. Collins recounts his experiences in Colorado and discusses the future of IBD treatment. From the nuances of cannabis use in managing IBD symptoms to the exciting potential of selective human receptor-modifying peptides, this episode promises to expand your understanding and offer hope for more effective therapies on the horizon. Plus, enjoy a humorous account of altitude adaptation and its quirky effects on newcomers and the unexpected twists in cannabis research funding.Links: Journal article: Manipulation of the Endocannabinoid System in Colitis: A Comprehensive ReviewJournal article: Adherence, Safety, and Effectiveness of Medical Cannabis and Epidemiological Characteristics of the Patient Population: A Prospective StudyInformation on medical cannabis and IBD: Crohn's & Colitis Foundation- USAResearch funding opportunities- Crohn's & Colitis Foundation- USALet's get social!!Follow us on Instagram!Follow us on Facebook!Follow us on Twitter!

Ondřej Slabý is head of the Department of Biology at the Faculty of Medicine, leads the Center for Precision Medicine at University Hospital Brno. He is also Chairman of the Czech Health Research Council and Advisor to the Minister of Health. His expertise in cancer biology supports advancements in targeted therapies. Jiří Šána is an associate professor at the Faculty of Medicine and the Masaryk Memorial Cancer Institute. He is a key member of the Ondřej Slabý Research Group and has a strong focus on cancer research, particularly in the areas of molecular biology and genomics. His research contributions include studying exosomal microRNAs in gliomas, which have implications for diagnostics and innovative therapies. BBMRI.cz is the Czech national node of the European Biobanking and BioMolecular Resources Research Infrastructure (BBMRI-ERIC), which supports biobanking initiatives and collaboration across Europe. BBMRI.cz provides access to a network of biological samples, data, and resources, offering researchers a comprehensive repository for biomedical and health research in the Czech Republic.

Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel prize in physiology or medicine for their discovery of microRNA, tiny biological molecules that tell the cells in our body what kind of cell to be by turning on and off certain genes.In this episode, we speak to Ambros, who is professor of natural sciences at UMass Chan Medical School in the US, about the discovery that led to his Nobel prize and find out what he's researching now. And we hear from Justin Stebbing, professor of biomedical sciences at Anglia Ruskin University in the UK, about how a deeper understanding of microRNA is opening up new avenues for potential treatment of diseases such as cancer. This episode was produced by Gemma Ware, Katie Flood and Mend Mariwany. Sound design was by Michelle Macklem and our theme music is by Neeta Sarl. Full credits for this episode are available. Sign up here for a free daily newsletter from The Conversation.If you like the show, please consider donating to The Conversation, which is an independent, not-for-profit news organisation. And please do rate and review the show wherever you listen.Further reading:MicroRNA − a new Nobel laureate describes the scientific process of discovering these tiny molecules that turn genes on and offMicroRNA is the Nobel-winning master regulator of the genome – researchers are learning to treat disease by harnessing how it controls genesNobel prize in medicine awarded for discovery of microRNAs, the molecules that control our genesFull coverage of the 2024 Nobel prizes on The Conversation Hosted on Acast. See acast.com/privacy for more information.

A Nobel prize for understanding how genes are turned on and offThe early-morning call from Sweden came on Monday to American molecular biologist Gary Ruvkun for his work in discovering microRNAs, which are essential for regulating genetic activity in plants and animals. Ruvkun says that research based on this work helps us understand basic biology, but has also provided significant insight into disease and might even help us understand whether there is life on other planets. Biologists discover a new microbial world in your bathroomResearchers have found a new biodiversity hotspot. Environmental microbiologist Erica Hartmann and her team sampled showerheads and toothbrushes in ordinary bathrooms, and found a host of bacteria and hundreds of previously unknown viruses. But don't panic: much of this new life are bacteriophages — viruses that infect bacteria — which are harmless to humans and could be potential weapons against the bacteria that can cause human disease. The study was published in the journal Frontiers in Microbiomes.How we might zap an asteroid on a collision course with EarthA new experiment using the world's most powerful radiation source has shown the way to deflecting asteroids with X-rays. The X-rays were used to vaporize some of the surface of a model asteroid, creating a rocket-like effect. Dr Nathan Moore, a physicist at the Sandia National Laboratories in New Mexico, says it's a proof of principle for the concept of deflecting a real asteroid using X-rays generated by a powerful nuclear explosion. The study was published in the journal Nature Physics. Exploring the origins of Australia's iconic, if controversial, wild dogThe Australian Dingo has a fierce reputation as a predator, leading to European settlers attempting to exterminate it in the 19th century. But the dingo's origin story has not been well understood. For years, it was assumed the dingo originated from India, given its similarities to the Indian pariah dog, or from New Guinea. Dr. Loukas Koungolos, a research associate at the University of Sydney, led the study looking at dingo fossils and found out where it likely came from, and how the domestic dogs of ancient people became a wild predator down under. The study was published in the journal Scientific Reports. Can we treat autoimmune disease by manipulating the immune system? Autoimmune diseases like Lupus can be a result of critical immune cells attacking our own bodies. New advances are pointing to ways we might be able to reverse this. Researchers have repurposed a relatively new cancer treatment, called CAR-T therapy that can reprogram immune cells to attack cancer cells, to reset the immune system in patients with lupus to neutralize its autoimmune attack. Dr. Georg Schett and his colleagues, from the Friedrich Alexander University of Erlangen in Germany, were the first to use this immunotherapy to successfully treat lupus patients. That research appeared in the journal Nature Medicine with a follow-up in The New England Journal of Medicine.Other researchers are focussing on understanding — and possibly reversing — what triggers the immune cells to go awry in the first place. Dr. Jaehyuk Choi, from Northwestern University, said they found a molecule that lupus patients are deficient in. In cell culture they demonstrated that correcting this deficiency can reprogram certain immune T-cells to stop directing the attack on the body which they hope could potentially reverse the effects of lupus. His research was published in Nature.

microRNA: zwei US-amerikanische Forscher haben sie zufällig entdeckt - in einem unscheinbaren Fadenwurm. Sie regulieren unsere Gene, bestimmen mit, ob wir krank werden oder gesund bleiben: Jetzt werden Victor Ambros und Gary Ruvkun für die Entdeckung mit dem Medizin-Nobelpreis 2024 ausgezeichnet, denn das Verständnis der Moleküle ermöglicht ganz neue Therapien. In dieser Podcast Folge fragen wir: was sind microRNAs, was können sie? Und wie können wir sie nutzen, um Krankheiten wie Krebs, Diabetes oder Herzschwäche zu bekämpfen?

Die Themen von Minh Thu und Flo am 08.10.2024: (00:00:00) Medizin-Nobelpreis: Zwei US-Biologen bekommen den Preis für die Entdeckung von MicroRNAs. Mit deren Hilfe könnten viele Krankheiten geheilt werden. (00:01:54) Kevin Kühnert: Der SPD-Generalsekretär ist krank. Deswegen tritt er zurück. Wahrscheinlich wird Matthias Miersch seinen Job übernehmen. (00:07:03) Blauer Haken: Google will dabei unterstützen, dass man echte Online-Shops schneller erkennt. Dafür testet das Unternehmen in den USA gerade einen blauen Haken bei den Suchergebnissen. (00:10:46) P. Diddy: Er ist einer der erfolgreichsten und bekanntesten US-Rapper weltweit. Jetzt sitzt er in Haft. Ihm wird unter anderem sexueller Missbrauch und Menschenhandel vorgeworfen. (00:17:31) Aufesser: Die Szene ist in Freiburg nicht neu. Aber Studis, die gerade ihr Semester starten, wundern sich über die "Bänderer", die in der Mensa das Essen von anderen aufessen. Der Fakeshop-Finder der Verbraucherzentrale: https://www.verbraucherzentrale.de/fakeshopfinder-71560 Ihr wollt uns was sagen? Habt Lob oder Kritik? Dann schickt uns eine (Sprach-)Nachricht an 0151 15071635 oder per Mail unter 0630@wdr.de Von 0630.

Mit der Beschreibung der kleinen RNA-Moleküle haben die Preisträger Victor Ambros und Gary Ruvkun einen Prozess der Genregulation erklärt. MicroRNAs steuern die Produktion von Proteinen und sind damit entscheidend für die Entwicklung eines Organismus. Von Anneke Meyer

Der Nobelpreis für Medizin geht 2024 an die US-Amerikaner Victor Ambros und Gary Ruvkun – für die Entdeckung der microRNAs. Sie steuern mit, wie unsere Gene sich regulieren und warum verschiedene Zelltypen im Körper sich unterschiedlich entwickeln. Martin Gramlich im Gespräch mit Ulrike Till, SWR-Wissenschaftsredaktion.

In this episode of the Epigenetics Podcast, we talked with Johnathan Whetstine from Fox Chase Cancer Center about his work on how histone demethylases affect gene expression and cancer cell stability. The Interview start by discussing a pivotal paper from Jonathan's lab in 2010, where they identified a role for the KDM4A histone demethylase in replication timing and cell cycle progression. They elaborate on the discoveries made regarding the link between histone marks, replication timing, and gene expression control. Jonathan explains the impact of microRNAs on regulating KDM4A and how protein turnover rates can influence cellular responses to treatments like mTOR inhibitors. Further, they explore the causal relationship between histone marks and replication timing, demonstrating how alterations in epigenetic regulation can affect genome stability. Jonathan shares insights from his latest research on H3K9 methylation balance at the MLL-KM2A locus, elucidating how these epigenetic modifications regulate amplifications and rearrangements in cancer cells. The episode concludes with a discussion on the establishment of the Cancer Epigenetics Institute at Fox Chase Cancer Center, aiming to bridge academia and industry to accelerate translational research in cancer epigenetics.   References Black, J. C., Allen, A., Van Rechem, C., Forbes, E., Longworth, M., Tschöp, K., Rinehart, C., Quiton, J., Walsh, R., Smallwood, A., Dyson, N. J., & Whetstine, J. R. (2010). Conserved antagonism between JMJD2A/KDM4A and HP1γ during cell cycle progression. Molecular cell, 40(5), 736–748. https://doi.org/10.1016/j.molcel.2010.11.008 Mishra, S., Van Rechem, C., Pal, S., Clarke, T. L., Chakraborty, D., Mahan, S. D., Black, J. C., Murphy, S. E., Lawrence, M. S., Daniels, D. L., & Whetstine, J. R. (2018). Cross-talk between Lysine-Modifying Enzymes Controls Site-Specific DNA Amplifications. Cell, 174(4), 803–817.e16. https://doi.org/10.1016/j.cell.2018.06.018 Van Rechem, C., Ji, F., Chakraborty, D., Black, J. C., Sadreyev, R. I., & Whetstine, J. R. (2021). Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell reports, 37(1), 109799. https://doi.org/10.1016/j.celrep.2021.109799 Gray, Z. H., Chakraborty, D., Duttweiler, R. R., Alekbaeva, G. D., Murphy, S. E., Chetal, K., Ji, F., Ferman, B. I., Honer, M. A., Wang, Z., Myers, C., Sun, R., Kaniskan, H. Ü., Toma, M. M., Bondarenko, E. A., Santoro, J. N., Miranda, C., Dillingham, M. E., Tang, R., Gozani, O., … Whetstine, J. R. (2023). Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement. Cell, 186(21), 4528–4545.e18. https://doi.org/10.1016/j.cell.2023.09.009   Related Episodes The Impact of Chromatin Modifiers on Disease Development and Progression (Capucine van Rechem)   Contact Epigenetics Podcast on X Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Epigenetics Podcast on Threads Active Motif on X Active Motif on LinkedIn Email: podcast@activemotif.com

Guest: David Henshall - Professor of Physiology and Medical Physics at RCSI and author of Fine-Tuning Life: A Guide to MicroRNAs, Your Genome's Master Regulators.

Hello Interactors, The lengthening northern days have unleashed verdant chaos in my yard and it's challenging my desire for order. Some unruly growth demands surrendering control, embracing life's rhizomatic entanglements — an invitation to honor multiplicity over singularity, relation over individuality, and emergence over stasis.Let's dig in…FERN FRENZY IN FULL FORCEThose skinny unattractive immigrants are invading. They're nudging their way through every nook and cranny stealing resources and opportunity from those already here. Before long, they'll be taking over the place. I'm talking about Leptinella squalida (Derived from the Greek "leptos" meaning slender and the Latin “squalid” meaning unattractive). That is the scientific name for a New Zealand native ground cover commonly referred to as ‘Brass buttons' and it's taking over my garden.Leptinella squalida is rhizomatous. It sends rootlike horizontal shallow subterranean stems — a rhizome — in a multitude of unpredictable directions. At various intervals in its journey, it progressively produces small nodules that send whisker roots below while sprouting shoots vertically to the surface to form miniature fern-like fronds — sometimes green and other times ‘brass' colored. Once a year it produces a yellow ‘button' blossom that can send seeds aloft leapfrogging the host to colonize another territory.I planted it in a shady moist area of my small backyard after ripping out a grass lawn. Liptinella squalida makes an even carpet that can withstand a fair bit of foot traffic, making it an attractive alternative to grass. Unfortunately, other plants can't withstand is aggressive propagation, starving them of light and nutrients. That's exactly what this exponentially expanding rhizome is doing to the slower growing, less aggressively sprawling Sedum rupestre 'Angelina' — a variety I also helped colonize from Western Europe.I suspect strict immigration laws should be applied to my little rambunctious rhizomatous island ferns. Last week I eradicated an entire section at the border with a shovel and then carefully extracted the spindly rhizomes from the starved roots and foliage of the ‘Angelina.' I'm contemplating building a subterranean Trump-like wall to resist the invaders. I may even perform widespread extirpation and dig it all up — especially given the primary section of Brass buttons have also been colonized. They are slowly being overtaken by another aggressive invasive species — clover.I didn't plan for this, but I did create the conditions for it to occur. In place of a grass lawn — which offers nothing to ecology in any shape or form — I planted a variety of low growing ground covers, sedums, and clumping ornamental grasses. Many of these ground covers have now intermingled. Some are more dominant in areas than others forming a diverse kaleidoscope of height, color, and texture. There's little strict cartesian geometric control I can apply to this tufted tapestry without hard physical barriers. And even then, their airborne spores can gleefully fly where the wind may carry them — oblivious to any tyrannical terrestrial territorial triangulations I may map in my head.Rhizomes are their own kind of experimental map. They randomly route with their roots. Their genes map the way as MicroRNAs modulate their sway. Meanwhile, subterranean phytohormones signal route initiation and elongation in a coordinated but random multi-directional, non-linear physical cartographic network.Rhizomic networks have no real beginning or end. They make connections in a non-hierarchical, decentralized way without a single origin or terminus. It is in a continual emergent state of being in the middle of having been made and becoming something new. There is no dualistic hierarchical parent/child branching that dominates Western mental images of hierarchical networks — like a family tree or even a real tree where a trunk sprouts limbs with branches that terminate with leaves. Rhizomatous networks defy rational Cartesian logic.I've been reflecting on the tension I'm experiencing as I wrestle and reason with my garden. On the one hand, I'm drawn to the top-down control of crafting a particular order and aesthetic as an amateur landscape architect. The same desire explains my affinity for urban and transportation planning and design…and I suppose my three decades of user interface design. I like attempts at bringing clarity to complexity.Modern urban planning tries to achieve the same thing. Urban planning has historically relied on hierarchical models characterized by centralized control and top-down implementation. These traditional approaches often use structural or generative frameworks to shape and represent urban spaces. Emphasizing coherence and order, urban planning typically adheres to mapped zoning regulations and legally controlled growth patterns. The focus is usually on achieving defined end-states or visions, imposing order through marginated space with bordered zones and predetermined paths dictated by urban transportation planning policies.The same can be said for the planning of countries and states. Colonial powers imposed structured urban plans to assert control and organize territories. Their maps, laws, police, and military impose order through variegated spaces at larger scales characterized by bordered zones and throughways. This reflects a continuity in the desire to manage and control urban growth and development of entire regions and even continents.FRICTION FORMS FLUID FRAMEWORKS The rhizome rejects arborescent structures, favoring non-linear, decentralized networks and connections, incompatible with traditional models. The French philosophers Gilles Deleuze and Félix Guattari's influential "A Thousand Plateaus" introduced the "rhizome" philosophical concept - a non-hierarchical, decentralized network characterized by multiplicity, heterogeneity, and non-linearity. Challenging Western metaphysics, it proposed rethinking reality as a dynamic, interconnected assemblage, embracing a rhizomorphic approach of continuous transformation and new connections over linear thinking.Insisting on mapping reality through open-ended experimentation rather than tracing existing structures, the concept embraces spontaneous ruptures forming new connections within emergent cultural networks resembling rhizomes. Having no beginning or end, existing in a constant state of becoming, it resists linear urban narratives and stagnant pure identities. Encouraging "lines of flight," the rhizome breaks from constraints of traditional thinking. The urban as a "smooth space" occupied by the rhizome contrasts sharply with hierarchies of Cartesian power and order.Human cultures also show evidence of embracing this mode of thinking. They too form new connections regardless of imaginary borders.  Jean-Loup Amselle is a French anthropologist known for his studies on African societies, cultural hybridization, and postcolonialism. He introduced the concept of "branchement" (branching) to describe the fluid and interconnected nature of cultures that remind me of what I'm witnessing in my back yard.Amselle's analysis of the N'ko movement in West Africa, which aimed to "debranch" the Manding culture from Arabic and European influences, offers parallels to the Palestinian context and others like Sudan and Ukraine.The Palestinian struggle for self-determination and cultural preservation resists perceived Israeli/Western dominance by asserting Palestinian identity and drawing on global solidarity networks. It shows how local struggles are part of broader global narratives surrounding identities and cultures. This conflict fuels identity-based movements reflecting Amselle's "identity wars" brought on by globalization and strict mapped borders. Amselle's framework rejects fixed identities, emphasizing the interconnections shaping Palestinian, Israeli, Jewish, and Arab identities. The concept of "branchement" highlights the complex entanglements of histories and global forces in the Palestinian conflict, challenging simplistic narratives of cultural purity and separation.The same desire for purity and separation is what led me to ponder border control in my own backyard. I'm even contemplating extermination. All because I saw friction at a border where one plant was not ‘plugging in' to the existing root network, but ‘debranching' another plants by taking over their lives and land.Anna Lowenhaupt Tsing is an anthropologist and professor at the University of California, Santa Cruz. She's known for her interdisciplinary work on globalization, ecology, and the Anthropocene, and for her acclaimed 2005 book "Friction: An Ethnography of Global Connection,"She writes, "Cultures are continually co-produced in the interaction I call 'friction': the awkward, unequal, unstable, and creative qualities of interconnection across difference."Tsing argues that global connections and universalizing projects like dominant forms of Western capitalism, science, and politics do not spread seamlessly but encounter friction and resistance when they engage with specific localities and cultures. These interactions produce new articulations and connections that challenge the universalizing claims of global forces. This, like Amselle, emphasizes the entanglement and co-production of cultures through these encounters.These "zones of awkward engagement" or "cultural friction" are sites where universals collide with particular situations, producing unexpected outcomes and articulations. That's what I witnessed between my “brass buttons” and “Angelina”.“Zones of awkward engagement” and “cultural friction” exist at a city level too as immigrant populations integrate (“plug in” or branch) into established neighborhoods. This can create “cultural friction” as neighborhoods become “zones of awkward engagement”. Zoning and racial or socio-economic redlining are attempts at legal, cartographic, and cultural purity and separation that create awkward zones of friction.But Tsing highlights the importance of collaborations and coalitions that emerge from these zones of awkward engagement. She says, "Despite imperial standards for civil society, I have wandered into coalitions built on awkwardly linked incompatibilities." These collaborations create new interests and ways of being, challenging the singularity of global forces and enabling practices of collaborative knowing and working.PLANETARY PATHS, RHIZOME ROUTESI'm starting to see that local urban frictions, be they down the street or in the streets of Cairo, Chicago, Caraco, or Cape Town, are complex entanglements of histories and global forces. They branch like rhizomes in local frictions of awkward engagement, but also branch to entire other parts of the world. My backyard is a reflection of this. I created a ‘branchement' by planting plants native to vastly separated parts of the globe — New Zealand and Western Europe.Neil Brenner is a critical urban theorist at the University of Chicago and Christian Schmid is a sociologist and urban researcher at ETH Zurich. They're known for the influential concept of "planetary urbanization." They claim urbanization processes today are no longer confined to the traditional boundaries of cities, but rather extend across the entire planetary surface.They argue the classic "city-centric" view is inadequate to capture the multiscalar and multiterritorial dynamics of contemporary urbanization.Instead, they propose that urbanization today is a planetary phenomenon that cuts across the urban/rural divide and transcends the boundaries of individual cities or metropolitan regions. Urbanization unfolds through the constant production, transformation, and operation of socio-spatial configurations at multiple geographic scales, from the body to the globe.This includes the urbanization of seemingly "non-urban" zones like oceans, deserts, and wilderness areas being operationalized and transformed through various urbanization processes. While cities remain vital arenas for urbanization processes, they are embedded within and co-constituted by broader planetary urbanization dynamics that extend far beyond their boundaries. They argue urban theory must move beyond the city as its primary unit of analysis and develop new frameworks, methodologies, and cartographies to grasp the multiscalar and multiterritorial nature of planetary urbanization.This starts by recognizing the rhizomatic interconnections and interdependencies shaping urbanization at various scales, from local to global, and the diverse socio-spatial configurations and infrastructures that form the "urbanization fabric" across the planet. They argue that the "urban" is no longer a bounded condition but a generalized, planetary condition of socio-spatial transformation.The rhizomatic approach emphasizes non-linear and decentralized networks. It offers a valuable framework for urban planning, ecological management, and cultural integration. And even my garden. Just as Leptinella squalida defies linear control in my garden, urban spaces and cultural landscapes resist traditional hierarchical planning. This perspective promotes adaptability and inclusivity, fostering environments that evolve organically and embrace multiplicity and spontaneous connections. They reject unfair dominance or ‘debranching' or mechanisms by which dominant cultures or systems attempt to appropriate, assimilate, or subjugate other cultures or elements within their sphere of influence.Deleuze and Guattari's rhizome and plateau concepts critique cultural dominance and embrace multiplicity, diversity, and coexistence without imposing dominant structures. Applying these ideas to urban integration highlights the potential for hybrid solutions and collaborative networks that recognize fluid identities and dynamic cultural interactions. Amselle's "branchement" and Tsing's "cultural friction" emphasize productive tensions from encounters, challenging narratives of purity.Randomly routing rhizomatous roots, their genes mapping the way, are like the informal settlements and migrant networks. Their sways are modulated by global flows of capital with labor signaling route initiation and elongation in random multi-directional, non-linear physical and virtual networks that reject cartographic convention. Ultimately, this rhizomatic approach aligns with Neil Brenner and Christian Schmid's concept of planetary urbanization by acknowledging the interconnected and multiscalar nature of urban and cultural processes. It calls for new frameworks to understand and address the complex socio-spatial transformations shaping our world. How do we move beyond hierarchical, top-down models that use structural frameworks to shape urban spaces through regulated mapped zones, centralized control, and predetermined paths?Instead of aiming to impose order and coherence by striving to achieve defined end-state visions of bordered, marginated spaces, how might we embrace the interconnected rhizomatous roots and vines of the global urban interlacement — without one crowding out another? Maybe it's time we accept the woven flows of cultures, resources, and infrastructures of the past — and the ever-emerging present middle of rhizomatous networks — made from interplace, the interactions of people and place. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit interplace.io

https://passionstruck.com/passion-struck-book/—Order a copy of my new book, "Passion Struck: Twelve Powerful Principles to Unlock Your Purpose and Ignite Your Most Intentional Life," today! The book was picked by the Next Big Idea Club as a must-read for 2024, the winner of the Business Business Minds Best Book 2024, and a finalist for the Eric Hoffer First Horizon Award for best debut novel.In this episode of Passion Struck, host John R. Miles interviews Dr. Michael Greger, a renowned physician and author who shares valuable insights on preventing diseases, improving health, and promoting longevity through lifestyle interventions. The episode covers a wide range of topics, including the impact of diet on heart disease, strategies for preserving bone health, tips for maintaining cognitive function and enhancing sexual health. Full show notes and resources can be found here:  https://passionstruck.com/dr-michael-greger-on-blueprint-for-healthy-aging/In this episode, you will learn:The importance of lifestyle interventions and promoting health and longevity based on his personal experience with his grandmother's recovery from heart disease.The impact of nutrition on preventing diseases like heart disease and cancer.Insights on the Mediterranean and Okinawan diets, emphasizing the benefits of whole plant foods for overall health.Strategies for preserving bone strength, cognitive health, and sexual function as part of an anti-aging approach.Xenohormesis and microRNA manipulation as potential mechanisms for improving health and longevity through plant-based diets and exercise.All things Dr. Michael Greger: https://nutritionfacts.org/SponsorsBrought to you by Indeed. Head to https://www.indeed.com/passionstruck, where you can receive a $75 credit to attract, interview, and hire in one place.Brought to you by Nom Nom: Go Right Now for 50% off your no-risk two week trial at https://trynom.com/passionstruck.Brought to you by Cozy Earth. Cozy Earth provided an exclusive offer for my listeners. 35% off site-wide when you use the code “PASSIONSTRUCK” at https://cozyearth.com/This episode is brought to you by BetterHelp. Give online therapy a try at https://www.betterhelp.com/PASSIONSTRUCK, and get on your way to being your best self.This episode is brought to you By Constant Contact:  Helping the Small Stand Tall. Just go to Constant Contact dot com right now. So get going, and start GROWING your business today with a free trial at Constant Contact dot com.--► For information about advertisers and promo codes, go to:https://passionstruck.com/deals/Catch More of Passion StruckWatch my interview with Dr. Lucia Aronica On The Impact Of Personalized Nutrition On EpigeneticsMy solo episode on how to heal from the consequences of abuseCan't miss my episode with Dr. Will Cole On How To Restore Your Gut-Feelings ConnectionListen to my interview with Dr. Kara Fitzgerald On How To Become A Younger You By Reversing Your Biological AgeMy solo episode on The Science Of Healthy HabitsCheck Out my episode with Dr. Mark Hyman On The Secrets To Living Young ForeverLike this show? Please leave us a review here-- even one sentence helps! Consider including your Twitter or Instagram handle so we can thank you personally!How to Connect with JohnConnect with John on Twitter at @John_RMiles and on Instagram at @john_R_Miles.Subscribe to our main YouTube Channel Here: https://www.youtube.com/c/JohnRMilesSubscribe to our YouTube Clips Channel: https://www.youtube.com/@passionstruckclips

Before the 1990s, small bits of RNA were considered junk by most, but the 1993 discovery of microRNA (miRNAs) began to reveal that bits of only 19-24 nucleotides of RNA can have an important gene regulation function in cells. Since their discovery, there has been a flurry of work to catalog known miRNAs and understand their functions, which include being tied to specific disease states such as leukemia. According to our guest, Dr. Guy Novotny, Molecular Biologist at Herlev Hospital in Copenhagen, it's now relatively easy to identify a miRNAs and follow their expression, but to figure out what they're actually doing is a real challenge. We hear how he and his team have recently adopted digital PCR, and the benefits that come with it, to study microRNAs and figure out what proteins they're regulating the expression of. This includes basic research, where Guy is “adding to the big pile of data that's existing out there,” and he also does clinical research that has a closer connection to specific disease states and subject outcomes. As always, you'll get to learn about his career journey and learn that there's really not much that cake cannot fix.Visit the Absolute Gene-ius page to learn more about the guests, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

BUFFALO, NY- February 13, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 2, entitled, “IL-17 promotes IL-18 production via the MEK/ERK/miR-4492 axis in osteoarthritis synovial fibroblasts.” The concept of osteoarthritis (OA) as a low-grade inflammatory joint disorder has been widely accepted. Many inflammatory mediators are implicated in the pathogenesis of OA. Interleukin (IL)-18 is a pleiotropic cytokine with versatile cellular functions that are pathogenetically important in immune responses, as well as autoimmune, inflammatory, and infectious diseases. IL-17, a proinflammatory cytokine mainly secreted by Th17 cells, is upregulated in OA patients. However, the role of IL-17 in OA progression is unclear. In this new study, researchers Kun-Tsan Lee, Chih-Yang Lin, Shan-Chi Liu, Xiu-Yuan He, Chun-Hao Tsai, Chih-Yuan Ko, Yuan-Hsin Tsai, Chia-Chia Chao, Po-Chun Chen, and Chih-Hsin Tang from National Chung-Hsing University, Taichung Veterans General Hospital, Shin-Kong Wu Ho-Su Memorial Hospital, Mackay Medical College, China Medical University, Show-Chwan Memorial Hospital, Fu-Jen Catholic University, National Taiwan Normal University, Asia University, and China Medical University Hsinchu Hospital used synovial tissues collected from healthy donors and OA patients to detect the expression level of IL-18 by immunohistochemistry stain. “Elucidation of the molecular mechanisms and main factors involved in OA pathogenesis may help with the development of novel therapeutic targets that relieve OA pain or prevent the disease from progressing.” The OA synovial fibroblasts (OASFs) were incubated with recombinant IL-17 and subjected to Western blot, qPCR, and ELISA to examine IL-18 expression level. The chemical inhibitors and siRNAs which targeted signal pathways were used to investigate signal pathways involved in IL-17-induced IL-18 expression. The microRNAs which participated IL-18 expression were surveyed with online databases miRWalk and miRDB, followed by validation with qPCR. This study revealed significantly higher levels of IL-18 expression in synovial tissue from OA patients compared with healthy controls, as well as increased IL-18 expression in OASFs from rats with severe OA. In vitro findings indicated that IL-17 dose-dependently promoted IL-18 production in OASFs. Molecular investigations revealed that the MEK/ERK/miR-4492 axis stimulated IL-18 production when OASFs were treated with IL-17. “This study provides novel insights into the role of IL-17 in the pathogenesis of OA, which may help to inform OA treatment in the future.” DOI - https://doi.org/10.18632/aging.205462 Corresponding authors - Po-Chun Chen - pcchen@ntnu.edu.tw, and Chih-Hsin Tang - chtang@mail.cmu.edu.tw Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts 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: 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 Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

En el episodio de hoy, nos acompaña el Dr. Amilton de Mello, líder del Programa de Ciencia de la Carne en la Universidad de Nevada, Reno. En esta conversación, el Dr. De Mello compartirá sus conocimientos sobre las microRNAs y su papel clave en la biogénesis, así como información valiosa sobre la producción y nutrición de la carne. Discutiremos aspectos fascinantes, desde el proceso de síntesis de microARNs hasta la influencia de los lípidos en la protección de proteínas. Además, exploraremos los tipos de carne en las que actualmente se enfoca el Dr. De Mello, con énfasis en las de diferencias entre carne de res y proteínas de plantas.

有識者会議、Seattle Hub for SynBio、マイク談義、理論系とのコラボについて雑談。論文紹介は、性周期に依存した報酬予測誤差シグナルの違い、Cas9 RNPそのものを細胞内に導入する手法、マウス用VRゴーグル、細胞種特異的なmiRNAをbulkのRNA seqで読む手法、ヒトからラットへの恐怖伝達、など (12/10 収録) Show Notes (番組HP): 雑談パート グローバル・スタートアップ・キャンパス構想に関する有識者会議 齋藤さんNR回 1 2 使った発表資料(pdf) Nature Biotech のChurchラボに関する記事 (pdf) ヴィースのHow We Work ヴィースのしくみに関する記事 Business Development人材のリスト Allen +UW+CZIのSeattle Hub for Synthetic Biology Jay Shendure David Baker Rui Costa 浜崎さん 林さん 浜崎さんの歴史的な仕事 コンデンサマイク vs ダイナミックマイク Blue Yeti Brooks Brothers破産 今年のBlack Fridayはそんなに良くない？：10月からの割引が結構あったという話らしい？ Shure MV7 Shure SM58 Shure Beta 87A イアンの回 昔の北沢さん回 MOTU M2 Shure SM7B (Geforce RTX) 3090 Neumann U87 Ai U47 Frank OceanがBlondeのレコーディングで使用 Jeremiah Cohen UWのEric Shea-Brown 豊泉さん Stefan Mihalas MindScope終了 Shaul Druckmann 最後の方の稲垣さんの仕事 Sandro Romani M3 Pro Max 論文紹介パート 論文１：Estrogenic control of reward prediction errors and reinforcement learning Christine Constantinopleラボ Randy Brunoラボ Brunoラボ時代の仕事 Thalamo-cortical Axonのターゲットlayerは皮質によって異なる (モダリティではなく一次/二次感覚野の違いでした 脇) Bruno、ポスドク時代の超絶技巧 Larkumラボ の上だけ止めるmanipulation：たとえばコレのBaclofen局所投与 Brodyラボ Brodyの所で出した論文 1 2 塩野七生 ローマ人の物語 コンスタンティノープルの陥落 中島さんのCellの仕事 さやかさん回 1 2 3 4 タスクの詳細が載ったNature Communicationsの仕事 Silvia Arber optogenetic activation assesses what a neuron can do, but not what a neuron does do さやかさんの論文 AllenのABC Atlas GPCRのInternalizationによる不活性化 DATのアンタゴニストGBR 12909 柳下さんの一連の仕事 – Slice: 1; Behavior:2 George Augustine Erwin Neher 細胞内カルシウムのモデリングの仕事 論文２：Engineering self-deliverable ribonucleoproteins for genome editing in the brain Doudnaラボ SV40 NLSをつけるとそのまま入る、の論文 Cell Penetrating Peptide に関するレビュー 筆頭著者が同時に出していたLNPによる投与のプレプリント Broadの人達がやっているデリバリー 1 2 3 論文３： Full field-of-view virtual reality goggles for mice Daniel Dombeck David Tank ２光子顕微鏡の下でマウスを走らせたNeuron論文 (2007) 海馬での応用が2010 NN Chris Harveyの仕事 Moserとかがオーサーに入ってる、VR使用時の注意点ディスカッション Zemax 論文４：Mime-seq 2.0: a method to sequence microRNAs from specific mouse cell types Loisa Cochella Mime seqその１ in Nat Meth miRNAによるAstrocyte以外でのTransgene分解 glycolRNA Cell 2021 Bertozzi 筆頭著者のRyan Flynn 続報プレプリント Bertozziは元々糖鎖合成の化学者でした 論文５：Rats respond to aversive emotional arousal of human handlers with the activation of the basolateral and central amygdala ハンドラーの性によって行動が変わる、の論文 ラット、かくれんぼする ラット、くすぐられて笑う Brecht Contributed Submissionがなくなった? ->嘘でした、まだあります。 Editorial Notes: マイク沼、CPU/GPU沼、対物レンズ沼は奥が深そうで怖い (脇) 昔はひたすらマーガレットおばさんのシャツとニットを着てましたが、体がデカくなって着れなくなったので全部捨てて、以降ほぼ全部ユニクロ(か山系)です(萩)

Dr. Peter Hotez is a veritable force. He has been the tip of the spear among physicians and scientists for taking on anti-science and has put himself and his family at serious risk.Along with Dr. Maria Bottazzi, he developed the Corbevax Covid vaccine —without a patent— that has already been given to over 10 million people, and was nominated for the Nobel Peace Prize. Here an uninhibited, casual and extended conversation about his career, tangling with the likes of RFK Jr, Joe Rogan, Tucker Carlson, Steve Bannon, and an organized, funded, anti-science mob, along with related topics.Today is publication day for his new book, The Deadly Rise of Anti-Science.Transcript (AI generated)Eric Topol (00:00):Hello, this is Eric Topol with Ground Truths, and I'm with my friend and colleague who's an extraordinary fellow, Dr. Peter Hotez. He's the founding dean of the National School of Tropical Medicine and University professor at Baylor, also at Texas Children's founding editor of the Public Library Science and Neglected Tropical Disease Journal. and I think this is Peter, your fifth book.Peter Hotez (00:28):That's my fifth single author book. That's right, that's right.Eric Topol (00:32):Fifth book. So that's pretty amazing. Peter's welcome and it's great to have a chance to have this conversation with you.Peter Hotez (00:39):Oh, it's great to be here and great to be with you, Eric, and you know, I've learned so much from you during this pandemic, and my only regret is not getting to know you before the pandemic. My life would've been far richer. AndPeter Hotez (00:53):I think, I think I first got to really know about you. You were are my medical school, Baylor College of Medicine, awarded you an honorary doctorate, and that's when I began reading about it. Oh. I said, holy cow. Why didn't, why haven't I been with this guy before? SoEric Topol (01:08):It's, oh my gosh. So you must have been there that year. And I came to the graduation.Peter Hotez (01:12):No, I actually was speaking at another graduation. That's why I couldn't be there, . Ah,Eric Topol (01:18):Right. As you typically do. Right. Well, you know, it's kind of amazing to track your career besides, you know, your baccalaureate at Yale and PhD at Rockefeller and MD at Cornell. But you started off, I, I think deep into hookworm. Is that where you kind of got your start?Peter Hotez (01:36):Yeah, and I'm still, and I'm still there actually, the hookworm vaccine that I started working on as an MD-PhD student at Rockefeller and Cornell is now in phase 2 clinical trials. Wow. So, which is, I tell people, is about the average timeframe --about 40 years-- is about a, not an unusual timeframe. These parasites are obviously very tough targets. oh man. And then we have AOIs vaccine and clinical trials and a Chagas disease vaccine. That's always been my lifelong passion is making vaccines for these neglected parasitic infections. And the story with Covid was I had a collaboration with Dr. Sarah Lustig at the New York Blood Center, who, when we were working on a river blindness vaccine, and she said, Hey, I want you to meet these two scientists, New York Blood Center. They're working on something called coronaviruses vaccines.(02:27):They were making vaccines for severe acute respiratory syndrome and SARS and ultimately MERS. And so we, we plugged their, their, some of their discoveries into our vaccine development machine. And they had found that if you were using the receptor binding domain of the, of the spike protein of SARS and ultimately MERS it produced an equivalent protective immune response neutralizing antibodies without the immune enhancement. And that's what we wrote to the NIT to do. And they supported us with a $6 million grant back in 2012 to make SARS and MERS vaccines. And, and then when Covid 19 hit, when the sequence came online and BioXriv in like early 2020, we just pivoted our program to Covid and, and we were able to hit the ground running and it worked. Everything just clicked and worked really well. And stars aligned and we were then transferred that technology.(03:26):We did it with no patent minimizing strings attached to India, Indonesia, Bangladesh. any place that we felt had the ability to scale up and produce it, India went the furthest. They developed it into Corbevax, which has reached 75 million kids in India. And another 10 million as their, for their primary immunization. Another 10 million is adult booster. And then Indonesia developed their own version of our, of our technology called IndoVac. And, and that's also reaching millions of, of people. And now they're using it as a, also as a booster for Pfizer, because I think it may be a superior booster. So it was really exciting to s you know, after working in parasitic disease vaccines, which are tough targets and decades to get it through the clinical trials because the pressure was on to move quickly goes to show you when people prioritize it. And also the fact that I think viruses are more straightforward targets than complex parasites. And well, so that in all about a hundred million doses have been administered andEric Topol (04:33):Yeah, no, it's just a spectacular story, Corbevax and these other named of the vaccine that, that you and Maria Bottazzi put together and without a patent at incredibly low cost and not in the us, which is so remarkable because as we exchanged recently, the us the companies, and that's three Moderna, Pfizer, and Novavax are going to charge well over $110 per booster of the, the new booster updated XBB.1.5. And you've got one that could be $2 or $4 that's,Peter Hotez (05:11):And it's getting, so we're making, we're making the XBB recombinant protein booster of ours. And part of it's the technology, you can, you know, it's done through microbial fermentation in yeast, and it's been in a big bioreactor. And it's an older technology that's been around a couple of decades, and there's no limit to the amount you could scale. The yields are really high. So we can do this for two to $3 a dose, and it'd even be less, it wasn't for the cost of the adjuvant. The C P G, the nucleotide is probably the most expensive component, but the antigen is, you know, probably pennies to, to, you know, when you're doing it at that scale. And, and so that, that's really meaningful. I'd like to get our XBB booster into the us It's,Eric Topol (05:55):Yeah, it's just no respect from,Peter Hotez (05:58):We're not a pharma company, so we don't, we didn't get support from Operation Warp Speed, and so we didn't get any US subsidies for that. And it's just very hard to get on the radar screen of BARDA and those agencies and, 'cause that's, they're all set up to work with pharma companies.Eric Topol (06:16):Yeah, I know. It's, it's just not right. And who pays for this is the people, the public, because they, you know, the affordability is going to have a big influence on who gets boosters and is drivingPeter Hotez (06:27):. Yeah. So, so what I say is we, we provide, you know, the anti-vaccine guys, like the call me a Shill for pharma, not knowing what they're talking about. We've done the opposite, right? We've provided a path that shows you don't need to go to big pharma all the time. And, and so they should be embracing what we're doing. So we, we've, you know, have this new model for how you can get low cost vaccines out there. Not, not to demonize the pharma companies either. They, they do what they do and they do a lot of important innovation. But, but there are other pathways, especially for resource coordination. So we'd love to get this vaccine in, in the us I think it's looking a little work just, just as well, it's, you know, butEric Topol (07:12):You, yeah, I mean, it's not, I don't want ot demonize the vaccine companies either, but to raise the price fivefold just because it's not getting governed subsidy and the billions that have been provided by the government through taxpayer monies. Yeah.Peter Hotez (07:28):Well, the Kaiser Family Foundation reported that they did an analysis that, that pharma, I think it was Pfizer and Moderna got 25 to 30 billion Yeah. Dollars in US subsidies, either for development costs for Moderna. I think Pfizer didn't accept development costs, but they both took advanced purchase money, so $30 billion. And you know, that's not how you show gratitude to the American people byEric Topol (07:55):JackingPeter Hotez (07:56):Up the price times for, I think I said, guys, you know, have some situational awareness. I mean, do you want people to hate you? Yeah.Eric Topol (08:04):That's what it looks like. Well, speaking of before I get to kind of the anti-science, the, THE DEADLY RISE OF ANTI-SCIENCE, your new book, I do want to set it up that, you know, you spent a lot of your career besides working on these tropical diseases, challenging diseases, you know, Leischmania, and you know, Chagas, and the ones you've mentioned. You've also stood up quite a bit for the low middle income countries with books that you've written previously about forgotten people, Blue Marble Health. And so, I, I, before I, I don't want to dismiss that 'cause it's really important and it ties in with what the work you've done with the, the Covax or Covid vaccine. Now, what I really want to get into is the book that you wrote that kind of ushered in your very deep personal in anti-science and anti-vax, which I'm going in a minute ask you to differentiate. But your daughter, Rachel, you wrote a book about her and about vaccines not causing autism. So can you tell us about that?Peter Hotez (09:11):Yeah. So as you point out, my first two books were about these, what I would call forgotten diseases of Forgotten people. In fact, that's what the first book was called, forgotten People, forgotten Diseases, which my kids used to call Dad's Forgotten book on Forgotten people, Forgotten Diseases, all the, all the, now it's in his third edition. So, but it talks about, you know, the, how important these conditions are. It's just that they're widely prevalent. It's just that they're occurring among people who live in extreme poverty, including people in poverty in the United States. That's why we set up our School of Tropical Medicine on the US Gulf Coast. I didn't do it for the summer weather which is these days in this heat dome. It's like, well, living on planet Mercury right now, in here, here in Texas.(09:58):But then, so that, that's what, that's how I started learning how to advocate, you know, for people and for diseases through neglected diseases. But, you know, when we came to Texas, we saw this very aggressive anti-vaccine movement, and they were making false claims that vaccines cause autism. And, and I said, look, I'm, you know, I'm a vaccine scientist here in Texas. I have a daughter with autism, Rachel, with an, an intellectual disabilities. And so if I don't say something who does, and, and then wrote the book, vaccines did not cause Rachel's Autism, which unfortunately made me public enemy number one or two with anti-vaccine groups. but you know, it, it, it does a deep dive explaining the science, showing there's absolutely no link between vaccines and autism, but also an absence of plausibility because what we know about autism, how it begins in early fetal brain development through the action of autism genes.(10:54):And we actually did whole exome genomic sequencing on, on Rachel and my wife Ann and I, and we found Rachel's autism gene, which is like many of them in, involved in early neuronal communication and connections. It was actually a neuronal cytoskeleton gene, as are many, in this case, a neuronal spectrum. And that one hadn't been reported before, but other neuronal cytoskeleton genes had been reported by the Broad Institute at Harvard, m i t and others. And, and that was important to have that alternative narrative because the refrain from always was, okay, doc, if vaccines don't do it, what does cause autism? And, and being able to have that other side of the story, I think is very compelling.Eric Topol (11:37):What was it, the, the fabricated paper by Andrew Wakefield and the Lancet that, that got all this started? Or did it really annotate the ? There wasPeter Hotez (11:47):Something before in the eighties about the DPT, the diptheria, pertussis tetanus vaccine claiming it caused, you know, seizures and then could lead to neurodevelopmental difficulties. But it really took off with the Wakefield paper in 1998, published in The Lancet. And that claimed that the MMR vaccine, a live virus vaccine, had the ability to replicate in the colon of kids. And somehow that led to pervasive developmental disorder. That was the term used back then. And I was Rachel's diagnosis. And it never made sense to me how something, 'cause the reason it's pervasive is it's, it's global in, in the central nervous system in, in the brain. And how, how could something postnatally do something like that? I mean, there is, there are epigenetic underpinnings of autism as well, and that's fun. Eric, you ever talk to, ever try to talk to lay audience about epigenetics? That's a tough one. That's, that's a tough one. You start talking about microRNAs and DNA methylation, histone modification. The, the lights go out pretty quickly, butEric Topol (12:46):Chromatin and histone modification. Right? Bye-bye. Yeah, you got that one.Peter Hotez (12:51):That, so that's,Eric Topol (12:52):But that, that was your really, you knowPeter Hotez (12:55):But that's when, you know, I started going up against Robert F. Kennedy Jr. And, and, and all that was, that was pre-pandemic.Eric Topol (13:03):That was in 2018, right?Peter Hotez (13:05):2017 Trump came out and said, you know, it was about to be inaugurated and, and RFK Jr said he was going be appointed to run a vaccine commission by the Trump administration. And, and I actually was sitting, you know, in my office and my assistant said Dr. Francis Collins and Dr. Anthony Fauci are on the phone. Do you have time to talk with us ? And I said, yeah, I think so. And they arranged, they had arranged for me to, because I have a daughter with autism could articulate why vaccines don't cause out arranged for me to speak with RFK Jr threw it through a mediator and, and, and it didn't go well. He was just really dug in and, and soEric Topol (13:49):He, he was just as bad then as now.Peter Hotez (13:52):Yeah. I mean, it was just, you know, kept on, you know, as I say, moving the goalposts, you couldn't pin him down. Was he talking about MMR? Was he talking about the am Marisol, was he talking about spacing vaccines too close together? He just, that always kept on moving around and, and then it was not even autism at times. You were talking about it was something called chronic illness, you know, you know, what do you do with that? Mm-hmm. . So I, and that's one when I was challenged by, you know, Joe Rogan and Elon to debate RFK Jr, one of the reasons I didn't want to do it, because I, I knew, you know, doing it in public would be no different from doing this in, in, in private, that it would not be a productive conversation.Eric Topol (14:39):Yeah, no, that I can, I do want to get into that, because that was the latest chapter of kind of vicious anti-science, which was taking on covid and vaccines and the whole ball of wax whereby you were challenged by Joe Rogan on his very big podcast, which apparently is, you know, bigger than CNN  various cable news networks,Peter Hotez (15:07):Which I had done, I had been on his show a couple of times. Yeah. And that was, and that was okay. I mean, I actually liked the experience quite a bit. AndEric Topol (15:15):And he challenged you to go on with RFK Jr. And then Elon Musk, you know, joined and, you know, basically Peter Hotez (15:21):Actually, he started before then, about the week before, or a few days before, Steve Bannon publicly declared me a criminal. And you know, which I said, wow, that's, that's something. And then Roger Stone weighed in. So it was this whole sort of frontal attack from, well, people with extremist viewpoints. And there'sEric Topol (15:41):Been a long history, and a Tucker Carlson in the book, you quote, he referring to Hotezis a misinformation machine constantly spewing insanity. Speaking of projecting things, my goodness. Yeah.Peter Hotez (15:54):Yeah. Well, he did that. You know, he, that was the, that was in 2022. It was, he went on his broadcast the evening after the evening of the, in the, during that day I, with Maria, I was, we were nominated for the Nobel Peace Prize. And I guess, and I don't know if the two are related or not, I think it may have driven him off the edge, and then he just went on this rant against me. And, you know, claimed I have no experience anything about Covid. I mean, we had made two covid vaccines, right. And transferred the technology nominated for the Nobel Peace Prize and just, you know, omitted all of that. But this is how these guys work. It's, it's all about asserting control. And, and it seems to come from an extremist element of the, of the far right.(16:39): and, and, and it's not that I'm a very political person at all. I mean, you know, I've been here in Texas now for 12 years, and I've gotten, you know, I've gotten to know people like Jim Bakker and his wife Susan Baker and, and you know, a lot of prominent Republicans here in Texas, that that wasn't an issue. This is something sort of weird and, and twisted. And, and the point that I make in the book is, and it's not just a theoretical concern or a construct, it's the fact that so many Americans lost their lives during the delta and BA.1 omicron waves in 2021 and 2022, after vaccines were widely and freely available because they refused a vaccine. so vaccines were rolled out in 2021. we started strong and then vaccination rates stalled. And then we didn't get very far by this after the spring because there was this launch of an, of, of a wave of what I call anti-vaccine or anti-science aggression, convinced that deliberately sought to convince Americans not to take a covid vaccine.Eric Topol (17:56):Chapter, yeah. Your chapter in the book Red Covid. Yeah, gets into it quantifies it, hundreds of thousands of lives lost. And I know you've seen some of the papers whereby studies in red states or states like Ohio and Florida showing the, the, the connection between this.Peter Hotez (18:15):Yeah, I, I relied heavily on this guy Charles Gaba, who has a, a website called ACA signups. And he did some really in, you know, strong analysis showing that the, that the people who were refusing covid vaccines and losing their lives were overwhelmingly in red states and could even show the redder the county as measured by voters, the lower the immunization rate and higher the death rates. And the term Red Covid came from David Leonhart of the New York Times wrote an article about Charles Gaba's work, and he called it Red Covid and did a lot of updates. And the data is so strong. I mean, so much so that one person at the Kaiser Family Foundation wrote, if you wanted to ask me whether or not a person was vaccinated, and I can only know one thing about them, you know, she said, the one thing I'd want to know is what political party they're affiliated with.(19:09):It was, it's, it's that strong. And it's, and it's not that I care about your politics, even your extreme views, but somehow we have to uncouple this one from it, right. Because somehow not getting vaccinated been added to the canon of stuff that you're supposed to believe in. If you are, if you're down that rabbit hole watching Fox News every night, or, or listening to Rogan Podcasts and that sort of stuff. And somehow we have to uncouple those two, and it's the hardest thing I've ever had to do. First of all, it's unpleasant to talk about, because all of, you know, your training, Eric mine as well is, you know, said you don't talk about politics and you're, you know, we're supposed to be above all that. But what do you do when the death and dying is so strong on, on one side?(19:58):And, and I, I was in east Texas not too long ago, giving grand rounds at a new medical school in East Texas and Tyler, Texas, and very conservative part of the state. And, you know, basically everyone you talked to has lost a loved one mm-hmm. because they refused a Covid vaccine and died. I mean, that's, that's where you really start to see that. And then, and these people are wonderful people. I gave you know Bob Harrington at oh yes, at at Stanford Medicine, now he's going be the Dean of Cornell. He, he invited me with Michelle Berry to, to give grand rounds, medical grand rounds at Stanford. And I said, look, if, if my car had broken down and the flat had a flat tire, and you, and I can't fix, I'm, I'm a disaster at fixing anything.(20:49):So if you said, okay, where you had the choice, where, where do you want your car broken down in Palo Alto, California, or Stanford is, or very wealthy enclave or East Texas, I'd say I'd pick East Texas in a second. 'cause in East Texas, they'd be fighting over who you know, is going to rush to help you change your tire. Right? And these are, you know, just incredible people. And they were victims. They were victims of this far right. Attacks from, from Fox News. And one of the things I do in the book is, you know, the documentation is really strong media matters. The Watchdog group has looked at the evening broadcast of Tucker Carlson, Laura Ingram, and, and Hannity, and, you know, can I, you know, actually identify the anti-vaccine content with each broadcast during the summer and fall. And then our a social science research group out of ETH Zurich, the Federal University of Technology of Zurich, where Einstein studied, actually, you know, one of the great universities did another analysis and showed that watching Fox News is one of the great predictors of refusing a vaccine.(21:52):And, and so that, those were the amplifiers, but those generating a lot of the messages were elected leaders coming out of the House Freedom Caucus, or Senator, you know, Johnson's conservative senate that, I don't even like to use the word conservative, because it's not really that they're conservative, they're extremists. And yeah, a Senator Johnson of Wisconsin, or Rand Paul, you know, of, of Kentucky, you know, all the physician know what Yeah. And know physician and the CPAC conference of conservatives in Dallas, in 2021, they said, first you're gonna, they're going to vaccinate you, and then they're going to take away your guns and your Bibles. And as ridiculous as that sounds to us, people in my state of Texas and elsewhere in the South accepted it and didn't take a covid vaccine and pay for it with their lives. And, and how do we, you know, begin walking that back?(22:45):And, and the point of writing the book said, well, the first step is to at least describe it so people can know what we're talking about. Because I think right now, when you look at the way people talk about anti-vaccine or anti-science stuff, they, they call it misinformation or the infodemic, like it's just some random junk that appears out of nowhere on the internet. And it's not any of those things. It's, it's organized, it's well financed. It's politically motivated, and it's killing Americans on, on a massive scale. So I said, look, you know, I, I went, I'm did my MD and PhD in New York at Rockefeller and Cornell. I devoted my life to becoming a vaccine scientist. You know, the motto of Rockefeller universities to be the Rockefeller Institute of Medical Research translates to science for the benefit of humanity. And, and I believe making vaccines is one of the high expressions. And I think most physician scientists believe, I think you believe that too. And that's why you're, you're in this as well, you know, not vaccines, but you know, other lifesaving interventions. And, and so I said, well, now making vaccines is not enough. 'cause now we have to counter all of this anti-vaccine stuff, and there's, there's nobody better, you know, in terms of my training and my background going up against anti-vaccine movements because of Rachel to do this. So I, I've done it and yeah.Eric Topol (24:11):Well, you've done it. All right. you,Peter Hotez (24:14):That's my wife. Ann says you've done it. Alright, .Eric Topol (24:17):Well, as I wrote in your, with your book of blurb about you are a new species, the physician scientist warrior, and you are Peter, because you're the only one of all the physicians. We're talking about a million docs almost in this country who has stood up and you've put your life at risk, your family at risk, you've had death threats, you've had the people you know, come right to your house. and so what you've described this kind of coalescence of political will of extremists, media, of course, amplification because it benefits them. They, they're selling more you know, they get more viewers, more the spots for commercials and more they can charge. And then you're even, as you described in the book, so well, is you even have outside interested parties like Russia as part of this organization, of this coalescence of forces that are taking on the truth, that are promoting anti-science, that are winding up, people are dying, or, yeah. Or having a, you know, serious morbidity,Peter Hotez (25:26):Right? Yeah. In the case of, in the case of Russia, , it's a slightly different motivation. What they're doing is they're filling the internet and social media with both anti-vaccine messages and pro-vaccine messages. Because they have a different agenda. Their agenda is destabilized democracies. So what they're doing is they're cherry picking certain issues that they can use as a wedge to sow discord. And so when they saw the stuff about vaccines, yeah, they'll flood it with both pro and anti-vaccine message. And you see the stuff on Twitter, so much of it is computer generated, and it's just repeats the same stuff over and over again. And, and a lot of that are, you know, some of that not only, only Russia, I think China's doing it, North Korea, Iran's doing it, but particularly Russia. And that was documented by a colleague of mine, David Broniatowski who's a computer scientist at George Washington University, has really done a deep dive in that. So so'sEric Topol (26:22):I think a lot of people are not aware that's what your book, book brings to light of how organized, how financed, you know, how this thing is a machine from coming from many different domains, you know, and for different interests as you, as you just summarized, it's, it's actually scary. And besides you standing up and facing, you know, the really ultimate bravery with the, all of the, these factions attacking you, literally ad hominem, you know, personally attacking you, then you have you know, this continues to get legs throughout the pandemic, and there's no counter as you've, as you've touched on what is going to be done. You can't stand up alone on this.Peter Hotez (27:09):Well, there's, there's a couple of things. First of all, it's not only attacking the science, it's attacking the scientists. Right, right,Eric Topol (27:15):Right.Peter Hotez (27:16):Exactly. It's, it's portraying and you get get it too, as well. I mean, it's basically portraying scientists as enemies of the state. which I think is so dangerous. I mean, as I like to say, you know, this is a nation that's built on science and technology, right? The, you know, the strengths of our research universities and institutions like Scripps, like Baylor, like Rockefeller, like MIT and Stanford, and University of Michigan and University of Chicago. This is what, you know, helped us defeat fascism in World War II as evidenced by the Oppenheimer movie, right. Or, and or allowed us to achieve so many things, why people so admire our nation. When I served as US Science Envoy and the Obama administration, the State Department, and the White House. I mean, that's where people loved our country, is they all wanna study at our research universities, or they want their kids to study at our research universities.(28:10):And, and by attacking not only science, but the scientists, I think it's weakening our stature globally. And, and, and, and I think that's, that, that's another aspect. I think the other problem is we, we don't get the backing that I think we should from the scientific societies in the Times, even the National Academies. I think they, they could be out there more. exactly why, you know, I think part of it is they see, they see how I get beat up and they say, well, what's that? Right? Yeah. And I, and I understand that, but I think also, you know, they, they depend on, oftentimes on government funding. And I think they're worried that, you know, if they're, again, it's this idea that you have to be politically neutral, even if it favors the torment or the aggressor to paraphrase Desmond Tutu, that's part of it as well.(29:09):I mean, it, I mean, I do find it meaningful. It's scary at times, and I, but I do find it meaningful to ha to have this role. But getting, getting more help and backing, I mean, we're our, our university, I mean, Baylor College of Medicine, Texas Children's Hospital has been pretty good. You know, Stan, you know, having my back, it's not that way at every, and I know Scripps has been really strong with what Kristian Anderson's had to deal with around you know, all the phony bologna around covid origins. But, but not all academic health centers are that way. And, and I think we need our university presidents to be more vocal on this issue. And, and too often they're not as well as our academies and our, our scientific societies, because this is, I believe, going to do irreparable harm to, to science. Well, yeah.Eric Topol (30:04):You know, in my experience too, we, we've actually seen, you know, academic physicians who have basically, you know, supported conspiracy theories who have detracted from evidence and science, you knowin a major way. Some of the leading universities here as you, as you mentioned. And when I've contacted and others, their leadership, they say, well, freedom of speech, freedom of speech. 'cause they're afraid to confront them because, you know, all the different things. We've, we, you've mentioned social media, but no, the universities don't want to get attacked on social media. They're afraid of that. They're afraid of, of calling out, you know, one of the people, faculty members who are deliberately, you know garnering a lot of, yeah. And,Peter Hotez (30:56):And the point is, is it's not just, you know, freedom of speech in the sense of espousing you know, crazy views. It's the fact that they're going on the attack against mm-hmm. . I mean, I don't attack these guys, but they attacked me with, with impunity and Yes. Say terrible thing, untrue things about me. I mean, where's there's, isn't there something called professionalism or, or ethics, yeah. Right. That don't, don't, don't, don't we, aren't we supposed to be in instilling that in our, in our faculty and, and that that doesn't seem to happen.Eric Topol (31:28):So that'sPeter Hotez (31:28):Troubling asEric Topol (31:29):Well. They're, they're making credible scientists who are doing the best they can into pinatas Right. And attacking them. And with, and it can't, it can't be reciprocated because that's, that's beneath professionalism. I mean, just as you say. So, you know, you just keep, they just keep going at it. So what you have is now we've added all these different entities and all add more. One more is ai, which is going to further blur the truth.Peter Hotez (31:59):Yeah, Renee DiResta at the Stanford Internet Observatory, I don't if you know Renee, she does fabulous work. And she's written about, you know, what happens when, you know, all of the anti-science, anti-vaccine stuff is now imbued with ai, and, you know, it's going become even more sophisticated and more difficultEric Topol (32:17):To No, there's, there's gonna be a video of you saying that, you know, these vaccines are killing people but don't get a booster and it'll be just like you with your voice. Yeah.Peter Hotez (32:28):Well, they already, they already have. Now these, there's these few things on YouTube that, that claim, I'm secretly Jack Black, the actor . And that the CIA has arranged it so that Jack Black plays this fictional character named Dr. Peter Hotez. And they do all these things like, you know, focus in on my eyes and do like eye identification. It's just, it's just nuts. I mean, what, what's out there?Eric Topol (32:54):Well, has there been a time in these months where you were very scared you, you're for yourself or your family because of all the incredible density and, and what appears to be very serious threats and duringPeter Hotez (33:08):, during, during the day, during the day, I'm okay. I mean, in, you know, when the, when the, when the Steve Bannon in stuff and Joe Rogan stuff, then I had the stalking at the house, and, you know, I had to have a Houston Police Department officer parked in front of my house or a Harris County Sheriff that, that was troublesome. But it, it's more of during the day, I am fine. I'm working, I'm talking, you know, to people like you and in lab meetings, doing what scientists do, writing grants and throwing pencils at the wall when you get a paper with a major review or, or a major revision or rejection. But, but it's, I think at night, you know, wake up in the middle of the night and the, it's, the stuff does start to mess with your head at times. And it'sEric Topol (33:54):Well, and you travel a lot and you, you've, I think expressed that, hey, you could be given a talk in an innocent place and somebody could come, you know, attack youPeter Hotez (34:04):There. Yeah. So I have to, I have, I have security now at, in major venues when I speak. and, you know, I had an, there was an incident at the World Vaccine Congress in Washington. There were protesters out in front of the, out in front of the convention center waiting for me that that wasn't fun. And so, even, you know, we've got, we'll see what happens with the, when the, you know, I'm doing a number of events around the book in Washington DC and New York and elsewhere. We'll, we'll see how that goes. soEric Topol (34:38):Well take it. You, you're, I know you well enough to know that you're an optimistic person. I mean, you've been smiling and we've been laughing during this and discussing some very heavy, serious stuff. What gives you still optimism that this can someday get on track?Peter Hotez (34:57):Well, I think it could get worse before it gets better, first of all. And, and two fronts. One, you know, I had the opportunity to meet with Dr. Tedros, the World Health Organization Director, general of World Health Organization towards the end of last year. And to say this could be the warmup act in the sense that now it's globalizing. I'm anticipating spillover all childhood immunization rates. And, you know, you're starting to see the same US style of anti-vaccine rhetoric now, you know, even in low and middle income countries on the African continent in South Asia. So I worry about, you know, measles and polio, both in the US and, and globally. I think that's, that's, I'm worried about that. The other is, you know, a lot of this is heating up, I think because of the 2024 presidential election. I think one was that with, with our, our mutual friend and colleague Anthony Fauci, now that he's out of government he's not as visible as he was.(35:58):I think they're, the, the extremists are looking around for another, they need a monster right. To, to galvanize the base. And I think I've become that monster. You know, that's, that's one thing I'm worried about. But also you with, I talk to probably someone you've seen on Twitter. and I've gotten to know her somewhat, I'm very impressed with her. Molly Chong Fast, who's a commentator on c n at M S N B C, and she, you know, put out there, and she told me privately and put it out in public that, you know, one of the reasons why things are so vicious around RFK Jr, as they see him as a third party candidate that could take Biden votes away and help create a path for Trump being elected. So by, you know, by having me debate him, it, it kind of elevated in, in its own way, elevated his stature and made him seem like a more serious person. Right, right. And my refusal, you know, popped their bubble. And that, that's one of the reasons why, why they're so angry. So this is very much tied, I think, to the 2024 presidential look. And that's what you're having seen with the House subcommittee hearings too, portraying scientists as enemies of the state. It's all for, I mean, I don't know if you've seen this, the, that House Subcommittee Twitter site, it actually says something like, we're selling popcorn, you know, we'reEric Topol (37:18):Yeah, I know. I mean,Peter Hotez (37:20):They're, they're not, they're not even pretending it's anything, theEric Topol (37:23):PoliticalPeter Hotez (37:23):Theater for Fox News soundbites. So I think we're gonna see they're the word.Eric Topol (37:27):Alright. Yeah.Peter Hotez (37:28):Yeah. And, and, but, you know, but the attacks on biomedical science, I think are gonna be, you know, have a long-term effect. If for no other reason, I think people are gonna think twice about wanting to do a PhD in biomedical scientist or become an MD PhD scientist when they see that, you know, we'reEric Topol (37:47):. Well, that's what you, you also covered that really well in the Yeah. In the book. But when you think about where we are now with climate crisis, or we're facing future pandemics, not just the one we're still working through here where is the hope that we can counter this? I mean, we need armies of people like you. We need, as you say, the scientific establishment and community all stand up. That, that gets me to one of the things that makes you differentiates you from most physicians and scientists. You write books, you are active on social media. You, you appear on the media. Most scientists grew up to have their head do the work, do good science, get their stuff published, and get grants and, you know, try to advance the field and physicians doing that, are taking care of patients, same kind of thing. What prompted you in your career to say, Hey, you know, that's not enough. I got another dimension. And why, how can we get millions of clinicians and scientists to rally to do what you'rePeter Hotez (39:01):Doing? Well, in my, in my case, I, it's not that I was deliberately seeking to be a public figure or what some call a public intellectual. It was more the case, the issues that I was most interested in, nobody was talking about. Mm. And nobody was going to talk about it. So if I didn't talk about it, it wasn't gonna be talked about. So neglected tropical diseases, you know? Yeah. For guard people was, and, and I had two colleagues in the uk, Alan Fannick and David Mullen, who felt the same way. And so we began be, we became the three Musketeers of the neglected tropical disease space. And I found that extremely meaningful and interesting. And it was the same with vaccines. So although I, I'm often in the, you know, doing a lot of public engagement, if you notice, I don't try to be like some people who do it very well, like as Sanjay Gupta or, or some others that will, or Megan Rainey that will talk about, you know, just about any health issue.(39:56):I, I don't try to do that. I sort of stay, it's a wide lane, but I try to stay in my lane around infectious, neglected diseases and, and, and vaccines. And I think that's very important. Now, in terms of, you know, the statement, most scientists or physician scientists wanna keep their head done, write their grants and paper. I think that's perfectly fine. I don't think you people should be forced to do it, but I think there's enough of us out there that wanna do it, but don't know how to get started and don't feel safe doing it. I, and so I think we need to change that culture. Mm-hmm. I think we need to offer science communication to our graduate students in their PhD programs or in MD PhD programs for those who wanna do it, or in residency training or fellowship training. And so that, because there, there are things you can learn.(40:46):I mean, we had to do it by trial and error, and in my case, more error than trial. But, but, but there is a, there is, there are things you can learn from people who do this professionally. So I think that's important. I think the other is we need to change the culture of the institutions. You know, I, I get evaluated just like you do like everybody, like any, you know, senior scientist or professor at university, and, you know, what do they ask me about? They ask me about my grants and, and my papers preferably in high impact journals, and they ask me, and I don't see patients anymore, so they don't ask me about my clinical revenue, but they ask me about my grants and papers and my grants and papers, and my grants and papers. There's not even any place on my form, my annual evaluation from, to put in the single author books. I've written much less, you know? Yeah. The, the opinion pieces I've written, or certainly not social media or even, or even the cable news channel. So, so it basically, the academic health center is sending the message. And I don't think that's unique. I think that's probably the rule in most places. I think the, the culture of academic health centers is they're basically, they're sending a message just saying, well, we don't consider that stuff important, and somehow we have to make it important. I think for those who wanna do itEric Topol (42:08):AbsolutelyPeter Hotez (42:09):To send that message,Eric Topol (42:10):You're, you're, you're pointing out a critical step that has to be undertaken in the future. it'll take time to get that to gel, hopefully, but if it's promoted actively, I certainly promote that. I know you do. Yeah. I think,Peter Hotez (42:23):I think most, most offices of communications at academic health centers, as I said, Baylor and Texas Children's is pretty good, better than most, but most, you know, don't even like their docs and scientists speaking out. Yeah. Right. They wanna control the message. It's all about, you know, they're very risk averse. They're protecting the reputation of the institution. They only see the risk side. They don't, you know, you know, you wanna speak about social justice or, or combating anti-science. Well, you know, we guess we can't stop you, but they sort of cringe at, at the idea. And then, you know, they say, well, you know, ultimately you're a professor or a scientist here, you have academic freedom.com, but don't screw this up. Right. And don institution at risk. Right.Eric Topol (43:07):Ab you're describing exactly how university communications worked.Peter Hotez (43:12):Yeah. ButEric Topol (43:13):ThePeter Hotez (43:13):Point is, and so you do it with the sort of Damocles over your head, and, and you know, as you know, and as anyone knows, if you do enough, you will screw it up eventually, right? Everybody does. And, and you know, you're gonna make mistakes. That's how you learn. You make mistakes and you, you auto correct. But, but you have to have that freedom to be able to make mistakes and Yeah. And right now that's not there either.Eric Topol (43:35):What, what you're driving at though altogether is that we're defenseless. That is, if you have an organized finance coordinated attack on science, and also of course on vaccines, and you have no defense, you have, I mean, it's hard for the government to stand up because they're part of what's the conspiracy theory is, is, is against, and you, and, and the scientific community, the clinician community is, you know, kind of handcuffed as you are getting at. And also, you know, that's not the culture that's unwilling, but something's gotta give. And this is one thing I think you're really reinforcing that, that should a pathway to countering. I mean, we can't clone you. You know, we can't, we need lots of warriors. We need, you know, thousands and hundreds of thousands of points of light who support data and evidence, you know, as best that they can. And we don't have that today.Peter Hotez (44:36):Yeah. And we, we need to cultivate that. So I'm in discussions not only with people like yourself, but other colleagues about should we try to create, whether it's a nonprofit of 5 0 1 C three or C four the climate scientists are ahead of the game on this. Yeah. Yeah. I, I talk to Michael Mann every now and then, and, you know, they've got a climate science defense fund. They, they seem to be, 'cause it, they've, they've experienced this for longer than we have. You know, the, this all started a decade before with tax against climate scientists, you know, should, in the book I talk about, should we create something like a Southern Poverty Law Center equivalent to, to protect science and scientists? And, and I think we need that because the existing institutions don't seem willing to, to create something like that. It's somehow seen as too edgy or too out there and Right.(45:30):And it shouldn't be. But, but again, this is a I think a, a great opportunity for college presidents to, to step up and, and they're not doing that. They're, they're also pretty risk averse. So I think, you know, getting, getting the heads of the academic health centers, getting the college president, university presidents to say, Hey, this is important because otherwise science is at risk. And, and you're already starting to see some crazy stuff come out of the N I h now about doing international research. They're trying to put in rules to say they want, you know, if you have international collaborators, you're supposed to collect their notebooks and translate the how are you gonna do that? That's, that's completely, IM it's important. I mean, it's, and who's gonna review it and who's gonna sign off in general legal counsel at the university on, that's basically gonna halt international research. And we have to recognize that we need this because the threats are coming. Right? I mean,Eric Topol (46:33):CliPeter Hotez (46:34):Climate change is real, and pandemic threats are real. We're gonna see another major coronavirus pandemic possibly before 2030 or a flu or an arbovirus. And, and we're, we're, we need, this is a time we need to be reinforcing our, our virology research and our infectious disease research, not a time to, you know, start dismantling it, which is what totally the house hearings are, are meant to do, and what some of these new n i h rulings are meant to do. So it's gonna take a lot of strong players and, and, and government and at universities to stand up to this.Eric Topol (47:14):Well, if we ever need to be vaccinated or immunized, it's against this. And I hope that something will give to start to provide an antidote to what is a relentless progression of united science that you so elegantly eloquently in, in your book, Peter. So thanks for writing that. thanks for joining today. I know we'll have, as we do every week conversations yeah. You,Peter Hotez (47:41):You've been a, you've been an amazing friend and colleague, Eric, and I've learned so much from you. And, andEric Topol (47:46):No, no. I, I feel I can't tell you thank you. I, I, I think it's completely reciprocal from what you bring to this table of trying to make this a better place for advancing science search for, for the truth of what's really going on out there, rather than having to deal with wacky, you know, extremists that are advancing things for various purposes that are, that are nefarious in many cases. So, appreciate it. we'll be talking some more and this has been a really for me, an enriching conversation.Peter Hotez (48:21):Same, same Eric. And thank you so much for giving this attention and the dialect to be continued.Thanks for listening, reading and subscribing to Ground Truths!Please share if you found this podcast worthwhileFull video link Get full access to Ground Truths at erictopol.substack.com/subscribe

In this episode, Dr. Mark Hoffman invites Dr. Ted Lee, an OBGYN specializing in MIGS and professor of OBGYN at University of Pittsburgh Medical Center, about the ambulatory workup of endometriosis patients. --- EARN CME Reflect on how this Podcast applies to your day-to-day and earn free AMA PRA Category 1 CMEs: https://earnc.me/bT7a9b --- SHOW NOTES The episode begins with the physicians discussing the difficulties of diagnosing endometriosis, including: the stigma of pelvic pain/not believing women's pain, recognition that pelvic pain is not normal, the discomfort of physicians asking the appropriate questions for pelvic pain, and the hesitancy towards surgery by physicians and patients all play a role. Many patients have been having pain for years that may have been covered up by OCP use or misdiagnosed as IBS or interstitial cystitis. Ted emphasizes the importance of a thorough history in diagnosing endometriosis. Essential information includes age of onset of symptoms, gravidity and parity, prior C-section (abdominal wall endometriosis) and the “3 D's” of dyspareunia, dyschezia, and most importantly dysmenorrhea. A quality physical exam can also elucidate endometriosis. Ted starts by palpating the anterior vaginal wall, then the levator ani muscles and cervix, and finally the rectovaginal exam. Palpation of the uterosacral ligament and posterior cul-de-sac in endometriosis patients causes a visceral reaction, and advanced disease may also have nodules felt. The majority of patients don't require additional imaging since ultrasound is insensitive for stage 1 and 2 endometriosis. Indications for MRI include endometrioma, nodularities felt on exam, and abdominal wall endometriosis. When it comes to surgery, both doctors emphasize the importance of having other surgeons on your team, including colorectal surgery, general surgery, and urology. Ted dives into some surgical tips and techniques from his years of experience. Finally, the physicians end by discussing the future of endometriosis diagnosis. A Japanese study has recently found fusobacterium in the uterine microbiome in endometriosis patients more often than those without. Also, a French study has taken saliva samples and found signature microRNAs for endometriosis. It will be interesting to see how studies like these change the future of endometriosis diagnosis and if it will bring new challenges, such as overtreatment and overdiagnosis. --- RESOURCES Muraoka, A., Suzuki, M., Hamaguchi, T., Watanabe, S., Iijima, K., Murofushi, Y., Shinjo, K., Osuka, S., Hariyama, Y., Ito, M., Ohno, K., Kiyono, T., Kyo, S., Iwase, A., Kikkawa, F., Kajiyama, H., & Kondo, Y. (2023). Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts. Science translational medicine, 15(700), eadd1531. https://doi.org/10.1126/scitranslmed.add1531 Bendifallah, S., Suisse, S., Puchar, A., Delbos, L., Poilblanc, M., Descamps, P., Golfier, F., Jornea, L., Bouteiller, D., Touboul, C., Dabi, Y., & Daraï, E. (2022). Salivary MicroRNA Signature for Diagnosis of Endometriosis. Journal of clinical medicine, 11(3), 612. https://doi.org/10.3390/jcm11030612

Alzheimer wird heute meist erst dann erkannt, wenn Gedächtnisstörungen oder andere geistige Beeinträchtigungen auftreten. Dann ist das Gehirn aber schon erheblich geschädigt: Krankheitsbedingte Veränderungen der Nervenzellen treten auf, lange bevor eine Person überhaupt bemerkt, dass das Gedächtnis gestört ist. Zu diesem Zeitpunkt können die bisher entwickelten Medikamente dann nicht mehr helfen. Ein Schwerpunkt der aktuellen Forschung ist daher die Früherkennung. Auch wenn es bislang noch kein Heilmittel gegen Alzheimer gibt – Früherkennung bietet zumindest prinzipiell die Chance für frühzeitige Gegenmaßnahmen. Außerdem gibt es durchaus die Vermutung, dass die diversen Studien zu neuen Wirkstoffen u. a. daran gescheitert sein könnten, dass die Studienteilnehmenden zu spät behandelt wurden. U. a. im Gehirn, Nervenwasser und Blut fahndet man daher nach frühzeitigen Kennzeichen einer Erkrankung (Biomarkern), etwa krankheitstypischen Proteinen. Und dabei hat man nicht nur eine frühere Diagnose im Sinn, man sucht auch nach Biomarken mit Prognosekraft – um vorhersagen zu können, wie die Erkrankung künftig verlaufen wird. Der Neurologe Prof. Dr. André Fischer, Sprecher am DZNE-Standort Göttingen, hat kürzlich im Blut Moleküle – sogenannte microRNAs – identifiziert, deren Konzentration mit der geistigen Leistungsfähigkeit zusammenhängt und die auf eine bevorstehende Demenz hindeuten können, bevor erste Symptome auftreten. Noch muss der neu gefundene Biomarker weiter geprüft werden, zudem ist das Messverfahren noch nicht praxistauglich. Ziel von André Fischer und seinem Forschungsteam ist daher die Entwicklung eines einfachen, kostengünstigen Bluttests, ähnlich dem Schnelltest auf SARS-CoV-2 – mit dem Unterschied, dass man für den Alzheimer-Schnelltest einen Blutstropfen benötigen würde. Im Interview mit Sabine Heinrich erklärt André Fischer, wie künftig mit Hilfe des Tests das Risiko für eine Demenzerkrankung abgeschätzt werden könnte, wann er auf den Markt kommen soll und für wen er sich eignet. Zudem spricht er darüber, warum die microRNAs den Studiendaten zufolge möglicherweise auch Ansatzpunkte für neue Demenztherapien sein könnten und was jeder selbst tun kann, um das Risiko einer Alzheimer-Erkrankung zu verringern. Aber hören Sie selbst.

This month on Episode 45 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the February 3rd and February 17th issues of Circulation Research. This episode also features an interview with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.   Article highlights:   Pi, et al. Metabolomic Signatures in PAH   Carnevale, et al. Thrombosis TLR4-Mediated in SARS-CoV-2 Infection   Cai, et al. Macrophage ADAR1 in AAA   Koide, et al. sEVs Accelerate Vascular Calcification in CKD   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 Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting the articles from our February 3rd and 17th issues of Circulation Research. I'm also going to have a chat with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study, Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. But before I get to the interviews, here are a few article highlights.   Cindy St. Hilaire:        The first article I want to highlight comes from the laboratory of Dr Peter Leary at the University of Washington, and the title is Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes. Pulmonary Arterial Hypertension or PAH is a rare but life-threatening disease in which progressive thickening of the walls of the lung's blood vessels causes increased blood pressure and that increased blood pressure ultimately damages the heart's right ventricle.   Interestingly, progression to heart failure varies considerably among patients, but the reasons why there is variability are not well understood. To find out, this group turned their attention to patient metabolomes, which differ significantly from those of healthy people and thus may also change with severity. Blood samples from 117 PAH patients were analyzed for more than a thousand metabolites by mass spectrometry and the patient's progress was followed for the next three years. 22 patients died within a three-year period and 27 developed significant right ventricle dilation. Other measures of severity included pulmonary vascular resistance, exercise capacity and levels of BNP, which is a metric of heart health. Two metabolic pathways, those relating to polyamine and histidine metabolism, were found to be linked with all measures of severity suggesting a key role for them in disease pathology. While determining how these pathways influence disease as a subject for further study, the current findings may nevertheless lead to new prognostic indicators to inform patient care.   Cindy St. Hilaire:        The next article I want to discuss is coming from our February 3rd issue of Circulation Research and this is coming from the laboratory of Dr Francisco Violi at the University of Rome and the title is Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Thrombosis can be a complication of COVID-19 and it is associated with poor outcomes, including death. However, the exact mechanism by which the virus activates platelets, which are the cells that drive thrombosis, is not clear. For one thing, platelets do not appear to express the receptor for SARS-CoV-2. They do however, express the TLR4 receptor and that's a receptor that mediates entry of other viruses as part of the immune response. And TLR4 is ramped up in COVID-19 patient platelets. This group now confirms that, indeed, SARS-CoV-2 interacts with TLR4, which in turn triggers thrombosis.   The team analyzed platelets from 25 patients and 10 healthy controls and they found that the platelet activation and thrombic activity were both boosted in the patient samples and could not be blocked using a TLR4 inhibitor. Additionally, immunoprecipitation and immunofluorescent experiments further revealed colocalization between the virus protein and the TLR4 receptor on patient platelets. The team went on to show that the signaling pathway involved reactive oxygen species producing factors p47phox and Nox2, and that inhibition of phox 47, like that of the TLR4 receptor itsel,f could prevent platelet activation. As such, this study suggests that inhibiting either of these proteins may form the basis of an antithrombotic treatment for COVID-19.   Cindy St. Hilaire:        The third article I want to highlight is coming from the lab of Shi-You Chen at University of Missouri and the title of this article is ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm. Macrophage activation plays a critical role in abdominal aortic aneurysm development, or AAA development. Inflammation is a component of this pathology; however, the mechanisms controlling macrophage activation and vascular inflammation in AAA are largely unknown. The ADAR1 enzyme catalyzes the conversion of adenosine to inosine in RNA molecules and thus this conversion can serve as a rheostat to regulate RNA structure or the gene coding sequence of proteins. Several studies have explored the role of ADAR1 in inflammation, but its precise contribution is not fully understood, so the objective of this group was to study the role of ADAR1 in macrophage activation and AAA formation.   Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development and dissection and angiotensin II infusion of ApoE knockout mice combined with a macrophage specific knockout of ADAR1 was used to study the role of ADAR1 macrophage specific contributions to AAA formation and dissection. Allograft transplantation of wild type abdominal aortas to ADAR1 haploinsufficient recipient mice significantly attenuated AAA formation. ADAR1 deficiency in hematopoietic stem cells also decreased the prevalence and the severity of AAA and it also inhibited macrophage infiltration into the aortic wall. ADAR1 deletion blocked the classic macrophage activation pathway. It diminished NF-κB signaling and it enhanced the expression of a number of anti-inflammatory microRNAs. Reconstitution of ADAR1 deficient but not wild type human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Together these results suggest that macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism of editing the microRNAs that target NF-κB signaling, which ultimately promotes vascular inflammation in AAA.     Cindy St. Hilaire:        The last article I want to highlight is also from our February 17th issue of Circulation Research and it is coming from the lab of Shintaro Mandai at Tokyo Medical and Dental University and the title of the article is Circulating Extracellular Vesicle Propagated MicroRNA signatures as a Vascular Calcification Factor in Chronic Kidney Disease. Chronic Kidney Disease or CKD accelerates vascular calcification in part by promoting the phenotypic switching of vascular smooth muscle cells to osteoblast like cells. This study investigated the role of circulating small extracellular vesicles or SUVs from the kidneys in promoting this osteogenic switch. CKD was induced in rats and in mice by an adenine induced tubular interstitial fibrosis and serum from these animals induced calcification in in vitro cultures of A-10 embryonic rat smooth muscle cells. Intraperitoneal administration of a compound that prevents SEV biosynthesis and release inhibited thoracic aortic calcification in CKD mice under a high phosphorus diet. In Chronic Kidney Disease, the microRNA transcriptome of SUVs revealed a depletion of four microRNAs and the expression of the microRNAs inversely correlated with kidney function in CKD patients.   In vitro studies found that transected microRNA mimics prevented smooth muscle cell calcification in vitro. In silico analyses revealed that VEGF-A was a convergent target of all four microRNAs and leveraging this, the group used in vitro and in vivo models of calcification to show the inhibition of the VEGF-A, VEGFR-2 signaling pathway mitigated calcification. So in addition to identifying a new potential therapeutic target, these SUV propagated microRNAs are a potential biomarker that can be used for screening patients to determine the severity of CKD and possibly even vascular calcification.   Cindy St. Hilaire:        Today I have with me Dr Hind Lal who's an associate professor of medicine at the University of Alabama Birmingham and his post-doctoral fellow and the lead author of the study Dr Tousif Sultan. And their manuscript is titled Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. And this article is in our February 3rd issue of Circulation Research. So thank you both so much for joining me today.   Tousif Sultan:              Thank you.   Hind Lal:                     Thank you for taking time.   Cindy St. Hilaire:        So ponatinib, it's a tyrosine kinase inhibitor and from my understanding it's the only treatment option for a specific group of patients who have chronic myelogenous leukemia and they have to harbor a specific mutation. And while this drug helps to keep these patients alive essentially, it's extremely cardiotoxic. So cardiotoxicity is somewhat of a new field. So Dr Lal, I was wondering how did you get into this line of research?    Hind Lal:                    So I was fortunate enough to be in the lab of Dr Tom Force and he was kind of father of this new area, now is very developed, it's called cardio-oncology. On those days there were basically everything started in cardio-oncology. So I just recall the first tyrosine kinase approved by FDA was in 2000 and that was... Imagine and our paper came in Nature Medicine 2005 and discovering there is... so to elaborate it a little bit, the cancer therapy broadly divided in two parts. One is called non-targeted therapy like chemotherapy, radiations, et cetera, and then there are cytotoxic drugs. So those cytotoxic drugs because they do not have any targeted name on it so they are, cardiotoxic are toxic to any organ was very obvious and understanding. When these targeted therapy came, which is mainly kinase inhibitor are monoclonal antibodies. So these are targeted to a specific pathway that is activated only in the cancer cells but not in any other cells in the body so they were proposed as like magic bullets that can take off the cancer without any cardiotoxity or minimal side effects. But even in the early phase like 2005 to 2010, these came out, these so-called targeted, they are not very targeted and they are not also the magic bullets and they have serious cardiotoxicity.   Cindy St. Hilaire:        And so what's the mechanism of action of ponatinib in the leukemia and how does that intersect with the cardiovascular system?   Hind Lal:                     Yeah, so this is very good question I must say. So what we believe at this point because, so leukemia if you know is driven by the famous Philadelphia chromosome, which is a translicational gene, one part of human chromosome nine and one part of human chromosome 22 and they translocate make a new gene which is BCR-ABL gene. And because it was discovered in Philadelphia UPENN, is named that Philadelphia chromosome, which is very established mechanism, that's how CML is driven. But what we have discovered that the cardiotoxicity driven by totally, totally different from the ponatinib is one of the inflammatory So it's kind of goodening. So this question is so good. One kind of toxicity is called on-target, when toxicity is mediated by the same mechanism, what is the mechanism of the drug to cure the cancer? So in that case your absolute is minimal because if you manipulate that, the drug's ability to cure the cancer will be affected but if the toxicity and the efficacy is driven by two different mechanism, then as in case of ponatinib seems like it's NLRP3 and inflammasome related mechanism. So this can be managed by manipulating this pathway without hampering the drug efficacy on the cancer.   Cindy St. Hilaire:        So what exactly is cardiotoxicity and how does it present itself in these patients?   Hind Lal:                     So these drugs like ponatinib, they call broader CVD effects. So it's not just cardiac, so they also in hypertensives and atherosclerosis and thrombosis, those kind of thing. But our lab is primarily focused on the heart. So that's why in this paper we have given impresses on the heart. So what we believe at this point that ponatinib lead to this proinflammatory pathway described in this paper, which is just 108A9-NLRP3-IL-1β and this inflammatory pathway lead to a cytokine storm very much like in the COVID-19 and these cytokine storms lead to excessive myocarditis and then finally cardiac dysfunction.   Cindy St. Hilaire:        Is the cytokine storm just local in the cardiac tissue or is it also systemic in the patients? Is cardiotoxicity localized only or is it a more systemic problem?   Tousif Sultan:              I would like to add in this paper we have included that we look this cytokine things and explain blood circulation, bone marrow. So the effect is everywhere, it's not local. So we didn't check other organs, maybe other organs also being affected with the ponatinib treatment.   Cindy St. Hilaire:        And what's the initial phenotype of a patient has when they start to get cardiotoxicity, what's kind of like a telltale symptom?   Hind Lal:                     So good thing that in recent years cardio-oncology developed. So initially the patient that were going for cancer treatment, they were not monitored very closely. So they only end up in cardiology clinic when they are having some cardiac events already. So thanks to the lot of development and growth in the cardio-oncology field, now most patients who going for a long-term cancer treatment, they are closely monitored by cardiology clinics.   Cindy St. Hilaire:        Got it. So they can often catch it before a symptom or an event. That's wonderful.   Hind Lal:                     Yeah, so there's a lot of development in monitoring.   Cindy St. Hilaire:        Wonderful. So you were really interested in figuring out why ponatinib induces cardiotoxicity and you mentioned that really up until now it's been very difficult to study and that's because of the limitation of available murine models. If you just inject a wild type mouse with ponatinib, nothing happens really. So what was your approach to finding relatively good murine models? How did you go about that?   Hind Lal:                     So this is the top scientific question you can ask. So like science, the field is try and try again. So initially this is the first paper with the ponatinib toxicity using the real in vivo models. Any paper before this including ours studies published, they were done on the cellular model in hiPSC, that isolated cardiomyocytes. So you directly putting the ponatinib directly the isolated cells. So this is first case when we were trying to do in vivo, maybe other attempt in vivo but at least not published. So first we also treated the animals with ponatinib and that failed, we don't see any cardiotoxic effect. And then when we going back to the literature, the clinical data is very, very clear from pharmacovigilance that ponatinib is cardiotoxic in humans. So when we're not able to see any phenotype in mouse, we realize that we are not mimicking what's happening in the humans.   So we certainly missing something. Now once again I quote this COVID-19, so many people get infected with COVID-19 but people are having preexisting conditions are on high risk to developing CVD. So there was some literature on that line. So we use this very, very same concept that if there is preexisting conditions, so likely who'd have developing future cardiac event will be more. So we use two model in this paper one atherosclerosis model which is APoE null mice mice, another is tag branding which is pressure overload model for the heart and as soon as we start using what we call comorbidity model like patient is having some preexisting conditions and we very clearly see the robust defect of ponatinib on cardiac dysfunction.   Cindy St. Hilaire:        Yeah, it's really, really well done and I really like that you use kind of two different models of this. Do you think it's also going to be operative in maybe like the diabetic mirroring models? Do you think if we expand to other comorbidities, you might also recapitulate the cardiotoxicity?   Hind Lal:                     So you got all the best questions.   Cindy St. Hilaire:        Thank you. I try.   Hind Lal:                     So because this is CML drug and lot of the risk factor for cardiovascular and cancer are common and even metabolic disease. So most of the time these patients are elderly patients and they're having metabolic conditions and most of the time they have blood pressure or something CVD risk factors. So I agree with you, it'll be very relevant to expand this to the diabetes or metabolic models, but these were the first study, we put all our focus to get this one out so news is there then we can expand the field adding additional models et cetera. But I agree with you that will be very logical next step to do.   Cindy St. Hilaire:        Yeah. And so I guess going back to what you know from the human study or the clinical trials or the human observations, are different populations of patients with CML more predisposed to cardio toxicity than others or is that not known yet?   Hind Lal:                     So one other area called pharmacovigilance. So what pharmacovigilance does patient all over the world taking these drugs. So WHO have their own vigilance system and FDA have their own, so it's called BG-Base for the WHO and it's called the FAERS for the FDA. So one can go back in those data sets and see if X patient taking this Y drug and what kind of symptoms or adverse effect they are seeing and if these symptoms are associated with something else. So there is data that if patients having CVD risk factor, they are more prone to develop ponatinib induced cardiac events. But it needs more polish like you asked the just previous question, diabetes versus maybe blood pressure means hypertension, atherosclerosis, or thrombosis. So it has not been delineated further but in a one big bucket if patients are having CVD risk factor before they are more prone and more likely to develop the cardiac events.   Cindy St. Hilaire:        So after you established that these two murine models could pretty robustly recapitulate the human phenotype, what did you do next? How did you come upon the S100A8/A9-NLRP3-IL-1β signaling circuit? How did you get to that?   Hind Lal:                     So in basic science work, whenever we do mouse is called until we get there is cardiac dysfunction, it's called phenotype, right? So mouse had a cardiac phenotype. So next step is, "Why? What is leading to that phenotype?" That's what we call mechanism. So there the best idea to fit the mechanism is using one of the unbiased approaches like you do unbiased proteomics, unbiased RNC analysis, something like this that will analyze the entire transcript like RNC and say, "Okay, these pathway are," then you can do further analysis that will indicate these pathway are different, are altered. So in this case we used RNC analysis and it came out that this yes A8 and yes A9, 100A8 and nine, they were the most upregulated in this whole set. And thereafter we were very lucky. So we started this study at Vanderbilt, where my lab was and thereafter we very lucky to move here and found Sultan who had a lot of experience with this inflammation and immune system and then Sultan may add something on this so he'll be the better person to say something on this.   Tousif Sultan:              So after our RNC analysis, so we got this S100A8 and nine as top hit with the ponatinib treatment. So then we validated this finding with our flow cytometric, qRT PCR aand then we started which pathway is going to release cytokine and all that. So we found that is NLRP3 inflammasome.   Cindy St. Hilaire:        Yeah and well and I guess maybe step back, what is S100A8/A9? What are those? Tousif Sultan:              Yeah, S10A8/A9 is a calcium binding protein. So that's also called alarmin and they basically binds with the pathogen associated pattern and other TLR2 like receptors and then start inflammatory pathway to release cytokine and all that and it's stable in heterodimer form. So S100A8 heterodimer with A9 and then bind with TLR and a start in this inflammatory pathway.   Cindy St. Hilaire:        And what type of cell is that happening in? Is that happening in the immune cells only or is it also in the cardiomyocyte, or...?   Tousif Sultan:              Yeah, we have included all this data. So from where this alarmin is coming with ponatinib treatment, so literature also suggested that neutrophils and monocytes, those cells are the potential to release the alarmin. So here we also found these two type of cells, neutrophils and monocytes. They release huge alarmin with the treatment of ponatinib.   Cindy St. Hilaire:        And so really taking this really neat mechanism to the next level, you then tried attenuating it by using broad anti-inflammatory steroid dexamethasone but also by targeting these specific components, the NLRP and the S100A specific inhibitors and they worked well. It worked really nicely. Does your data show that any of these therapies work better than the other and then are these viable options to use in humans?   Hind Lal:                     Yeah, we have some data in the paper. Are very broad which help a lot in COVID patients, far very acute infections. So in this case, situation is very different cause most of CML patients will going to take ponatinib for lifelong, there is no remission, right? So in those case, its certainly not a very attractive option. We have shown data in the paper that dexamethasone help with the heart but lead to some metabolic changes. So we have compared those with the NLRP3 inhibitors, those metabolic alterations, dexa versus the NLRP3 inhibitors, CY-09. And we demonstrated that targeting is specifically with paquinimod, our NLRP3 inhibitor CY-09, feel better. It can still rescue the cardiac phenotype without having those adverse effect on metabolic parameters.   Cindy St. Hilaire:        That's wonderful. Do you think though that because you have to take ponatinib for life, that long-term NLRP inhibition would also cause problems or...?   Hind Lal:                     So because not every patient who taking ponatinib would develop the cardiac phenotype, right? Which is like a 10%, 12%, patient developing cardiac dysfunction. So I think someone like I strongly believe paquinimod, which is inhibitor of S100A9, will be really good option or at least we have enough data that make us nail for at least a small clinical trial. And we quickly moving on that. At UAB we have our clinical cardio-oncology program and we are already in touch with the director for the clinical cardio-oncology program. So what we trying to do in that small trial is if one of the standard therapy for heart like beta blocker or ARBs inhibitor, is there any preference like one work better than the other in the standard care? So first we doing that project, then we obviously looking forward if one small clinical trial can be done with paquinimod. I strongly believe it should be helpful.   Cindy St. Hilaire:        That is wonderful. And so do you think... There's other chemotherapeutic agents or probably even other non-cancer drugs that cause cardiotoxicity, do you think this mechanism, this pathway, this S100A-NLRP-IL-1β axis is operative in all cardiotoxicities or do you think it's going to be very specific to the ponatinib?   Hind Lal:                     So it's certainly not all, but it'll be certainly more than ponatinib. So in our lab we are using another kinase inhibitor, which is osimertinib and it's not published yet, but now we know that it's also cardiotoxic because it's taking metabolic root or energetics disruption but not this pro-inflammatory part, but we're doing another project which is strep pneumonia induced cardiac dysfunction, which is called pneumonia. So strep pneumoniae, which leads to the pneumonia ,and lot patient die because of the failing heart we see here in the hospitals and we see these pathways operational over there and we gearing up to do clinical trial on that aspect as well, but it's not generalized like all kind of heart will have the same mechanism.   Cindy St. Hilaire:        It's wonderful to see you're already taking those next steps towards really kind of bringing this to a translational/clinical study. So what was the most challenging aspect of this study?   Tousif Sultan:              The challenging aspect, ponatinib is a kinase inhibitor and that was surprising for us how it's activating immune cells. Generally kinase inhibitors, inhibits all the cells like that. So that was challenging. So we repeated it many times did in vitro experiment to confirm that. So we just added, just treated in vitro immune cells with the ponatinib and confirmed it. So that was little challenging.   Cindy St. Hilaire:        So what's next? You mentioned you're going to try some clinical trials, early stage clinical trials. What's next mechanistically, what do you want to go after?   Hind Lal:                     So what we are doing next and we are very, very eagerly trying to do that. So what it was done, we used the cardiac comorbidity models, but as you know, anybody who will take ponatinib will have cancer, right? So we strongly believe that we miss one factor. There was no cancer on these. So that is very logical next step. What that will allow us to do, what rescue experiment we'll have done in this paper. So we saw, "Okay, this rescue the cardiac phenotype, which is taken care of now," but very same time, we not able to demonstrate that this is happening without hurting the cancer efficacy. So if we have the dual comorbid mouse, which have CML a real thing and we have cardiac thing, then that will allow us to demonstrate, "Okay, we got something that can take care of the cardiac problem without hurting the efficacy on the cancer." And it will be best if you also help little bit to more potentiate the cancer efficacy.   Cindy St. Hilaire:        Yes. Excellent. Well, congratulations on a beautiful study, really exciting findings. Dr Lal and Dr Sultan, thank you so much for taking the time to talk with me today.   Tousif Sultan:              Thank you so much.   Hind Lal:                     Well thank you, Cynthia. We really appreciate your time. Thank you for having us.   Cindy St. Hilaire:        Yeah, it was great.   Cindy St. Hilaire:        That's it for our highlights from the February 3rd and February 17th issues of Circulation Research. Thank you so much 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 Hind Lal and Dr Tousif Sultan. This podcast is produced by Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, you're on-the-go source for most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2023. And the opinions expressed by the speakers in 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 17, 2022, entitled, “Serum microRNAs as new criteria for referral to early palliative care services in treatment-naïve advanced cancer patients.” A major obstacle to the implementation of early palliative care (EPC) is the lack of objective criteria for referral to EPC. Circulating microRNAs (miRNAs) have been recognized as promising biomarkers. In the current study, researchers Tomofumi Miura, Shuichi Mitsunaga, Juntaro Matsuzaki, Satoko Takizawa, Ken Kato, Atsushi Ochiai, and Takahiro Ochiya from National Cancer Center Research Institute, National Cancer Center Hospital, Keio University, Toray Industries, Inc., and Tokyo Medical University investigated objective definitions for referral to EPC using microRNA. A total of 178 serum samples were obtained from patients with lung, gastrointestinal, colorectal, bile duct, pancreas, and bladder cancers who were treatment-naïve and received chemotherapy between January 2011 and December 2013 at National Cancer Center Hospital East. “The aim of the present study was to develop predictive models using serum miRNAs for patients who [were] admitted to a PCU [palliative care unit] ≤6 months after starting anti-tumor treatment.” The team investigated expression levels of miRNAs using microarrays. The primary outcome was prediction of admission to a palliative care unit ≤6 months after first visit. Diagnostic models using clinical characteristics, miRNAs and combinations of both were constructed. The miRNA models were constructed using 6 miRNA levels. The best areas under the receiver operating characteristic curve (AUCs) of the clinical model was 0.741, while the average AUCs of miRNA-based models and combination models were 0.769 and 0.806, respectively. Combination models showed higher AUCs than the clinical model (p < 0.023). The researchers assert that the present combination models might offer new objective definitions for referral to EPC and thus contribute to real-world implementation of EPC. “The present study developed a predictive model using miRNA for patients admitted to a PCU ≤6 months after starting anti-tumor treatment. The present models might offer objective criteria for oncologists to facilitate the referral of patients to the EPC.” DOI: https://doi.org/10.18632/oncotarget.28327 Correspondence to: Shuichi Mitsunaga - smitsuna@east.ncc.go.jp Keywords: microRNA, early palliative care, integration, cancer, referral 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.

Videos : The Covid Redemption with Tim Robbins – #048 – Stay Free with Russell Brand MP calls for complete suspension of mRNA jab in extraordinary British Parliamentary speech Turmeric studied for its ability to seek out and destroy cancer stem cells, the source of all tumors Montclair State University, December 13, 202 Turmeric has gained immense popularity over the years not just for the unique flavor it adds to dishes like curries, but also for its various health benefits. One of its most promising therapeutic applications is as a natural remedy for cancer. Although the anticancer potential of turmeric isn't new, a recent study published in Cancer Letters further proved the importance of this golden spice in understanding and treating cancer. The team of American researchers evaluated the ability of curcumin, which is a polyphenol in turmeric, to target cancer stem cells that are assumed to be the primary cause of cancer tumor formation and malignancy. Unlike conventional cancer models used in previous studies, the cancer stem cell model suggests that only a small population of cancer cells drive the initiation, maintenance, and growth of tumors. These stem cells regularly undergo renewal and differentiation into other cancer cells, which no longer have the ability to regenerate themselves. Therefore, in this model, cancer stem cells that are not killed by treatments lead to the formation of more invasive and treatment-resistant tumors. In this study, the researchers found that curcumin is more effective in eradicating cancer since unlike conventional treatments, this polyphenol also targets cancer stem cells. It can do so through various mechanisms of action, which include the following. Regulation of cancer stem cell self-renewal pathway — There are different pathways involved in the self-renewal of cancer stem cells. These include the Wnt/beta-catenin, sonic hedgehog 89 (SHH), and Notch pathways. The researchers found that curcumin can directly or indirectly interfere with these pathways in 12 different cancer cell lines Modulation of microRNA — The body contains microRNAs, which are short RNA sequences that don't encode for anything. These microRNAs regulate more than 33 percent of protein-coding genes by targeting and binding to their corresponding messenger RNAs so that these won't be expressed. In this study, the authors observed that curcumin altered microRNA expression in cancer stem cells so that they can't produce everything that they need for tumor formation and growth. Direct anti-cancer activity — Curcumin selectively targets cancer cells and programs their death. When used in conjunction with conventional anticancer agents, this effect becomes more evident and the damage typically caused by chemotherapy is no longer observed. Overall, the results of this study show that for cancer treatments to be effective, they have to target and kill cancer stem cells just like turmeric does. Otherwise, these cancer stem cells will pave the way for the formation of more invasive and treatment-resistant tumors. (NEXT) Chiropractic spinal manipulation associated with reduction in low back surgery University Hospitals Cleveland Medical Center, December 19, 2022 A recent study from University Hospitals (UH) Connor Whole Health has found that adults who initially visit a chiropractor to receive spinal manipulation for low back pain caused by disc herniation or radiculopathy (i.e., sciatica) are less likely to undergo discectomy (i.e., disc surgery) over the subsequent two years. This study was recently published in the journal BMJ Open. In this retrospective cohort study, the authors selected adult patients, age 18 to 49, from a 101 million patient United States health records network (TriNetX, Cambridge, MA, U.S.). Patients with serious pathology or urgent indications for surgery were excluded from the study. Ultimately, the authors identified 5,785 patients who initially received chiropractic spinal manipulative therapy, and the same number of patients who received other forms of medical care for their low back pain. The authors used a statistical technique called propensity score matching to control for variables that could influence the likelihood that patients would undergo discectomy. In this process, they matched patients in both cohorts according to several such as age, sex, obesity, smoking, previous injections, and medications. The authors found that patients who initially received chiropractic spinal manipulation for their low back pain were significantly less likely to undergo lumbar discectomy through two years' follow-up. At one year follow-up, 1.5% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.2% of patients in the cohort receiving other care At two years' follow-up, 1.9% of the patients in the chiropractic cohort had undergone discectomy, compared to 2.4% of patients in the cohort receiving other care This study represents the first study to examine whether chiropractic care is associated with a reduction in likelihood of discectomy. (NEXT) High-intensity exercise delays Parkinson's progression Northwestern Medicine and University of Denver, December 11, 2022 High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine and University of Denver scientists. This is the first time scientists have tested the effects of high-intensity exercise on patients with Parkinson's disease, the second most common neurodegenerative disorder and the most common movement disorder, affecting more than a million people in the United States. It previously had been thought high-intensity exercise was too physically stressful for individuals with Parkinson's disease. “If you have Parkinson's disease and you want to delay the progression of your symptoms, you should exercise three times a week with your heart rate between 80 to 85 percent maximum. Because medications for Parkinson's have adverse side effects and reduced effectiveness over time, new treatments are needed. The randomized clinical trial included 128 participants ages 40 to 80 years old from Northwestern University, Rush University Medical Center, the University of Colorado and the University of Pittsburgh. Participants enrolled in the Study in Parkinson Disease of Exercise (SPARX) were at an early stage of the disease and not taking Parkinson's medication, ensuring the results of the study were related to the exercise and not affected by medication. “The earlier in the disease you intervene, the more likely it is you can prevent the progression of the disease,” Corcos said. “We delayed worsening of symptoms for six months; whether we can prevent progression any longer than six months will require further study.” Scientists examined the safety and effects of exercise three times weekly for six months at high intensity, 80 to 85 percent of maximum heart rate, and moderate intensity, 60 to 65 percent of maximum heart rate. They compared the results to a control group who did not exercise. After six months, participants were rated by clinicians on a Parkinson's disease scale ranging from 0 to 108. The higher the number, the more severe the symptoms. Participants in the study had a score of about 20 before exercise. Those in the high intensity group stayed at 20. The group with moderate exercise got worse by 1.5 points. The group that did not exercise worsened by three points. Three points out of a score of 20 points is a 15 percent change in the primary signs of the disease and considered clinically important to patients. It makes a difference in their quality of life. (NEXT) Meditation adapts the brain to respond better to feedback University of Surrey UK, December 11, 2022 In a study in the Journal of Cognitive, Affective & Behavioral Neuroscience researchers from the University of Surrey have discovered a link between meditation and how individuals respond to feedback. Participants in the study, a mixture of experienced, novice and non-meditators, were trained to select images associated with a reward. Each pair of images had varying probabilities of a reward e.g. images that result in a reward 80 per cent of the time versus those that result in a reward 20 per cent of the time. Participants eventually learnt to select the pairing with the higher outcome. Researchers found that participants who meditated were more successful in selecting high-probability pairings indicating a tendency to learn from positive outcomes, compared to non – meditators who learned the pattern via low-probability pairings suggesting a tendency to learn from negative outcomes. During the study participants were connected to an EEG, a non-invasive method that records electrical patterns in the brain. Results from the EEG found that while all three groups responded similarly to positive feedback, the neurological response to negative feedback was highest in the non-meditation group, followed by the novice group and then by the experienced meditation group. These results indicate that the brains of meditators are less affected by negative feedback, and that this may be a result of altered dopamine levels caused by meditation. Paul Knytl, lead author and PhD candidate in psychology at the University of Surrey, said: “Humans have been meditating for over 2000 years, but the neural mechanisms of this practice are still relatively unknown. These findings demonstrate that, on a deep level, meditators respond to feedback in a more even-handed way than non-meditators, which may help to explain some of the psychological benefits they experience from the practice.” (NEXT) Caution to pregnant women on red meat diabetes link University of Adelaide (Australia) December 12, 2022 Pregnant women and women planning to become pregnant can make use of the holiday season to adjust their diets and reduce the risk of gestational diabetes, according to researchers at the University of Adelaide's Robinson Institute. The recommendation comes at a time when there is increasing evidence to suggest that red meat is linked with a higher rate of gestational diabetes in pregnant women, which poses risks to the health of both the mother and the baby. In a commentary published in the jjournal Evidence-Based Nursing, author Philippa Middleton says the latest international research shows that women who eat a lot of red and processed meats even before they become pregnant have a significant risk of developing gestational diabetes. “There have been several reports linking red meat with increased risk of type 2 diabetes, and now the work of a number of research teams worldwide is showing this link for diabetes during pregnancy,” says Ms Middleton, who is one of the Robinson Institute's research leaders. “While this news is alarming, there are also some positives. The latest research from the United States has shown that eating fish and poultry does not increase the risk of gestational diabetes, and consuming more vegetable and non-meat protein is associated with a reduction in risk. “For example, just over half a serving of nuts per day can reduce the risk of gestational diabetes by 40%.” “Based on current evidence, pregnant women or women planning to become pregnant should consider eating more vegetable protein, and nuts, and replacing some red meat with fish and poultry. (NEXT) Treatment for lupus may depend on restoring proteins in patients' blood Singapore General Hospital, December 19, 2022 Restoring protein balance in the blood may be key to developing an effective treatment for lupus. The incurable autoimmune disease reportedly affects about 100 in every 100,000 people worldwide, and disproportionally affects women between 15 and 45 years-old and Asians. Lupus causes the body's immune system to attack itself, which can inflame several vital organs like the kidneys, brain, heart, and lungs. The aggressive nature of the disease is what makes it life-threatening for many who have it, especially since current treatments don't help that much. “We are excited about the possibility of a new treatment option for lupus as 30 to 60 percent of patients do not respond to conventional medications despite aggressive regimens. In the past 65 years, only three drugs for lupus have been approved by the United States Food and Drug Administration but these drugs have modest efficacy. There is therefore a real and urgent need for better therapies, particularly for the more severe spectrum of lupus that we see in Asia,” says senior author Andrea Low, the Head and Senior Consultant in the Department of Rheumatology & Immunology at Singapore General Hospital (SGH), in a media release. To reach their findings, Low and her team studied CXCL5, a protein that helps to regulate the immune system through neutrophils, which are a type of white blood cell. They revealed that lupus patients had considerably lower levels of the protein in their blood compared to healthy people, thus suggesting that it may have a connection to the disease. They also discovered that mice with severe lupus injected weekly with CXCL5 displayed restored protein balance. Moreover, their survival outcomes increased from 25 percent to over 75 percent after 10 weeks. Not only did the injections reduce mortality risk, but they didn't cause any adverse side-effects, study authors report. “Our study has shown CXCL5 to be safe. There was no liver or kidney toxicity or cancer inducing effects. Major components of the immune system were also not compromised,” reports principal investigator Dr Fan Xiubo, Senior Research Fellow, Department of Clinical Translational Research, SGH. The entire team is hopeful that they can continue to build on their research to better the lives of patient's suffering from this debilitating disease. “To be in the forefront of medicine means we have to constantly further our understanding of diseases and offer patients better treatment options through rigorous scientific research. I'm heartened that the team has shed new light on lupus and the possibility of a more efficacious therapy for patients some years down the road,” says Professor Fong Kok Yong, Deputy Group CEO (Medical and Clinical Services), SingHealth, and Senior Consultant, Department Rheumatology & Immunology, SGH

This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more. But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation. However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries. Dr. Greg Hundley: Wow, Carolyn, this is a really interesting question. So what did they find? Dr. Carolyn Lam: In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous. And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba. Dr. Greg Hundley: Very nice Carolyn. Very important research in this area using that particular methodology. Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension. So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia. Dr. Carolyn Lam: Another one of those excellent translational pieces, isn't it Greg? So what did they find? Dr. Greg Hundley: Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy. And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease. Dr. Carolyn Lam: Aw, thanks Greg for explaining that so well. The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction? Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes. Dr. Greg Hundley: Oh wow. So Carolyn, important study. So what did they find? Dr. Carolyn Lam: Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis. So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR. Dr. Greg Hundley: Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science. Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.” And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.” Dr. Carolyn Lam: Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.” Now, let's go onto the feature discussion of all things MRI, shall we? Dr. Greg Hundley: You bet. More on manganese. Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland. Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just 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. Trisha Singh: Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought. In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term. Dr. Greg Hundley: Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide? Dr. Trisha Singh: So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would. And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other. And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis. Dr. Greg Hundley: Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically. Well, with that description, can you describe for us now, your study population and your study design? Dr. Trisha Singh: Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography. Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients. So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan. Dr. Greg Hundley: Very good. So two exams separated longitudinally over time. What were your study results? Dr. Trisha Singh: Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome. Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content. And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find. Dr. Greg Hundley: Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome? Dr. Trisha Singh: For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve. And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population. Dr. Greg Hundley: Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study? Dr. Trisha Singh: So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that. Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well. Dr. Greg Hundley: Very nice. And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred? Dr. Trisha Singh: Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart. Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak. Dr. Greg Hundley: Very good. Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo? Dr. Trisha Singh: So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture. And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome. Well, on behalf of Carolyn 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 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 ajjournals.org.

Alec sits down with Dr. Stephanie Seneff to discuss glyphosate, the childhood shot schedule, the em-are-in-ay shots, and their differences in perceptions on virology. For all of our links, visit: https://www.flowcode.com/page/thewayfwrd Stephanie Seneff is a Senior Research Scientist at the MIT Computer Science and Artificial Intelligence Laboratory.  She received the B.S. degree in Biophysics in 1968, the M.S. and E.E. degrees in Electrical Engineering in 1980, and the Ph.D degree in Electrical Engineering and Computer Science in 1985, all from MIT.  For over three decades, her research interests have always been at the intersection of biology and computation – developing a computational model for the human auditory system, understanding human language so as to develop algorithms and systems for human computer interactions, as well as applying natural language processing (NLP) techniques to gene predictions.   She has published over 170 refereed articles on these subjects, and has been invited to give keynote speeches at several international conferences.  She has also supervised numerous Master's and PhD theses at MIT.   In recent years, Dr. Seneff has focused her research interests back towards biology. She is concentrating mainly on the relationship between nutrition and health.  Since 2011, she has published over 30 papers, together with colleagues, in various peer-reviewed medical and health-related journals on topics such as modern-day diseases (e.g., Alzheimer, autism, cardiovascular diseases), analysis and search of databases of drug side effects using NLP techniques, and the impact of nutritional deficiencies and environmental toxins on human health.   Check out Dr. Seneff's book here: https://www.chelseagreen.com/product/toxic-legacy/   Some of Dr. Seneff's peer reviewed studies:   MRNA shots: 1. https://ijvtpr.com/index.php/IJVTPR/article/view/23 Worse than the disease? Reviewing some possible unintended consequences of mRNA vaccines against Covid-19.   2. https://www.sciencedirect.com/science/article/pii/S027869152200206X Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, Exosomes, and MicroRNAs   3. https://www.hilarispublisher.com/abstract/potential-mechanisms-for-human-genome-integration-of-genetic-code-from-sarscov2-mrna-vaccination-implications-for-diseas-92500.html Potential Mechanisms for Human Genome Integration of Genetic Code from SARS-CoV-2 mRNA Vaccination: Implications for Disease   Glyphosate & Aluminum: https://www.scirp.org/html/5-3000951_53106.htm Aluminum and Glyphosate Can Synergistically Induce Pineal Gland Pathology: Connection to Gut Dysbiosis and Neurological Disease     For more on The Way Forward, please visit https://thewayfwrd.com   Do you run a freedom-oriented or holistic health oriented business? Join our FREE business directory here:  https://thewayfwrd.com/directory-form/   Join our membership here!: https://thewayfwrd.com/membership-sign-up/   Like this episode? Then you'll love The Way Forward's new membership platform! For $17/month or $150/annually, you get:   SOURCE: a freedom & health oriented business directory exclusive discounts with partner brands and products exclusive podcast episodes courses + workshops weekly community calls + Q&As with guests past and future in-person event footage past, present, and all future livestream event footage live breathwork sessions, kundalini yoga, and meditations exclusive content from Alec Zeck, Garret Kramer, Mollie Engelhart, Brandon Bozarth + more   Sign up for our membership at: https://thewayfwrd.com/membership-sign-up/   Follow The Way Forward on telegram: https://t.me/thewayforwardformankind   Like us on Facebook: https://www.facebook.com/T.Way.Forward   Follow us on Instagram: https://www.instagram.com/the.way.fwrd/   Sign up for our newsletter: https://thewayfwrd.com/newsletter/   We stream our podcasts live every Wednesday. Watch live at:   Youtube: https://www.youtube.com/@TheWayFwrd   Unite: https://unite.live/channels/the-way-forward/the-way-forward   Bitchute: https://www.bitchute.com/channel/a3s3CiyELVd8/

Listen to Kasra Khalaj gave his presentation of "MicroRNAs in amniotic fluid stem cellextracellular vesicles modulate lung development in experimental congenital diaphragmatic hernia" at the first ever Best of the Best in Pediatric Surgery event.

This month on Episode 41 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 30 and October 14 issues of Circulation Research. This episode also features an interview with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, to discuss their study, Transcriptional and Immune Landscape of Cardiac Sarcoidosis.   Article highlights:   Tian, et al. EV-Mediated Heart Brain Communication in CHF   Wleklinski, et al.  Impaired Dynamic SR Ca Buffering Causes AD-CPVT2   Masson, et al. Orai1 Inhibition as a Treatment for PAH   Li, et al. F. Prausnitzii Ameliorates Chronic Kidney Disease   Cindy St. Hilaire:        Hi, and welcome to Discover Circ Res, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to highlight articles from our September 30th and October 14th issues of Circulation Research.                                           I'm also going to have a chat with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to discuss their study Transcriptional and Immune Landscape of Cardiac Sarcoidosis. But before I get to the interview, I'm going to highlight a few articles.   Cindy St. Hilaire: The first article I'm going to share is Extracellular Vesicles Regulate Sympathoexcitation by Nrf2 in Heart Failure. The first author of this study is Changhai Tian, and the corresponding author is Irving Zucker, and they are at University of Nebraska. After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling, and ultimately, heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI, likely due to upregulation of Nrf2-targeting microRNAs. These microRNAs can also be packaged into vesicles and released from stressed heart cells.   Now, this group has shown that rats and humans with chronic heart failure have an abundance of these microRNA-containing EVs in their blood. In the rats with chronic heart failure, these extracellular vesicles were found to be taken up by neurons of the rostral ventrolateral medulla, RVLM, wherein the microRNA suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system, and in the presence of EVs, it is ramped up by sympathetic excitation. Because such elevated sympathetic activity can induce the fight or flight response, including increased heart rate and blood pressure, this would likely worsen heart failure progression. The team, however, found that inhibiting microRNAs in the extracellular vesicles prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically.   Cindy St. Hilaire:        The next article I want to highlight is titled, Impaired Dynamic Sarcoplasmic Reticulum Calcium Buffering in Autosomal Dominant CPVT2. The first author of this study is Matthew Wleklinski, and the corresponding author is Bjӧrn Knollmann, and they are at Vanderbilt University.   Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure, and other features of the fight or flight response. For people with catecholaminergic polymorphic ventricular tachycardia, or CPVT, physical activity or stress can cause potentially lethal arrhythmias. Mutations of calsequestrin-2, or CASQ2, which is a sarcoplasmic reticulum calcium-binding protein, is a major cause of CPVT, and can be recessive or dominant in nature.   For many recessive mutations, disease occurs due to loss of CASQ2 protein. This group investigated a dominant lysine to arginine mutation in this protein, and found by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so, too, was the protein's subcellular localization. The mutation instead interfered with CASQ2's calcium binding or buffering capability within the sarcoplasmic reticulum. The result was that upon catecholamine injection or exercise, the unbound calcium released prematurely from the sarcoplasmic reticulum, triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations.   Cindy St. Hilaire:        The next article I want to highlight is from our October 14th issue of Circulation Research, and the title of the article is ORAI1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. The first author is Bastien Masson, and the corresponding author is Fabrice Antigny, and they're from Inserm in France. In pulmonary arterial hypertension, the arteries of the lungs become progressively obstructed, making it harder for the heart to pump blood through them, ultimately leading to right ventricular hypertrophy and heart failure. A contributing factor in the molecular pathology of pulmonary arterial hypertension is abnormal calcium handling within the pulmonary artery smooth muscle cells. Indeed, excess calcium signaling causes these cells to proliferate, migrate, and become resistant to apoptotic death, thus leading to narrowing of the vessel.   This group now identified the calcium channel ORAI1 as a major culprit behind this excess signaling. Samples of lung tissue from pulmonary arterial hypertension patients and a pulmonary arterial hypertension rat model had significantly upregulated expression of this channel compared with controls. And in patient pulmonary arterial smooth muscle cells, the high ORAI1 levels resulted in heightened calcium influx, heightened proliferation, heightened migration and reduced apoptosis. Inhibition of ORAI1 reversed these effects. Furthermore, in pulmonary hypertension model rats, ORAI1 inhibition reduced right ventricle systolic pressure and attenuated right ventricle hypertrophy when compared with untreated controls. This study indicates that ORAI1 inhibitors could be a new potential target for treating this incurable condition.   Cindy St. Hilaire:        The last article I want to share is titled Faecalibacterium Prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. The first author of this study is Hong-Bao Li, and the corresponding author is Tao Yang, and they are from the University of Toledo.   Progressive renal inflammation and fibrosis accompanied by hypertension are hallmarks of chronic kidney disease, which is an incurable condition affecting a significant chunk of the world's population. Studies indicate that chronic kidney disease is linked to gut dysbiosis. Specifically, depletion of lactobacillus bifidobacterium and faecalibacterium, prompting investigations into the use of probiotics. While supplements including lactobacillus and bifidobacterium have shown little effectiveness in chronic kidney disease, supplementations with F. prausnitzii have not been investigated.   Now, this group has shown in a mouse model of chronic kidney disease that oral administration of F. prausnitzii has beneficial effects on renal function, reducing renal fibrosis and inflammation. This bacterial supplementation also produced the short chain fatty acid butyrate, which was found to be at unusually low levels in the blood samples from the CKD model mice and from chronic kidney disease patients. Oral supplementation with this bacterium boosted butyrate levels in the mice, and in fact, oral administration of butyrate itself mimicked the effects of the bacteria. These findings suggest that supplementation with F. prausnitzii or, indeed, butyrate could be worth investigating as a treatment for chronic kidney disease.   Cindy St. Hilaire:        Today I have with me Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to talk about their paper, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. This is in our September 30th issue of Circulation Research. Welcome, and thank you for taking the time to speak with me today.   Chieh-Yu Lin:             Thank you for inviting us. It's a great honor to be here today.   Kory Lavine:               Thank you.   Cindy St. Hilaire:        Really great paper, ton of data, and hopefully, we can pick some of it apart. But before we get into it, I actually want to just talk about sarcoidosis generally. I know it's a systemic inflammatory disease that has this kind of aggregation of immune cells as its culprit, and it can happen in a bunch of different organs. It's mostly in the lung, but it's also, like you're studying, in the heart. Can you just give us a little bit of background? What is sarcoidosis, and how common is cardiac sarcoidosis?   Chieh-Yu Lin:             Well, this is actually a great question, and I'll try to answer it. You actually capture one of the most important kind of features for sarcoidosis. It happens in all kind of organ system, mostly commonly in lung, in lymph nodes, but also in heart, spleen, even in brain, or even orbit, like eyes. It's really a truly multisystemic disease that has been characterized by this aggregate of macrophages, or myeloid cells, with scattered multinucleated giant cells, as the name implies, have multiple nuclear big, chunky, cells that form an aggregate. That's kind of like a pathognomonic feature for sarcoidosis, whether it's happening in lung, in the heart. When any organ system, a lot of studies has been done, but as of now, a very clear pathogenesis or mechanism has been, I would say, still pretty elusive, or still remain quite unclear, despite all the great effort has been made in this field. The other thing is that a lot of the studies actually focusing on pulmonary sarcoidosis for good reasons. Actually, that's one of the most common manifestations. For cardiac sarcoidosis, although it's only effect in probably, I would say depends on the data, 20% to 30% of the outpatient that with sarcoidosis, with or without lung involvement. It's actually carry a very significant clinical implications as of matter that the presentation of cardiac sarcoidosis can be devastating and sometimes actually fatal. Some of the study actually show that cardiac sarcoidosis actually higher, up to 80%, just because the first presentation's actually, unfortunately, sudden cardiac death. That's why Kory and I, we teamed up. I'm a cardiothoracic pathologist, so in my clinical practice I see specimens and samples from human body, from patient suffer from sarcoidosis, both in lung, lymph node, and heart. Kory is an outstanding heart failure, heart transplant cardiologist, see the other end, which is the patient care. This disease, specifically in heart, its presentation and its pathogens in heart, really attracts our attention.   Cindy St. Hilaire:        Do we know any or some of the potential causes? Why it would start, maybe in a different patient population, but also in the heart versus the lung? Do we know anything about that process?   Kory Lavine:              We know nothing about it. Sarcoid has no known etiology. There's been thoughts in the past that it may be driven by infection, the typical pathogens or autoimmune ideologies, but really, there's little data out there to support those possibilities. Right now, the field's wide open. The other challenge is we don't really have a good way to treat this disease, so a lot of the therapies available are things like steroids, which can have some effect on the disease but carry a lot of risk of complications. The other agents that we sometimes use to lower the doses of steroids, things like methotrexate and azathioprine, are only modestly effective.   These are really the motivation for Chieh-Yu and myself to pursue this. We don't really know what causes the disease, and we don't really have very good treatments. We really wanted to take the first step, that's to study the real disease, and understand what are the pathologic cell types that are present within the granuloma, which is these aggregation of immune cells that Chieh-Yu was speaking about.   Cindy St. Hilaire:        What is actually happening at the beginning of this disease? These granulomas form, and then what is the pathological progression in the heart? What goes on there?   Chieh-Yu Lin:             This is actually another great question that I will say there's not much that has been discovered because, especially in human tissue, every time we have a sample, it's actually a kind of time point. We cannot do a longitudinal study. But in general speaking, very little is known about how it's initiated because it will need to accumulate to a certain disease burden for this to have a clinical symptom sign and be manifested, and then being clinically studied. We do know that in both heart and lung after treatment of progressions, it's usually in, a general speaking, going through a phase from a more proliferative means that it's creating more granulomas, more  inflammatory cell aggregate, to a more fibrotic phase. Means that sometimes you actually see the granuloma start to disappear or dissipate, and then showing this kind of dense collagen and fibrosis. That has been commonly documented in both lung and heart sarcoidosis. The other things is that very difficult to study this disease that we do not have a great animal model, so we cannot use animal model to try to approximate or really study the disease pathogenesis. There are several animal models they try to use microbacteria or infectious agents, and these infectious agents can create morphologically similar granuloma, per se, but just like in human body. For instance, patients suffer from TB in their lung, biopsy will show this. But clinically, these are two very distinct disease entities, even though they look alike. Even in the heart, one of the conditions that we study in our paper is giant cell myocarditis, as the name implying having multinucleated giant cells granuloma. It looks really alike under microscopy for pathologists like me, but their clinical course in response to treatment is drastically different. This type of barriers and in the current limitations of our study tool makes, as Kory just said, this is really a wide open. We just know so little despite all the effort.   Cindy St. Hilaire:        Yeah. I'm guessing based on this granuloma information, to start with, the obvious question you went after is going after the immune cell populations that possibly contribute to sarcoidosis. To do this, because you have the human tissue, you went for single cell transcriptional profiling, which is a great use of the technology. But what biological sources did you use, and how did you go about choosing patient? Because the great thing about single cell is you can do just that, you can look at however many thousands of cells in one patient. But how do you make sure or check that that is broadly seen versus just a co-founding observation in that patient?   Kory Lavine:               We use explanted hearts and heart tissue from patients that underwent either heart transplantation or implementation of LVADs. It's a pretty big hunk of myocardium, and we're lucky to work with outstanding pathologists both at WashU, JU, as well as our collaborators at Duke. Between the two institutions, we're able to pull together a collection of tissues where we knew there were granulomas within that piece of tissue we analyzed. You bring up an important challenge. You need to make sure the disease and cause of the disease is present in the tissue that you're analyzing, otherwise you'll not come up with the data that really is informative.   Chieh-Yu Lin:             Kory beautifully answered the question, but I just wanted to add one little thing, and that's also why we use various different modalities. Some of them is more inside you, like the NanoString Technologies' spatial transcriptomic. You can visualize and confirm that we are studying the phenomenon that has been described for sarcoidosis, and then using multichannel immunofluorescence to validate our sequencing data, to complement such limitations of certain technology.   Cindy St. Hilaire:        Especially, I feel like with this diseased tissue that it's such a large tissue, there's so much information, it's really hard to dig in and figure out where the signal is. This was a wonderful paper for kind of highlighting, integrating all these new technologies with also just classical staining. Makes for great pictures as well. How does this cellular landscape of cardiac sarcoidosis compare to a normal heart? What'd you find?   Chieh-Yu Lin:             This is a great question. Compared to normal heart, we have been talking about this accumulation of macrophages with scattered multinucleated giant cells. For the similar landscape, first and foremost, you do not see those type of accumulations in brain microscopy or by myeloid markers in the heart. Although, indeed, in even normal heart tissue we have rest and macrophages. It just doesn't form such morphological alterations. But then we dive deep into it, and then we found that from a different cell type perspective, we realized that the granuloma is composed by several different type of inflammatory cells, with most of the T cells and NKT cells kind of adding periphery. The myeloid cells, including the multinucleated giant cells also, are kind of in the center of the granuloma of the sarcoidosis. Then, we further dive in and realize that there are at least six different subtype of myeloid cells that is contributing to the formation of this very eye-catching distinctive granular malformations, and to just never feel first off and foremost, of course, is those multinucleated giant cells that is really distinct, even on the line microscopy] routine change stand.   And then we have a typical monocyte that's more like a precursor being recently recruited to the heart, and we finally sent the other four different type of myeloid cell that carry different markers, and then improving the resident macrophages. Especially for me as a pathologist, I'm using my eye and looking at stand every day, is actually these six type of cells, myeloid cells, actually form a very beautiful special kind of distribution with the connections or special arrangement with all different type, kind of like multinucleated giant cell in the middle, flanked by HLA-DR positive epithelioid macrophages, kind of scatter, and then with dendritic cells and a typical monocyte at the peripheral, and then resident macrophage kind of like in the mix of the seas of granuloma information. All these are distinct from normal heart tissues that does carry a certain amount of macrophages, but just don't form this orchestrated architectural distinct structure that's composed of this very complicated landscape.   Cindy St. Hilaire:        Those images, I think it was figure six, it's just gorgeous to look at, the model you made. One of the questions I was thinking is there must be a significance between these cells that are on the periphery and those that are in the center of this granuloma. Do you have an idea or can we speculate as to are some more cause and some more consequence of the granuloma? Were you able to capture any more information about maybe the initiating steps of these from your study?   Kory Lavine:              That's a great question, and a question the field has had for a long time. Now, we know there's different populations of cells. The single cell data allows us to understand what are the transcriptional differences and distinctions between them to gain some insights. One thing that we do know from the field is that disease activity correlates with mTOR activity within these granulomas. We took advantage of phospho-S6 kinase staining as a downstream marker of mTOR activity, and Ki-67 is a marker of self proliferation.   Which of these populations within the granuloma might be most active with respect to mTOR and respect to proliferation? If you ask most people in the field, they would jump up and say, "It's the giant cell in the middle." We found that that's not actually the case at all. It's the macrophages that surround the giant cell, the ones that are HLA-DR positive, the epithelioid macrophages, and the ones that are SYLT-3 positive that are scattered around them. That's really interesting and could make a lot of sense, and leads to hypothesis that perhaps activation mTOR signaling within certain parts of the granuloma might be sufficient to set up the rest of the architecture. That's something that we can explore in animal models, and are doing so to try to create a cause and effect relationship. Cindy St. Hilaire:        Yeah, and I was actually thinking about this, too, in relation to kind of the resident macrophages versus infiltrating macrophages or even just infiltrating immune cells. Do you know the original source of the cells that make up the granuloma? Is it mostly resident immune, or are they recruited in?   Kory Lavine:               We can make predictions from the single cell data where you can use trajectory analysis to make strong predictions about what the origin of different populations might be. What those analyses predicted is that the giant cells and the cells that surround the giant cells, the HLA-DR positive and SYLT-3 positive macrophages, come from monocytes. That's the prediction, and, of course, resident macrophages do not. However, that prediction has to be tested, and that's the beauty and importance of developing animal models. The wonderful thing today is we now have genetic tools to do that. We can ask that question.   Cindy St. Hilaire:        I don't know. Maybe you don't want to spoil the lead of the next paper, but what kind of mouse model are you thinking about trying?   Kory Lavine:               Yeah. First of all, let me talk about the tools that are available, because they're published in Circulation Research, of course. We have a nice tool to specifically mark, track and delete in tissue resident macrophages using a CX3CR1 ERT pre-mouse, and taking advantage of the concept that tissue macrophages don't turn over from monocytes and turn over from themselves. We can give tamoxifen to label all monocytes macrophages in Dcs with that CRE, and then wait a period of time where only the resident macrophages remain labeled. We can use that trick to modulate mTOR signaling as a first step, and ask whether mTOR signaling is required in that population. We've now developed a new genetic tool to do the same thing in just recruited macrophages.   Cindy St. Hilaire:        What was the most challenging aspect of this study? There's a lot of moving parts. I'm sure probably the data analysis alone is challenging, but what would you say is the most challenging?   Kory Lavine:               I think you alluded to this early on, but the most challenging thing is collecting the right tissues to analyze, and that's not a small feat or a small effort here. All the technologies are a lot of fun, and everything works so well today compared to many years ago when we trained, so it's an exciting time to do science. The most challenging and time-consuming component was assembling a group of tissues that we could do single-cell sequencing on between our group and our colleagues at Duke, and then creating validation cohorts that we did across several different institutions, including our own as well as Stanford. That team effort in building that team is the most important, challenging, and honestly, enjoyable part of this.   Chieh-Yu Lin:             I cannot agree more what Kory just said. I think that that's the challenging and the fun part, and that we're very fortunate to really have a great team to tackle this questions in multiple from multiple institute. I just want to add one more thing that, particularly for me as a cardiopathologist, one of the hardest things is I've known how to look or diagnose sarcoidosis for years, but seeing the data emerging that is so complicated and then beyond my reliable eyes in understanding, it's kind of mentally very challenging but very fun to really open and broaden the vision. It's not just how it looks like just giant cells in macrophages.   Cindy St. Hilaire:        What do you think about in terms of diagnostics or even potential therapies? How do you think this data that you have now can be leveraged towards those objectives, whether it's screening for new cell types that are really key to this granuloma formation versus therapeutically targeting them?   Kory Lavine:              This study opens new doors, and right now, diagnosis of sarcoids islimited by trying to biopsy, which, in the heart, is limited by sample bias. You certainly can biopsy the wrong area because you don't know whether a granuloma is in the area or not. We do do some cardiac and other imaging studies like FDG-PET scans, which are helpful but are not perfect, and each of them has their individual limitations. One of the beauties of our study is it identifies new markers of macrophage populations that live within the granuloma, many of which are unique to this disease.   That suggests that there's maybe an opportunity to develop imaging tracers that can identify those populations more specifically than our current PET imaging studies do, which rely simply on glucose uptake. It also opens up the possibility that we may able to take blood samples and identify some of these cell types within the blood, and have more simple testing for our patients. I think in terms of therapy, you alluded to it earlier, these concepts about mTOR signaling, that could be a new therapeutic avenue that needs to be rigorously explored in preclinical models. We're lucky already to have very good mTOR inhibitors available in clinical practice today.   Cindy St. Hilaire:        Obviously, opening new doors is amazing because it's more information, but often a good study leads to even more questions to be asked. What question, or maybe what questions, are you guys going to go after next?   Chieh-Yu Lin:             Well, that list is very long, and then that's actually the exciting thing about doing this research. There's no bad questions, in some sense. All the way from diagnosis, management, monitoring, therapeutic, how we predict where the patient can respond, that's the whole clinical side. Even the basic science side, we still haven't really answered the question, although our data suggests where that multinucleated giant cells coming from. It's very eye catching. How do they form, even though our data suggests it's from the recruited macrophages. But that's still a long way from the recruited macrophage,  monocyte to that gigantic bag of nuclei in the very fluffy cytoplasm.   And then, how the granuloma, as we discussed earlier in this discussion, really initially from a relatively normal background myocardium to form this disease process. There are just so many questions that we can ask. There are, of course, several fronts that we would like to focus on. Kory already nicely listed some of them. First and foremost is actually to establish animal model to enable us to do more details in mechanistic studies, because human tissue, as good as it is, it's kind of like a snapshot, just one time point, and it really limits our ability to test our hypothesis. Animal model, certainly, is one of the major directions that we are going forward, but also the other side, like more clinical science also to develop novel noninvasive methodologies to diagnose and to hopefully monitor this patient population in a better way.       Cindy St. Hilaire:        Well, it's beautiful work. I was actually reading this paper this weekend at a brunch place just next door to my house, and the guy sitting next to me happened to see over my shoulder the title and said that his father had passed away from it. This is hopefully going to help lots of people in the future, and really help to make the models that we need to ask, "What's happening in this disease?" Thank you so much for taking the time to speak with me, and congratulations on what seems to be a landmark study in understanding what's going on in this disease.   Chieh-Yu Lin:             Thank you so much. It's a pleasure.   Cindy St. Hilaire:        That's it for our highlights from the September 30th and October 14th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page, and follow us on Twitter and Instagram with the handle @CircRes, and hashtag Discover Circ Res. Thank you so much to our guests, Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover Circ Res, 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 speakers in this podcast are their own, and not necessarily those of the editors of the American Heart Association. For more information, please visit ahajournals.org.  

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

Extreme weather events have been recorded at both of Earth's polar regions, as the Arctic and Antarctic are hit by major heat waves. To put this into context, Rowan speaks with climate scientist and Hot Air author Peter Stott.How did octopuses get to be so clever? Their intelligence is unusual for an invertebrate, so researchers have been trying to track down what's going on in their brains. The team examines new findings which suggest it has something to do with microRNAs.Black holes have always been mysterious, but a problem known as the ‘black hole paradox' has been bothering physicists because it undermines what we know about quantum mechanics. Now, as the team explains, there could be a (vaguely confusing) solution. They also mark a major milestone in the search for new exoplanets.The team reviews a compelling new sci-fi opera that's showing in New York. Upload is about a daughter who is trying to come to terms with the decision of her father to physically die in order to have his consciousness uploaded to a computer.And we hear the *delightful* sound of an orangutan ‘kiss squeak', as the team finds out what this vocal call tells us about the evolution of speech in primates.On the pod are Rowan Hooper, Penny Sarchet, Leah Crane and Timothy Revell. To read about these stories and much more, subscribe at newscientist.com/podcasts.For a 20 per cent discount subscription to New Scientist magazine, go to newscientist.com/pod20.For a 50 per cent discount on New Scientist Academy courses, use the code POD50 at checkout at newscientist.com/courses. Offer ends on March 31st.The second in the Big Thinkers online series goes live on Thursday 31st March, 6-7pm BST. Claudia de Rham, Professor of Physics at Imperial College London, explores ‘what we don't know about gravity'. For more information visit newscientist.com/gravity See acast.com/privacy for privacy and opt-out information.

MIT Sr. Research Scientist Dr. Stephanie Seneff joins "Faithful Freedom with Teryn Gregson" to explain why we may being seeing a rise in neurodegenerative diseases this year like Parkinson's & Alzheimer's, how you can detox naturally after the COVID vaccine and warnings for our kids. ► Subscribe to the podcast newsletter: https://teryngregson.com/podcast► Subscribe to the podcast:iTunes: https://podcasts.apple.com/us/podcast/faithful-freedom-with-teryn-gregson/id1598602749Spotify: https://open.spotify.com/show/6dKsn0JqtNJfarUUVYuv5v?si=a810d53643fb4017Google Play: https://podcasts.google.com/feed/aHR0cHM6Ly9pbmZvNjA1NzAucG9kb21hdGljLmNvbS9yc3MyLnhtbAYouTube: https://www.youtube.com/teryngregsonRumble: https://rumble.com/c/c-1020046► Subscribe to the We The Patriots USA newsletter: https://wethepatriotsusa.org/news-updates/► Dr. Stephanie Seneff and Greg Nigh, "Worse than the disease?" https://ijvtpr.com/index.php/IJVTPR/article/view/23 ► Innate Immune Suppression by SARS-CoV-2 mRNA Vaccinations: The role of G-quadruplexes, exosomes and microRNAs https://www.authorea.com/users/455597/articles/552937-innate-immune-suppression-by-sars-cov-2-mrna-vaccinations-the-role-of-g-quadruplexes-exosomes-and-micrornas

The brilliant Dr. Stephanie Seneff dissects her newest published research paper. Learn everything you need to know about MRNA vaccines in this episode. https://www.researchgate.net/publication/357994624_Innate_Immune_Suppression_by_SARS-CoV-2_mRNA_Vaccinations_The_role_of_G-quadruplexes_exosomes_and_microRNAs

The brilliant Dr. Stephanie Seneff dissects her newest published research paper. Learn everything you need to know about MRNA vaccines in this episode. https://www.researchgate.net/publication/357994624_Innate_Immune_Suppression_by_SARS-CoV-2_mRNA_Vaccinations_The_role_of_G-quadruplexes_exosomes_and_microRNAs

The brilliant Dr. Stephanie Seneff dissects her newest published research paper. Learn everything you need to know about MRNA vaccines in this episode. https://www.researchgate.net/publication/357994624_Innate_Immune_Suppression_by_SARS-CoV-2_mRNA_Vaccinations_The_role_of_G-quadruplexes_exosomes_and_microRNAs