Podcasts about micrornas

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.

O furacão Milton deve tocar o solo do estado da Flórida, nos Estados Unidos, durante esta quarta-feira e já atingiu ventos de até 285 km/h. Ele ganhou 150 Km/h em somente 24 horas e pode se tornar o primeiro furacão de categoria 5 a tocar o solo dos EUA desde 2018. O presidente Joe Biden já declarou estado de emergência em todo o estado da Flórida. E mais: - Trump diz que os imigrantes levam muitos genes ruins aos Estados Unidos. Em programa de rádio, ele discutiu a política migratória de Kamala Harris e afirmou que milhares de imigrantes que chegam aos Estados Unidos são assassinos - Israel anuncia ter matado o chefe do Quartel-General do Hezbollah, Suhail Husseini. Ele foi atingido em um bombardeio realizado nas últimas horas em Beirute, capital do Líbano. Husseini era considerado um dos principais nomes do Hezbollah porque era o responsável pela logística do grupo extremista - Papa Francisco critica o que ele chamou de “vergonhosa incapacidade do mundo em parar a guerra no Oriente Médio”. O comentário foi feito para lembrar o primeiro ano do ataque do 7 de outubro, do Hamas contra Israel - O preço do Brent, barril que é referência para o preço do petróleo no mundo, ultrapassou os 80 dólares, pela primeira vez desde o final do mês de agosto. Essa alta pode ter consequências no mundo inteiro, inclusive no custo de transporte no Brasil - Segunda aeronave com brasileiros que deixaram o Líbano está a caminho do Brasil. O avião da Força Aérea Brasileira, com 227 pessoas saiu do Líbano ontem e deve pousar em São Paulo na manhã desta terça-feira - Prêmio Nobel de Medicina foi atribuído aos americanos Victor Ambros e Gary Ruvkun, pela descoberta dos microRNAs e o papel delas na evolução das células do corpo humano Estamos na 2ª fase do Prêmio Melhores Podcasts do Brasil, na categoria de “Assuntos Diversos”. Nos ajudem e deem seu voto https://www.premiompb.com.br Sigam a gente nas redes sociais Instagram mundo_180_segundos e Linkedin Mundo em 180 Segundos Assistam os episódio no Youtube e na live do Instagram

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

David Henshall discusses the role and importance the role of microRNAs in epilepsy; which act as master regulators of gene activity and help stabilise the gene pathway. He discusses the potential of RNA therapy in treating epilepsy and the challenges of delivering RNA molecules to the brain. Henshall's book, 'Fine Tuning Life: A Guide to MicroRNAs, Your Genome's Master Regulators,' explores the fascinating world of microRNAs and their impact on gene regulation. ----------------------------------------- David's book 

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.

In this podcast, Robert MacNeill, Professor Michael Bartlett of the University of Georgia and Dr. Guilherme Guimaraes of Biogen, will focus on oligonucleotide LC-MS covering the exciting key challenges, the pivotal nature of sensitivity in such assays, and the various analytical approaches and technologies that have been used, currently in use or being developed. The episode explores the following:How recent liquid chromatographic and mass spectral innovations have impacted the bioanalysis of these drug modalitiesWhere innovation is taking us particularly in terms of the increasing profile of high-resolution mass spectrometry and the push toward chromatographic miniaturizationSpeakers:Michael G. Bartlett, Ph.D., FAAPS – University Professor, Associate Dean for Science Education, Research and Technology, College of Pharmacy, University of Georgia  – Professor, Department of Metabolism, Digestion and Reproduction at Imperial CollegeOver the past 29 years at the University of Georgia, Dr. Bartlett's group has been involved in the development, validation and implementation of novel bioanalytical methodologies to advance biomedical research.  His laboratory works broadly in the areas of drug discovery, development and toxicology resulting in over 190 peer-reviewed publications in a wide variety of areas.  His research has been supported by the NIH, EPA, DOD, ACS and industry.   One area where Dr. Bartlett's lab has gained particular notoriety is in the use of LC-MS to analyze oligonucleotides. This work began during his time at the University of Utah but has accelerated over the past 15 years. Dr. Bartlett's group has studied many aspects involved in the use of LC-MS to evaluate therapeutic oligonucleotides for quality control, bioanalysis, pharmacokinetics and metabolism. They have also adapted many of these approaches to analyze microRNAs as potential disease biomarkers.  Finally, they have actively worked with many companies on the use of LC-MS to determine oligonucleotides including Pfizer, Ionis, ProQR, Newomics and Waters.   Guilherme Guimaraes – Scientist DMPK at Biogen Dr. Guilherme (Gui) Guimaraes is a scientist in drug metabolism and pharmacokinetics at Biogen. He is responsible for bioanalytical analysis of small molecules and antisense oligonucleotides.  Gui holds a Ph.D in pharmaceutical and biomedical sciences and a masters in international biomedical regulatory sciences from the University of Georgia. His graduate work was focused on the application of novel analytical strategies to improve the chromatographic performance and sensitivity of oligonucleotide LC-MS methods. Some of these strategies include the use of low adsorption surfaces and HILIC microflow LC – nanoelectrospray MS.  Stay tuned for more podcasts in our Pharmaron DMPK Insights Series!

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.

Blog summary of a research paper published in Volume 15, Issue 5 of Aging (Aging-US): “Cellular senescence with SASP in periodontal ligament cells triggers inflammation in aging periodontal tissue.” _____________________________________________ Repercussions of poor dental health aren't limited to mere social stigmas. Poor dental health can impart serious consequences on an individual's overall health. Periodontal disease broadly refers to any disease that affects the gums and the surrounding tissues that support the teeth, including the periodontal ligament (PDL) and alveolar bone. Periodontal disease can increase the risk of heart disease, stroke and diabetes by allowing bacteria to enter the bloodstream, causing inflammation and organ damage. Periodontitis is a more advanced stage of periodontal disease. It is thought to be the most common infectious disease in the United States—affecting more than 40% of adults over 30 years old. Previous research has suggested that aging is a significant risk factor for periodontitis, although the underlying mechanisms are unclear. “The direct cause of periodontitis is periodontopathic bacteria, while various environmental factors affect the severity of periodontitis. Previous epidemiological studies have shown positive correlations between aging and periodontitis. However, whether and how aging is linked to periodontal health and disease in biological processes is poorly understood.” Full blog - https://aging-us.org/2023/03/a-promising-approach-to-preventing-periodontitis/ DOI - https://doi.org/10.18632/aging.204569 Corresponding author - Motozo Yamashita - yamashita.motozou.dent@osaka-u.ac.jp Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204569 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, cellular senescence, periodontitis, periodontal ligament, SASP, microRNAs, SIRT1 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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.

Everyone knows that we are not all the same, there is wonderful diversity in our bodies, our genetics, our lifestyles, and our preferences. And yet, when it comes to nutrition, the most successful public health messages are the broad guidelines, which suggests one size can fit all.   Think five-a-day, taking Vitamin D through the autumn and winter, and so on. At the same time, the science behind nutrition, the understanding of our metabolism and of our gut microbiome, has been increasing at a fantastic rate. The question is: how do you bring these two worlds together?   How do you bring the best of intricate nutritional science to a broader population? Could the answer lay in precision nutrition?   It is an emerging and exciting field which helps tailor dietary recommendations and nutritional guidelines, and there is some evidence it can have remarkable health impacts. It is an area which seems to offer huge potential, but exactly how much is yet to be discovered. Karen Vousden, Principal Group Leader, Francis Crick Institute Karen received her PhD from the University of London and following postdoctoral fellowships at the ICR and NCI, she returned to London to establish a research group at the Ludwig Institute.  Returning to the US, she was Chief of the Regulation of Cell Growth Laboratory at the NCI before coming back to the UK to take on the role of Director of the CRUK Beatson Institute in Glasgow.   In 2017, she moved her research group to the Francis Crick Institute in London and served as Chief Scientist for Cancer Research UK from 2016-2022. Karen's research has made contributions to our understanding of how the tumour suppressor protein p53 is regulated and the functions of p53 that contribute to its ability to control cancer progression.   During these studies, her group revealed an unexpected ability of p53 to help cells adapt and survive under transient periods of nutrient starvation.  This work led to a more general investigation of cancer cell metabolism, focused on exploring the role of oxidative stress and serine metabolism in cancer development and metastatic progression. Greg Hannon, Director of Cancer Research UK Cambridge Institute Greg Hannon FRS FMedSci is a professor of molecular cancer biology and director of the Cancer Research UK Cambridge Research Institute at the University of Cambridge.   Professor Hannon is internationally recognised for his contributions to small RNA biology, cancer biology, and mammalian genomics.  He has a long history in the discovery of cancer genes, beginning with work at CSHL that led to the identification of CDK inhibitors and their links to cancer.   More recently, his work has focused on small RNA biology, which led to an understanding of the biochemical mechanisms and biological functions of RNAi.   Building upon this foundation, he has developed widely-used tools and strategies for manipulation of gene expression in mammalian cells and animals and has generated genome-wide shRNA libraries that are available to the cancer community.   He was among the first to uncover roles for microRNAs in cancer, including the discovery of the miR-17-92 cluster as an oncogene, the placement of miR-34 within the p53 pathways, and the understanding that let-7 and miR-93 are critical regulators of both normal stem cells and tumour initiating cells in several tissues.   His laboratory also discovered the piRNA pathway and linked this to transposon repression and the protection of germ cell genomes. 

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.  

Listen to a blog summary about a trending research paper published by Aging (Aging-US as the cover of Volume 14, Issue 17, entitled, "Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study.” __________________________________________ Can factors in our bloodstream tell us about our cognitive abilities or predict cognitive decline later in life? Among individuals with dementias, including Alzheimer's disease (AD), studies have identified extracellular microRNAs (miRNAs) as potential biomarkers of cognitive impairment. In cognitively normal individuals, however, this association has not yet been fully investigated. “Understanding the functions of miRNAs in the earliest stages of cognitive decline will expand our knowledge on the biology of prodromal AD and the roles of circulating miRNAs in neurodegenerative diseases and could result in identification of therapeutic targets to guide drug development [17].” In a new research paper, published on the cover of Volume 14, Issue 17, of Aging (listed as “Aging (Albany NY)” by Medline/PubMed and “Aging-US” by Web of Science), researchers Nicole Comfort, Haotian Wu, Peter De Hoff, Aishwarya Vuppala, Pantel S. Vokonas, Avron Spiro, Marc Weisskopf, Brent A. Coull, Louise C. Laurent, Andrea A. Baccarelli, and Joel Schwartz from Columbia University Mailman School of Public Health, University of California San Diego, VA Boston Healthcare System, Boston University School of Medicine, and Harvard TH Chan School of Public Health investigated expression levels of extracellular miRNAs circulating in blood plasma taken from cognitively normal men and the association between these miRNAs and cognitive function. Their secondary goal was to investigate the genes and biological pathways associated with miRNAs linked to cognitive function or decline. The research paper was published on September 6, 2022, and entitled, “Extracellular microRNA and cognitive function in a prospective cohort of older men: The Veterans Affairs Normative Aging Study.” Full blog - https://aging-us.org/2022/09/can-micrornas-in-the-bloodstream-signal-cognitive-decline/ DOI - https://doi.org/10.18632/aging.204268 Corresponding author - Nicole Comfort - nicole.comfort@columbia.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204268 Press release - https://aging-us.com/news_room/Extracellular-microRNA-and-cognitive-function-in-a-prospective-cohort-of-older-men Keywords - aging, plasma, extracellular RNA, RNA-seq, microRNA, cognitive decline, cognitive impairment About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Cognition is, according to the Oxford dictionary, the “mental action or process of acquiring knowledge and understanding through thought, experience, and the senses.” In simpler terms, cognition is basically how we think. But what determines how we think? There has to be some influence from the environment. After all, the experiences we have can shape what we remember, and basically how we perceive the world. That can't be the only thing though, because cognition comes from the brain, and our brains are made with the genetic information we get from our parents. How in the world can we even start to look at this question? Cognition is a very complicated process. There are many specific mechanisms involved, and multiple levels where things can go wrong. To learn about normal cognition, scientists will often look at cognitive disorders. By understanding more about where things go wrong, they can use that information to gain insight into cognition in general, and even try to develop treatments.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 4 Cancer.Net Specialty Editors discuss new research in prostate, bladder, kidney, and testicular cancers presented at the 2022 Genitourinary Cancers Symposium and 2022 ASCO Annual Meeting. This episode has been adapted from the recording of a live Cancer.Net webinar held June 15th, 2022, led by Dr. Neeraj Agarwal, Dr. Timothy Gilligan, Dr. Petros Grivas, and Dr. Tian Zhang. Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig (TOSS-ig) Cancer Center. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center. Dr. Zhang is an Associate Professor of Internal Medicine at UT Southwestern Medical Center and a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. Full disclosures for Dr. Agarwal, Dr. Gilligan, Dr. Grivas, and Dr. Zhang are available at Cancer.Net. Greg Guthrie: Good afternoon, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team. I'll be your host for today's Research Round Up webinar focusing on cancers of the genitourinary tract. Cancer.Net is the patient information website of the American Society of Clinical Oncology, known as ASCO. So today, we'll be addressing research from 2 2022 scientific meetings, the ASCO Annual Meeting held in Chicago in June and the Genitourinary Cancers Symposium held in San Francisco in February. Our participants today are all Specialty Editors of the Cancer.Net Editorial Board, and they are Dr. Neeraj Agarwal of the Huntsman Cancer Institute in University of Utah, Dr. Timothy Gilligan of the Cleveland Clinic Taussig Cancer Center, Dr. Petros Grivas of the Fred Hutchinson Cancer Research Center and University of Washington, and Dr. Tian Zhang of the University of Texas Southwestern Medical Center. Thank you, everyone, for joining us today. So starting us off today is Dr. Agarwal who will be talking about research in prostate cancer. Go ahead, Dr. Agarwal. Dr. Agarwal: Hi. Thank you, Greg. So I'd like to start with 2 studies. They both are in prostate cancer which will be followed by my colleagues presenting studies in other cancers in bladder cancer and kidney cancer. So I'll start with this abstract, which was highly discussed by the doctors at the ASCO Annual Meeting a few weeks ago, and it has a lot of relevance in our practice. So this is abstract #5000 presented by Dr. Michael Hofman, and this was the update on a clinical trial which compared lutetium PSMA-617, or lutetium PSMA, to put it simply, with cabazitaxel in patients with metastatic castration-resistant prostate cancer who had disease progression after receiving docetaxel chemotherapy. So, who were the patients who were enrolled on the study? These patients had, as I said, metastatic castration-resistant prostate cancer, who had disease progression after docetaxel chemotherapy, and who had to have high PSMA-expressing prostate cancer. And the way they assessed the presence of high PSMA expression was by using a specialized kind of PET scan known as Gallium 68 PSMA-11 PET scan. In addition, they made sure that these patients do not have another type of prostate cancer, also call it dedifferentiated prostate cancer, by making sure that those patients did not have a traditional PET scan-positive disease. So this was a highly selected patient population who were expressing PSMA on their prostate cancer. Prior to this presentation, the earlier presentation had shown that lutetium PSMA was superior to cabazitaxel as far as progression-free survival is concerned and also was associated with lower incidence of grade 3 or 4 side effects. In this update, after a longer follow-up of 3 years, Dr. Hofman and Dr. Davis, who is a senior author, they presented the data on overall survival, which was a secondary analysis, and overall survival was similar with cabazitaxel as well as lutetium PSMA in the range of 19 months. We did not see any new safety signal. So, what does it mean for us? What does this mean for our patients? My key takeaway message here is, lutetium PSMA is a suitable option for men with metastatic castrate-resistant prostate cancer who are expressing high PSMA on their prostate cancer after they had sustained disease progression after docetaxel. However, cabazitaxel is also a valid option in this setting. I would like to add my own view in addition to this because lutetium PSMA was better tolerated and was also associated with better progression-free survival. In my patients who are progressing on docetaxel chemotherapy, I would like to use lutetium PSMA first followed by cabazitaxel chemotherapy. So that would be my key takeaway from this abstract. Now we can move to the next abstract. This was also an update, a much longer update, on ENZAMET trial. If you recall, ENZAMET trial was one of those trials which established that deeper androgen blockade, or deeper androgen signaling inhibitors such as enzalutamide, apalutamide, or abiraterone, these trials were conducted in 2015 onwards, and all these trials showed that upfront using deeper androgen signaling inhibitors at the time of metastatic hormone-sensitive prostate cancer onset improved survival. So ENZAMET trial used enzalutamide, and it showed in the first analysis, which was presented by Dr. Davis and Dr. Sweeney in the 2019 ASCO Meeting Plenary session, that adding enzalutamide to androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer significantly improved survival. In this longer follow-up of 68 months, so we are talking about almost 6 years of follow-up, now, these investigators from ENZAMET trial, as presented by Dr. Davis, showed that the combination of enzalutamide with androgen deprivation therapy or testosterone suppression therapy continues to significantly improve survival in patients with newly diagnosed hormone-sensitive prostate cancer or metastatic prostate cancer. One interesting part of this unique aspect of this trial was that patients were allowed to receive docetaxel chemotherapy concurrently to the protocol treatment. And in this trial, 45% patients actually receive docetaxel chemotherapy. So 503 patients exactly out of 1,000-plus patients. So if you look at the subgroup analysis of those patients who received docetaxel chemotherapy, enzalutamide does not seem to benefit those patients from the overall survival perspective. So on the face of it, it looks like enzalutamide is not helping those patients who are receiving docetaxel concurrently. But there are some caveats with that kind of subgroup analysis. The first one is this is not a randomized assignment of docetaxel chemotherapy. Patients were determined to have docetaxel chemotherapy after discussion with their respective oncologist. This was not a prespecified analysis that so many patients with docetaxel will receive enzalutamide. Also, this was not a randomized assignment of docetaxel. And third, that I don't think this trial had enough power to look for that subgroup analysis. So my take on this trial is that updated results from this trial, almost 6 years of follow-up now show that enzalutamide continues to improve overall survival with a 30% reduction in risk of death in patients with metastatic castration-sensitive or hormone-sensitive prostate cancer. Furthermore, the effect of enzalutamide, in my view, on overall survival is independent of the receipt of docetaxel. If you look at the whole trial population for which the trial was covered for, enzalutamide improved survival for all patients. And based on these results, I feel more confident in saying that upfront intensification of treatment with deeper androgen inhibition remains a standard of care for our patients with metastatic hormone-sensitive prostate cancer and should be offered to all eligible patients with this condition. With that, I would like to wrap up the prostate cancer abstracts. Thank you very much. Greg Guthrie: And thank you, Dr. Agarwal. Next up, we will have Dr. Gilligan, who is going to be discussing testicular cancer. Dr. Gilligan: Thank you very much. So I have 2 studies I want to talk about and then just give a headline of some interesting things that I think are kind of coming down the road. Both of these abstracts have to do with improvement over time in specific patient populations we used to worry about. I'm not saying we don't worry about them anymore, but things are looking better now than they had 1 or 2 decades ago. So the first topic addresses late relapses in testicular cancer. And historically, we have been concerned that these patients did worse and had worse outcomes. And late relapse could variously be described as after 2 years or after 5 years. In the current study, they defined late relapse as being after 2 years and very late relapse as being after 5 years. And what was special about the study was that it captured the entire population of patients with testis cancer in Norway and Sweden so that it wasn't based on a center of excellence that gets selective referrals. It was actually a population-based study. And the key conclusion of the study was one I found, once again, that late relapses are rare. So for stage I patients, 2% of patients will relapse after 2 years, 1% after 5 years, and 0.5%, so 5 out of 1,000 patients, after 10 years. So if you're 2 years out, the likelihood of a relapse is quite low. And if you're 5 years out, it's half of that. In patients with metastatic disease, similarly, 3.6% relapse after 2 years, 1.6% after 5, and 0.8% after 10 years. And what was interesting to me was that if you looked at the more recent patients who were diagnosed after 1995 - I know that doesn't sound very recent, but they had even earlier patients also in the study - the very late relapse rate almost resolved and went away. It went from 2.2% all the way down to 0.8%. So I think with modern imaging, modern care patterns, we're seeing less of this than we used to. But overall, patients were doing better even if they do relapse late. One thing that was interesting in the study to me also was for stage I disease, we typically recommend surveillance rather than active treatment. So active treatment with non-seminomas would be a retroperitoneal lymph node dissection or more surgery or chemotherapy. With seminoma, it would usually be chemotherapy or radiation, although surgery is being investigated there now. And they did find that in men who chose surveillance, which we still recommend, the late relapse rate was a little bit higher, but it was still affecting a small percent of patients. So the relapse rate beyond 2 years was 4% rather than 1%, but out of 4,000 patients, there were only 3 deaths from late relapse. So this isn't changing the recommendation for surveillance, but it is an alert that patients who are on surveillance for stage I disease have a slightly higher risk of late relapse and that may affect how we follow them and specifically how long we follow them. One of the things that was interesting in the study is in the United States, we often stop scans at 5 years, but in the SWENOTECA countries, they continue scans all the way out to 10 years. I don't know that U.S. guidelines are going to change, but it was a provocative finding. The key thing, as I alluded to at the beginning, was that 61% of patients with late relapse were alive 10 years later, and while we would like that number to be higher, it used to be around 50% in older studies. So it's a significant improvement from where we were before. A particularly interesting thing to me was that patients relapsing 2 to 5 years out actually had the best prognosis. Patients who relapsed in years 1 to 2 had a worse prognosis and patients relapsing after 5 years had a worse prognosis, whereas the patients relapsing 2 to 5 years had a better prognosis. In the end, I think what this means for us is that patients are doing better. It's not going to really change our treatment patterns, but it's reassuring that we shouldn't be pessimistic about late relapses, and we still have a solid chance of curing them. So again, bottom line, most men with late relapse is cured and late relapse is less common now than it was earlier, particularly in non-seminomas. Let's go to the next study. So this is a different group of patients who had a particularly ominous prognosis historically and still we have a lot of room for improvement. These are patients with non-seminomas that start in the mediastinum. So in the chest, under the breastbone, under the sternum typically. And patients are treated aggressively upfront, they are considered poor risk at the initial time of diagnosis, and they're treated aggressively at the time with 4 cycles of BEP or 4 cycles of VIP chemotherapy. And then they go for surgery to remove any residual disease. And the hope is they're cured at that point because historically, if there was a relapse after chemotherapy and surgery, it was almost impossible to cure them. Indiana University published their results using high-dose chemotherapy in this population, and they reported that 30% of men who were treated with high-dose chemotherapy had no evidence of cancer after 2 years, and 35% were still alive. Obviously, we need longer follow-up, but most of the relapses you're going to see are going to be in the first 2 years. So while again, there is significant room for improvement here, this indicates that high-dose chemotherapy is a good option, and that has been a question. So this is reassuring in that regard. But it is a good option for men with relapsed mediastinal non-seminomas of the germ cell tumors. So there's hope there where in the past, this has felt a little bit helpless. The thing I wanted to also highlight was that there are 3 things I think are going to be interesting to keep an eye on over the next year. One is the use of surgery for early-stage seminomas. There are a number of papers out about that. I still think this is an investigational approach, and so I didn't want to go into great detail about it, but it is looking like that RPLND, or retroperitoneal lymph node dissection, will likely or may be an option for stage I and stage II seminoma in the future. We are getting more evidence for that. It's not quite as promising as we had hoped until there's more data that's needed, but it's looking like that will become an option. So for men with early-stage seminoma, at least raising the question whether surgery is an alternative to chemotherapy or radiation, is an important discussion to have with your oncologist. Secondly, MRI rather than CT scans for surveillance. So to keep an eye on men who have been treated or men who are just stage I and are being followed and typically come in routinely for CT scans, which expose people to ionizing radiation, which theoretically has a risk of causing cancer, there's more and more data that MRI is just as good as CT, and MRI does not use ionizing radiation. So there's probably going to be an expanding role for MRI as an alternative to CT scans. And lastly, the use of microRNA rather than just depending on serum tumor markers. So right now, we use the blood tests alpha-fetoprotein, beta hCG, extensively to monitor for relapse, and there's more and more evidence for using what we call microRNAs instead. It may be more accurate in multiple different settings. So it'll be interesting to see how that evolves and that's what I wanted to cover today. Thank you very much. Greg Guthrie: Thank you, Dr. Gilligan. And now we have Dr. Grivas, who's going to discuss some research in bladder cancer. Dr. Grivas: Thank you so much, Greg, and thanks Cancer.Net for the great opportunity to discuss this for our patients. We're very excited about the data from the ASCO Annual Meeting, and I would encourage the audience to review as possible other presentations as well. I'm going to cover 3 highlights. I'm going to start with the QUILT-3.032 study. This trial reported the final results of a clinical trial that took place in different centers and involved patients with what we used to call “superficial bladder cancer.” And the modern term is “non-muscle-invasive bladder cancer.” Bladder cancer that does not involve the muscle layers, not that deep in the bladder wall. Non-muscle-invasive bladder cancer is usually treated by our colleagues in urology with installation inside the bladder with an older form of immunotherapy which is BCG. And that's the most common way we treat this disease. And proportion of patients may have tumors that may not respond to BCG that may come back or persist despite the installation of the BCG in the bladder. And these patients usually have a standard of care of getting what we call radical cystectomy, meaning, removal of the bladder and the lymph nodes around the bladder, radical cystectomy and lymph node dissection. However, many patients may not have, I would say, the opportunity to get the surgery because the body may not be that strong to undergo that significant procedure. Very few patients may have that challenge because of other medical conditions or what we call poor performance status. Or some patients for quality-of-life reasons may try to keep their bladder as long as possible. And for some of those patients, that might be an option. And we have been looking for those options in the last few years. Intravesical, inside the bladder, installations of chemotherapy have been used with some positive results in some other studies. So that's an opportunity. We call this intravesical, inside the bladder, installations of chemotherapy, and the other option is an FDA-approved agent given intravenously inside the vein called pembrolizumab, which is in the form of immunotherapy. Of course, research continues. And this study I'm showing here from Dr. Chamie and colleagues, looked at this combination of BCG plus this molecule called N-803. This is another form of immunotherapy, and this was tested in patients who have this BCG-unresponsive, as we called it, non-muscle-invasive bladder cancer. The results were very promising. I would say impressive that it was a high response rate if we focus our attention on patients who had the superficial form carcinoma in situ, about 70% had no evidence of cancer upon further evaluation of the bladder. And in many of those patients that this response lasted for more than 2 years. 96% of patients avoided to have worsening of the bladder cancer in 2 years for those who had a response, and about 9 out of 10 avoided cystectomy again from those patients who had received the response. So it was 70% of all the population. And as you see, all patients, 100% were alive without dying from bladder cancer after 2 years, which again is a very promising finding. This combination, to conclude, this inside the bladder installations of BCG plus the N-803, looks very promising. For those patients with BCG-unresponsive non-muscle-invasive bladder cancer, that might be an option down the road, we have to see. Now I'm going to shift my attention to patients with metastatic or spread urothelial cancer. I want to point out that I'm a co-author in this abstract and I participated in that survey I will show you the results from. This is a population of patients who have spread cancer from the urinary tract, either the bladder was the most common origin or other parts of the urinary tract, for example, what we call kidney, pelvis and ureter, or rarely the urethra. The urothelial cancer that starts from those areas, again more commonly bladder, if it spreads, if it goes outside the urinary tract system, usually those patients get chemotherapy, what we call with an agent called cisplatin if they can tolerate that chemotherapy drug or carboplatin if they cannot tolerate the cisplatin drug. And usually either of these, cisplatin or carboplatin, is combined with a drug called gemcitabine. That's the most common chemotherapy used as initial therapy for patients with spread metastatic urothelial cancer. In this abstract, Dr. Gupta and colleagues tried to survey 60 medical oncologists, including myself, who treat urothelial cancer that considered experts in this disease type, to see if there are any features that could deter us from using chemotherapy in those patients. In other words, are there any features that may make us think that chemotherapy may be too risky for our patients and we should not do it? We should give immunotherapy instead. This is probably a small proportion of our patients, maybe 10 to 20% in our practice, may not be able tolerate that chemotherapy. And which are those features? Poor performance status, meaning the body is very tired and the patient is not moving too much, is confined in the chair or the bed most of the day, and rely on others on daily activities. This is what defines the performance status of ECOG 3. Peripheral neuropathy, meaning that there is numbness or tingling or weakness in the hands or the feet that impact the quality of life. And patients may have trouble buttoning buttons or tying laces, so impacting the quality of life. That's grade 2 neuropathy. Symptomatic severe heart failure, there is a grading system, like New York Heart Association Class III or IV that is significant, notable heart failure symptoms. And also, patients with kidney failure with what we call creatinine clearance below 30 cc per minute. That's a marker how we measure kidney function and the creatinine clearance more than 60 is usually close to normal. As the creatinine clearance drops and goes below 30, chemotherapy with these platinum agents may become a challenge by itself or if it's combined with the ECOG performance status of 2, which means more patients are not moving most of the day. So those features again have to do with the functionality of the day-to-day life. The presence of significant neuropathy, heart failure, and poor kidney function may potentially make the oncologist recommend immunotherapy versus the standard of care, which is chemotherapy, in those patients. And I would say if someone gets chemotherapy, which is the majority of patients, usually they may get immunotherapy later. So pretty much I would say discuss with the medical oncologist what is the right treatment for you. Most patients get chemotherapy up front, followed by immunotherapy. Some others may need to get immunotherapy, and those criteria help us make that patient selection for the right treatment at the right time. So I just alluded to you that most patients with spread or metastatic urothelial cancer, most of them receive chemotherapy. We discussed some criteria in the previous studies that we may use immunotherapy upfront instead of chemo, but for the vast majority of patients, chemotherapy is used upfront and that was based on the results of phase 3 clinical trial called JAVELIN Bladder 100. This was presented at the ASCO Annual Meeting in 2020 about 2 years ago, and it was published in a big journal. And that study showed that if you give chemotherapy upfront, those patients who can tolerate the chemotherapy, of course, who do not have the previously listed criteria, those patients benefit and live longer, so longer overall survival, meaning they live longer, and they have longer progression-free survival, meaning they live longer without worsening of the cancer if they get immunotherapy with, immunotherapy drug is given through the vein, called avelumab. If that is given after the end of chemotherapy for patients who have a response or stable disease, meaning no progression on chemotherapy. So if you get a complete response, meaning that the CAT scans look normal after chemotherapy as at least we can tell visually. Partial response, meaning that the CAT scans look better, but still we can see some cancer spots. Stable disease, meaning that the scans look stable compared to the beginning before we start chemotherapy. If someone has worsening of the cancer in chemotherapy, then the concept of maintenance therapy doesn't apply. So it's only for patients with complete response, partial response, or stable disease, SD. And the poster we had, and I can tell you - I was a co-author in the abstract and co-investigator in the trial, as a disclosure - was sort of the benefit of the patient with avelumab as maintenance therapy after chemotherapy was notable in patients with complete response, partial response, and stable disease. So in any of these 3 categories, avelumab immunotherapy should be offered as level 1 evidence and benefit patients in terms of overall survival and progression-free survival as long as there's no progression to the upfront initial chemotherapy of the patient with metastatic urothelial cancer received. Many other abstracts on these cancers were presented, and I would encourage you to look at them. Thank you so much for the opportunity today. Greg Guthrie: And thank you, Dr. Grivas. Next, we have Dr. Zhang who will discuss some research in kidney cancer. Dr. Zhang: Hi everyone, glad to be here today. I'll be discussing 2 highlights from ASCO 2022 in kidney cancer. The first one we wanted to highlight was a trial called EVEREST: everolimus for renal cancer ensuing surgical therapy, a phase 3 study. And in context, this study is a trial of evaluating everolimus, an mTOR inhibitor, in the post-surgical context. And we do have in the landscape 2 approved therapies, sunitinib and pembrolizumab. And as we have seen, some effective therapies in the refractory setting, many of these therapies are being tested in this postoperative space. So this particular study of EVEREST looked at patients with renal cell carcinoma who underwent resection for their primary nephrectomy and looking to evaluate postsurgical treatment. So everolimus has been approved as a treatment on its own in the refractory setting as well as in combination with lenvatinib. And so this question of whether everolimus alone could delay or prevent disease recurrence in the postoperative setting was tested in this EVEREST trial. The study ultimately enrolled more than 1,500 patients and assigned them to receiving either everolimus or placebo in the postoperative setting. Of these patients, 83% had clear cell kidney cancer and the remaining had non-clear cell kidney cancer. And the follow-up was quite long, over 5 years, and actually over 6 years, and the researchers looked at time until disease recurrence. And risk of recurrence was actually decreased by 15% in patients who were treated with everolimus compared to placebo. But the prespecified cut-off for a statistical significance was not quite reached, and the researchers took a specific look at a group of very high-risk patients defined by larger tumors, invasion of the perinephric fat in renal veins or invasion of nearby organs or known positive disease. And those patients with very high-risk disease had more benefit from everolimus compared to placebo. Of note, 37% of patients who were treated with everolimus had to stop treatment due to their side effects, and the most common severe side effects included mouth ulcers, high triglyceride levels, and high blood sugars. So ultimately this particular study did not show sufficient benefit of everolimus given the toxicity and lack of statistical significance. And so this is a balance between potential benefit in delaying recurrence versus treatment toxicities that we must have in this adjuvant setting. So what does this particular study mean for patients? Well, it was certainly a large phase 3 trial performed in the cooperative group setting and through the generosity of 1,500 patients and the principal investigators on the study, we learned this answer for a very important question of whether everolimus makes a difference in this postoperative setting. I think we're not using this in clinical context currently, but in this postoperative setting, we are always balancing this risk of toxicity with the potential for benefit and discussing the potential treatment options. I do not think this particular trial changes the standard of care in this adjuvant setting. And then I think finally for today's prepared talks, this abstract on depth of response and association with clinical outcomes with CheckMate 9ER patients treated with cabozantinib and nivolumab. So this was a post-trial analysis of patients who had kidney cancer with disease spread and treated with cabozantinib and nivolumab compared with sunitinib in the CheckMate 9ER study. And the context, this was the phase 3 trial in which the benefit of cabozantinib and nivolumab was established in the first-line setting and gained the registration and approval of this combination in the first-line treatment of metastatic kidney cancer. This particular analysis, presented at ASCO this year, was a post-trial prespecified analysis evaluating this depth of partial responses and associating those with clinical outcomes of time until disease progression as well as time until death. These depth of responses were defined as 80 to 100% for PR-1, 60 to 80% for PR-2, and then 30 to 60% as PR-3. And as we saw in this analysis, the deeper the responses on cabozantinib and nivolumab, the more correspondence with higher 12-month rates of disease-free progression compared with those same depths of responses from sunitinib. And there were similar 12-month overall survival rates for patients with similar depth of responses for either the cabozantinib and nivolumab combination compared with sunitinib. So I do think the degree of partial response in these settings is productive of time until progression and establishes further the efficacy and benefit of cabozantinib and nivolumab compared with sunitinib. And what does this trial mean for our patients? I think that early on, as we're looking for responses and radiographic changes for our patients on cabozantinib, nivolumab in the first-line setting, these deeper responses are associated with longer time until disease progression, and we can counsel patients, to discuss whether cabozantinib and nivolumab is working for them. This could be an early indicator for how patients will do overall on this combination. So with that I'd love to wrap up and turn it back over to you, Greg. Greg Guthrie: Thanks so much Dr. Zhang. And now it's time to move on into our Q&A session. This is for you, Dr. Agarwal. So the question is utility of triple therapy, ADT plus docetaxel plus ASI and metastatic hormone-sensitive prostate cancer given ENZAMET was inconsistent with PEACE-1 and ARASENS. Would you give ASI concurrent or sequential after chemotherapy for tolerability? I'm assuming ASI here is androgen suppression, correct? Dr. Agarwal: Yes. Great question. There are 2 questions here. Number 1, if I would use triplet therapy given the negative subgroup analysis of the ENZAMET trial, and number 2, what is the role of triplet therapy in general? The answer to the first question is ENZAMET trial, subgroup analysis is very different from preplanned, prespecified, well-powered analysis from PEACE-1 and the ARASENS trial. So yes, we saw discrepant results, but my impression from ENZAMET trial is enzalutamide is an effective option for all patients regardless of the receipt of docetaxel chemotherapy because that was a subgroup analysis. So I don't think it really affects negatively the results of the ARASENS and the PEACE-1 trial. But a bigger question here is triplet therapy versus doublet therapy? Is triplet therapy for all or doublet therapy for all? Answer is no. Triplet therapy trials only showed that adding a novel hormonal therapy or deeper androgen blockade to the backbone of ADT plus docetaxel improves survival. These trials did not answer the question, if adding docetaxel chemotherapy to ADT plus, for example, enzalutamide or darolutamide or apalutamide, will improve survival. We do not have that question answered by any of the trials and unlikely any other trial will answer that question. So my take ADT plus docetaxel is replaced by ADT plus docetaxel plus these deeper androgen blocker therapy. So wherever I was going to use docetaxel chemotherapy, so those are the patients with visceral metastases or in my practice, when I do comprehensive genomic profiling, I see those molecular aberrations which predict lack of response to deeper androgen blockade such as baseline AR variants. Or if I see 2 out of 3 mutations of p53, RB loss, p10 loss, if I see 2 out of these 3, I tend to think about docetaxel chemotherapy. So in those patients where I'm using ADT plus docetaxel, I would add another androgen receptor blocker such as abiraterone and darolutamide. But when I'm using enzalutamide or apalutamide which I use for majority of those patients, my patients with metastatic hormone-sensitive prostate cancer, I do not think about triplet therapy. Greg Guthrie: Thanks, Dr. Agarwal. We actually have a follow-up question, and this is, what is the role of oncology in low-stage early prostate cancer? Can neoadjuvant chemotherapy reduce the number of people who end up with metastatic prostate cancer? Dr. Agarwal: This answer is very simple. There is no role of neoadjuvant chemotherapy in high-risk localized prostate cancer or any localized prostate cancer setting. Greg Guthrie: Great. Thank you. Next question. I believe that this is for everybody. How long will it be until the information from the trials discussed will be used in the community clinics? What can patients do to bring this information to their less experienced doctors? Dr. Grivas: So, Greg, just to clarify the question, is it about the translation of the results of the clinic from ASCO to clinical practice, generically speaking, or any particular tumor type or any particular data results? Greg Guthrie: The way I read this question, it's more just kind of a broader scope question about just like, how long does the results of clinical trials make it to community practice, and what role can patients have in perhaps fostering this transmission of information? Dr. Grivas: Of course, I can start briefly, and then my colleagues can add. I would say the world we live in right now, the information travels very quickly. It's much faster compared to the past. And I think there is much more alignment, in my opinion, in terms of information access between academic oncologists and community oncologists. If, for example, a trial result comes at ASCO being presented, and then there's a follow-up approval authority from a regulatory agency, this agent may be accessible to both community and academic practices. Of course, there are always opportunities for education, and Dr. Agarwal is the director of the ASCO Daily News, and he knows that well to disseminate the information well, broadly, in an equitable manner across academic oncologist providers and community providers. And I think CME, continued medical education practices, can help in that regard. And obviously, the other aspect of that is the ongoing clinical trials and how we can do a better job disseminating the opportunity for equitable participation in clinical trials across racial groups, ethnicity groups, minority groups, to give them the chance to participate in ongoing clinical trials that may change the practice down the road, which are just early thoughts. But other colleagues can comment. Dr. Zhang: Yeah, if I could chime in. I think these continuing medical education programs, particularly in the context after large symposia like the ASCO Annual Meeting we just had, are particularly important. And the Best of ASCO series, as well as ASCO Direct Highlight series - I believe Dr. Grivas and I are hosting 2 of these - are very helpful, I think, to bring the latest findings from the ASCO Annual Meeting to our community colleagues. And they really are our colleagues. We work together with our oncologists within the community to take care of our patients, oftentimes for standard of care treatments. Patients can access them more in their backyards. And I think from a patient standpoint on the second part of the question, they're able to hear these from patient-friendly platforms and to bring that to the attention of their oncologist, wherever that may be. It all helps in the grand context of clinical care. So I hope that these trial results and the latest findings from ASCO can get inseminated very quickly.   Dr. Grivas: And to also add very briefly, the role of patient advocacy groups, and in the bladder cancer work, there are many, for example, the Bladder Cancer Advocacy Network, World Bladder Cancer Coalition, and many others can help also in that regard and teaming up with all of us to disseminate information and also clinical trial access. Greg Guthrie: Great. Thank you, everyone. We have a question for Dr. Grivas. After the survey results in the study you described, is there any plan to make a guideline or tool to make sure we standardize the definition of cisplatin/platinum ineligibility? Dr. Grivas: Great question. Just 1 more thing on my prior answer, kudos to Cancer.Net for serving that mission, Greg and Claire in that-- or the previous question to have a complete answer. Answering this new question here, which is very important. I think the next step is to try to publish the results of the survey. The survey like the previous one done by Dr. Galski about 10 years ago-- it's a survey on expert oncologists, and it's a consensus-based definition. It's criteria that we came up with together. And I think the next step here is to publish this in a peer-review process. And our hope is by publishing these results, we can have a more formal definition to help guide our practices in academia, but also in the community oncology practices and make sure that we have a standardized way that we approach this therapy selection and of course, to help design clinical trials that for this particular patient population in order to improve outcomes in this setting. So hopefully publication will come soon. Greg Guthrie: Thanks, Dr. Grivas. I'll just drop a really quick pitch there. Here at Cancer.Net, we do have a very broad array of information on clinical trials. And patients can come visit us at Cancer.Net and learn about clinical trials, what they mean, and how they help advance cancer research. We now have a question for Dr. Zhang. Based on the results of EVEREST and other trials approved systemic therapies in the adjuvant setting like sunitinib and pembrolizumab, are there ongoing other trials in this setting and is risk stratification used? Dr. Zhang: The short answer is yes. There are ongoing adjuvant trials that build on pembrolizumab in the adjuvant setting. There's one that is looking at the addition of belzutifan with pembrolizumab in the adjuvant setting. So that trial is a global trial which is about to get started, if not enrolling already. And in the context of adding on in the adjuvant setting, I do think we really need to discuss with our patients how much of a benefit the treatment will have versus the real toxicity in the postoperative setting, many patients will not have symptoms from their cancer, so they may have some pain or healing side effects from surgery, but they won't have symptoms from cancer. So any toxicities from medications can be further amplified, so are we truly giving a lot of benefit in that context or not. So that's an individualized decision, and I do think conversations must be had to make that decision together. Greg Guthrie: Thanks, Dr. Zhang. I want to ask a question myself of Dr. Gilligan. You had mentioned that microRNA is an emerging field of study, and I've heard about this in other types of cancer as well. I wonder if you could discuss that a little bit more. Dr. Gilligan: Yeah, microRNA, the promise that holds is being a more accurate detector, specifically of testicular cancer. So the problem we have with alpha fetoprotein and beta HCG is half of the testicular cancers may not make 1 or both of those markers. So people can relapse without the markers going up, even though markers are most commonly what we see, there are a couple of different scenarios. Someone has stage I testicular cancer, which means their testicles removed and all their scans show no evidence of cancer. We know that 25% or so of non-seminomas and 20% or so of seminomas will relapse, even though we can't see what the cancer is, and the markers are negative in that situation. MicroRNA may be able to detect those people who still have cancer much, much earlier. So we know that they're, in fact, not stage I and that they need active treatment right away. So that's one place. Another place that we're seeing evidence is that men who've had metastatic testicular cancer. They go through chemotherapy, and they have residual masses. And we're wondering if there's cancer in those masses or is it all dead scar tissue or is it teratoma? MicroRNAs may be able to allow us to determine who needs additional treatment, who needs surgery without having it. Right now, we typically go in and operate just to figure that out. So there are a number of situations in which we could more accurately stage patients and figure out who's cured and who's not cured much earlier in the course of disease. And for a patient, this would be fantastic, because right now, if you've got stage I disease with non-seminomas and you go on surveillance and somebody says you have a 25% risk the cancer is going to come back, that's a 1 in 4 chance that at some point in the next 2 years, most likely, or longer, you're going to have to suddenly drop everything and go through months of chemotherapy. If we knew on day 1, it looks like you're cured, but in fact, there's cancer hiding there somewhere, and we need to treat you now, that would be helpful to know so they can get it over with. And the other men, we could say we're really extremely confident that there's not a 25% risk, it's a 5% risk or something much lower. So there are a number of ways, if this really gets proven and there's emerging data that's promising, I think we could reassure men, treat them more appropriately, spare them unnecessary treatment, and give them more peace of mind. Greg Guthrie: Great. Thanks, Dr. Gilligan. I think we have a question from Dr. Grivas now. Dr. Grivas: Thank you, Greg. This is a great panel. I like to learn from my colleagues here. One question for Dr. Zhang, you have done so much work in the field, leading the field there, Dr. Zhang. Any comments about the ideal end points in the adjuvant setting in kidney cancer, urothelial cancer, disease-free survival or overall survival? Would you comment about how we design trials, and what will be an acceptable benchmark? And what is meaningful for patients, too, in the adjuvant treatment after radical surgery for kidney cancer and urothelial cancer? Dr. Zhang: Oh, that's a great question, Petros. Thank you so much for asking. We have discussed this many times together because you and bladder cancer and myself and kidney cancer, we're thinking a lot along the same lines right as new immunotherapies get approved in the postoperative setting, so disease-free survival as an endpoint and recurrence-free survival as an endpoint is a valid endpoint. It's a direct result of the randomized treatment on the trial, so I do think that is the valid endpoint, and it's an endpoint that the FDA has approved the sunitinib and pembrolizumab indications in kidney cancer, nivolumab and bladder cancer. So I think it's certainly a valid endpoint to delay disease recurrence. How much of that is meaningful degree of improvement for an individual patient? Their own measure of recurrence is either yes or no. It's much more binary than population effects. So how much does that translate into benefits for the patient? I think that warrants deeper individualized discussion. But these disease-free survival endpoints in all of these studies is a valid endpoint to see whether the treatment is worthy in delaying disease recurrence in each of these disease types. Greg Guthrie: Thanks, Dr. Zhang. We have one last question here, and I believe this is a follow-up for Dr. Gilligan. And what is the time frame for the rollout of microRNA 371 to the community? Dr. Gilligan: I don't know the answer to that. I'm not sure that we have enough data right now that it's going to get approved. I think we're headed in the right direction, but it's very hard to know what the timing of that is. There are trials going on, so I don't know at the moment of exactly what the scenarios are in which people are going to be, which patient populations are going to be eligible, but there are trials going on. I think I'm hoping within the next 2 years or so, but I really don't know what the time frame is, unfortunately. Dr. Grivas: And if I may add a more generic comment to Dr. Gilligan's wonderful answer is that when we have what we call biomarkers that are like metrics that can give us information about how the patient does over time, it's important to tease out what we call prognostic, meaning how can this biomarker give us a sense of the chance of recurrence, as Dr. Gilligan said, or death from the cancer. But also, the bigger question is, is it going to give us information to predict benefit from an individual therapy? And that's a bigger question in oncology that is a harder one. This predictive question and try to identify biomarkers and validate them to make sure they have, they're clinically useful. They can help us make treatment decisions in the clinic. And I'm very excited about what Dr. Gilligan discussed about the promise in the future. But more trials are needed for many biomarkers. Dr. Gilligan: I think when we do this update next year, we'll have significantly more data then, I'm hopeful. Greg Guthrie: Thank you to you all. Thank you, Dr. Agarwal. Thank you, Dr. Grivas. Thank you, Dr. Gilligan. Thank you, Dr. Zhang, for sharing this great research with us, as well as your expertise. It's been a real pleasure this afternoon. And to all of our viewers, thank you for joining us. You can find more coverage of the research from ASCO Annual Meeting and other scientific meetings at the Cancer.Net blog, which is at www.cancer.net/blog. And if you're interested in more Cancer.Net content, please sign up for a monthly Inside Cancer.Net newsletter or follow us on social media. We're on Facebook, Twitter, and YouTube where our handle is always @CancerDotNet, with dot spelled out. Thank you all, and be well. Thanks. ASCO: Thank you, Dr. Agarwal, Dr. Gilligan, Dr. Grivas, and Dr. Zhang. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

The study, which investigated a microRNA's links to autism, appears to contain duplicated and fabricated data, according to research integrity analysts. Those issues reflect a larger problem in the literature. The post Data irregularities surface for study of microRNAs in autism appeared first on Spectrum | Autism Research News.

The study, which investigated a microRNA's links to autism, appears to contain duplicated and fabricated data, according to research integrity analysts. Those issues reflect a larger problem in the literature.

The study, which investigated a microRNA's links to autism, appears to contain duplicated and fabricated data, according to research integrity analysts. Those issues reflect a larger problem in the literature.

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

Dr. Afshin Beheshti begins this episode by explaining what microRNAs are and why they are emerging as an important area of biological research. He then explains how microRNAs relate to viruses, which is a recently developing area of research in this already young field of study. Dr. Beheshti then tells the story of how he started to discover that microRNAs could be a driver of COVID-19 infections. His story begins by using microRNA analysis tools to analyze COVID-19 infected patients from China which predicted a handful of microRNAs that could be involved in COVID-19 infection. He discusses how his team decided to focus on microRNA 2392 and how he continued to dig further into how it could be connected to COVID-19. His story then weaves through tales of successful collaborations with a large team of scientists that led to studying RNA samples from deceased COVID-19 patients, testing expressing the microRNA in healthy cells, analyzing multiple organs in COVID-19 infections, and testing a delivery system for a microRNA antagonist as a potential novel therapeutic. We conclude with a quick discussion of the connection between microRNAs and space biology and space omics research. Learn more about this work by checking out Dr. Beheshti's preprint on these topics: https://www.biorxiv.org/content/10.1101/2021.04.23.441024v4.abstract

Dr. Jose Silva talks with Urologist Dr. Aditya Bagrodia from UT Southwestern Medical Center about the medical and surgical management of testicular cancer. --- EARN CME Reflect on how this Podcast applies to your day-to-day and earn AMA PRA Category 1 CMEs: https://earnc.me/Em4or1 --- SHOW NOTES In this episode of BackTable Urology, urologic oncologist Dr. Aditya Bagrodia joins our host Dr. Jose Silva to discuss the diagnosis, treatment, and long-term management of testicular cancer. The episode begins with an algorithm for initial work up of a testicular mass – scrotal ultrasound and tumor markers – and reviews the pre-orchiectomy timing of additional imaging and when more advanced imaging modalities like MRI or contrast-enhanced CT might be clinically useful. Dr. Bagrodia then walks through his surgical technique, highlighting practical tips to avoid common frustrations and complications. The pair also discuss operative technique and optimal timing for placement of testicular prostheses, as well as the role for partial orchiectomy in patients prioritizing fertility preservation and androgen production. Dr. Bagrodia discusses indications for adjuvant chemotherapy and radiation, with a focus on avoiding over-treatment in these young patients and opting for observation when appropriate. He reviews surveillance protocols based on pathological stage, then walks through the management of recurrent and metastatic disease with an emphasis on the importance of multidisciplinary care. The episode ends with an overview of Dr. Bagrodia's current research, microRNAs. He reviews the sensitivity and specificity of these unique microRNAs in testicular cancer, explaining their potential to truly individualize care by correctly diagnosing equivocal tumors and identifying residual or recurrent disease. --- RESOURCES AUA Guidelines: https://www.auanet.org/guidelines/guidelines/testicular-cancer-guideline EAU Guidelines: https://uroweb.org/guideline/testicular-cancer/ NCCN Guidelines: https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf