POPULARITY
8 episodes with eric small
8 episodes with eric small
8 episodes with eric small
8 episodes with eric small
2 episodes with eric small
2 episodes with eric small
8 episodes with eric small
To celebrate the launch of the DeMultiverse Phase 2, Jace and Rocky talk about the debut issues for each of the four series that were a part of the first DeMultiverse campaign; Layla in the Lands of After, Anyman, Godsend and Wisdom, plus the bonus book The Edward Gloom Mysteries. The guys talk about each story in depth including the overall themes, visuals and story and then it's time to rank them. Will they agree on the list or will they be completely different? You'll have to listen to find out. Also be sure to check out the campaign for the second issues of these stories, if you missed out in the first issues, you will certainly want to catch up and get the second installments! LAYLA IN THE LANDS OF AFTER is the story of a 13-year-old girl who finds herself transported to a magical land where trees read your thoughts, rivers sing, and animals talk. But Layla soon discovers that this isn't Oz or Wonderland. She's dead—and this is the Afterlife. Refusing to accept her fate, and with the help of a few friends she meets along the way -- both old and new -- Layla is determined to return to the land of the living and the loved ones she left behind. But will the creatures lurking in the darkness let her? In the late 1960s, ANYMAN, a hero from millions of years in the past arrives to rescue a modern world in crisis. Over five decades, Anyman becomes the inspiring symbol of all that's good in humanity, the superhero the entire world reveres. There's just one problem... Everything we know about him is a lie! Who is Anyman really? (Or, perhaps, the better question is: Who are THEY?) And who is the savage doppelgänger intent on destroying Anyman and his mysterious creators? GODSEND begins with the sudden appearance of a celestial being who might be a force for global salvation or global destruction. Who is this being? Where did it come from? And why is insecure and unremarkable junior high school teacher Eric Small so obsessed with it? Even Eric's not sure. Maybe the half-turtle, half-man currently standing in Eric's living room will have answers. GODSEND is a reality-shredding story with echoes of Jack Kirby's New Gods, Philip K. Dick, and The Matrix. WISDOM is the tale of Gabriel Wisdom: A devoted husband and father. Middling Shakespearean actor and magician. And, in time, a murderous gunfighter and formidable sorcerer, tasked with saving the planet from a supernatural war that could consume all of humanity. But Gabriel cares less about the world and more about the wife and daughter who have been kidnapped, and corrupted, by dark forces. It's Deadwood meets The Lord of the Rings in an epic fantasy played out against the backdrop of the Old West.
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small discusses systemic therapy treatment in advanced prostate cancer, including AR-targeted therapy. The presentation includes definitions of disease states, categories of treatment types, and standards in treatment selection. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39768]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small discusses systemic therapy treatment in advanced prostate cancer, including AR-targeted therapy. The presentation includes definitions of disease states, categories of treatment types, and standards in treatment selection. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39768]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small discusses systemic therapy treatment in advanced prostate cancer, including AR-targeted therapy. The presentation includes definitions of disease states, categories of treatment types, and standards in treatment selection. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39768]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small discusses systemic therapy treatment in advanced prostate cancer, including AR-targeted therapy. The presentation includes definitions of disease states, categories of treatment types, and standards in treatment selection. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39768]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small discusses systemic therapy treatment in advanced prostate cancer, including AR-targeted therapy. The presentation includes definitions of disease states, categories of treatment types, and standards in treatment selection. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39768]
As part of the 2024 Prostate Cancer Patient Conference, Drs. Julian Hong and Eric Small discuss oligometastatic prostate cancer and its management with radiation and systemic therapies. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39766]
As part of the 2024 Prostate Cancer Patient Conference, Drs. Julian Hong and Eric Small discuss oligometastatic prostate cancer and its management with radiation and systemic therapies. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39766]
As part of the 2024 Prostate Cancer Patient Conference, Drs. Julian Hong and Eric Small discuss oligometastatic prostate cancer and its management with radiation and systemic therapies. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39766]
As part of the 2024 Prostate Cancer Patient Conference, Drs. Julian Hong and Eric Small discuss oligometastatic prostate cancer and its management with radiation and systemic therapies. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39766]
As part of the 2024 Prostate Cancer Patient Conference, Drs. Julian Hong and Eric Small discuss oligometastatic prostate cancer and its management with radiation and systemic therapies. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39766]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small reviews Androgen Deprivation Therapy, including choices of agents, side effects, considerations in timing, duration, intensity of therapy, and discusses interpretation of clinical trial results. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39756]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small reviews Androgen Deprivation Therapy, including choices of agents, side effects, considerations in timing, duration, intensity of therapy, and discusses interpretation of clinical trial results. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39756]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small reviews Androgen Deprivation Therapy, including choices of agents, side effects, considerations in timing, duration, intensity of therapy, and discusses interpretation of clinical trial results. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39756]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small reviews Androgen Deprivation Therapy, including choices of agents, side effects, considerations in timing, duration, intensity of therapy, and discusses interpretation of clinical trial results. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39756]
As part of the 2024 Prostate Cancer Patient Conference, Dr. Eric Small reviews Androgen Deprivation Therapy, including choices of agents, side effects, considerations in timing, duration, intensity of therapy, and discusses interpretation of clinical trial results. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 39756]
Same question we always ask. Why is there another Roadhouse movie? Nothing new to see here beside Post Malone in the beginning which is ridicules. Connor Mcgregor does off and was the best part about this movie. If you are a fan of the original Roadhouse then maybe check this one out but download this episode now to hear what we think of the new Roadhouse. Eric-Small Jordan-Small
Drs. Eric Small, Anthony Zietman, and Eric Klein share their reflections as founders of the ASCO Genitourinary Cancers Symposium and discuss key moments in the Meeting's development, its role in advancing GU cancer research, and major challenges ahead for the field as the Symposium celebrates its 20-year anniversary. TRANSCRIPT Dr. Eric Small: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Eric Small, your guest host of this ASCO Daily News Podcast today. I'm the co-leader of the UCSF Prostate Cancer Program and deputy director and chief scientific officer at the UCSF Helen Diller Family Comprehensive Cancer Center. This year, quite amazingly, we're celebrating the 20th anniversary of the ASCO Genitourinary Cancers Symposium, which is hosted annually in San Francisco. The Symposium has heralded some of the biggest strides in GU oncology and has the largest multidisciplinary, global audience for GU cancer research. I was honored to have a role in the development of ASCO GU two decades ago, along with my friends and colleagues, Dr. Eric Klein, emeritus professor and chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. And Dr. Anthony Zietman, a professor of radiation oncology at Harvard Medical School and the Massachusetts General Hospital. On today's episode, we'll be reflecting on key moments in the meeting's development, its role in advancing GU cancers and GU cancer research, and major challenges that lay ahead for the field. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Eric and Anthony, I'm delighted to have this opportunity to catch up with you both to discuss ASCO GU, thank you for coming on the podcast today. Dr. Eric Klein: Thanks for having us. Dr. Anthony Zietman: Thanks for the invitation. Dr. Eric Small: Well, it's really exciting and it's wonderful to see the two of you. So, the ASCO GU Symposium has been a key annual event for all of us in the GU field. But to give our listeners some background, when the Symposium was first created, when we first met in San Francisco, starting on Thursday, February 17, 2005, it brought together 1,035 individuals interested in the prevention and treatment at that point of prostate cancer alone. At that time, the meeting was co-sponsored by ASCO, the American Society for Therapeutic Radiology and Oncology or ASTRO, the Society of Urologic Oncology (SUO), and the Prostate Cancer Foundation. It was actually the culmination of several years of planning. Clearly, it represented the first truly multidisciplinary scientific and educational meeting dedicated solely to prostate cancer, and we'll come back to talk about that. The meeting went back and forth between San Francisco and Florida for a few years before finally, settling permanently in San Francisco. In the last 20 years, ASCO and the Symposium's co-sponsors expanded the meeting to include all genitourinary specialties. This year, ASCO received more than 875 abstract submissions and anticipates that there will be even more attendees than last year. On a personal note, it's truly amazing to me that here we are, 20 years later, and the meeting is going stronger than we could ever have imagined. I must say that my motivation to help organize this meeting stem from two issues that were somewhat in tension with each other. First, the field of prostate cancer and prostate cancer research was just starting to take off at the time, and we really needed, as a community, a venue where across disciplines, we could talk and meet with each other. But that was in real tension, at least at ASCO, where we were relegated at the Annual Meeting to a tiny room at the far end of the convention center on the last day of ASCO, because really, that's all we could muster. And I do remember making a pitch, assuring folks that there was an unmet need, and that the field was going to take off, who knew? So, I'm wondering, and either of you can jump in (Dr. Klein, Dr. Zietman), tell us how you got involved in the first GU meeting, and what's the most salient feature of your involvement? Anthony, do you want to start? Dr. Anthony Zietman: I think it's really important to discuss the historical context at which this meeting was born. Back in the 1990s, we were incredibly polarized as specialties in GU oncology. PSA had been introduced in the late '80s, early '90s, screening was everywhere. There was a tidal wave of patients and an almost reckless race to treatment. All surgeons believed that all patients with localized early prostate cancer needed surgery and that they could do individually, a beautiful job. And all radiation oncologists believed that they could deliver morbidity-free treatment and could do it to everyone regardless of your age or stage. And there were a few, there were a few who thought maybe we didn't need to screen everyone, and maybe there was a little bit of overtreatment, maybe we've gone a little bit too far, but those voices were really suppressed in the '90s. Those voices didn't have a voice. Many of us also believed there was more morbidity to our treatment than we'd appreciated. And that was the media in which, us three, all young research physicians, probably all in our low forties were given the charge of this meeting. And the thing I most remember about it in the planning, is that we actually decided collectively to give voice to everyone, including maverick voices. It wasn't just about the party line, and it wasn't just about the North American line, there were Britts and there were Swedes, and there were Dutchmen who had very important things to say as well, and very, very different perspectives. And we also chose to give voice to young people as well as just our party elders, so to speak. I don't know which of us, if any of us, or maybe it was our society suggested but we do it all in a single room such that rad oncs and surgeons were all together, and it led to a kind of forced truthfulness, which started to break down this groupthink that we developed in our own silo. So, when I look back, I think that that context was very important and that what we sought as young program chairs was we sort of tapped in something that was latent in our field. Eric KIein, I don't know if you remember things as I did. Dr. Eric Klein: I do. And things were very siloed then. We had hired early in the mid-90s, I think, a young radiation oncologist named Pat Kupelian, who became a close collaborator and a good friend, and who really changed the narrative around treating prostate cancer at the Cleveland Clinic, which was all surgical prior to that time. And he did such high-quality work, it was hard not to pay attention. And he actually took it on himself in his early years when he wasn't very busy to sit down and go through all the patients that we had treated with prostate cancer at the Cleveland Clinic, radiation versus surgery, and had the temerity to write a manuscript that showed that there was no difference in survival, based on PSA biochemical recurrence and metastasis and that sort of thing. And that was sort of game changing. And it really clued me into the fact that for patient's sake, we needed to be talking to our colleagues. The second perspective was from the perspective of having attended a couple of Prostate Cancer Foundation meetings. And I think they really deserve credit for increasing the visibility of prostate cancer research, and funding it and recruiting really good scientists from other disciplines. When young scientists were told, and we heard this repeatedly, "Don't spend your career researching prostate cancer, it's a dead end." And PCF did a great job of having a multidisciplinary meeting, which was smaller and not so clinically focused, but also got me excited. Dr. Eric Small: I think you're right, Eric. And I think that the transdisciplinary nature, as Anthony pointed out was new, it was innovative. No one had really, really thought about it. It was at the margins in different meetings. Your comments about PCF, Prostate Cancer Foundation, resonate because we did take a page from their book in many ways although that meeting, as you point out, is much more basic research-focused. I don't know if you guys recall that first year, in fact, PCF was a co-sponsor. We actually had asked Mike Milken to give a talk and he did. And obviously, once we expanded to the broader GU cancers, it was less pertinent for PCF to be involved. But absolutely, I agree with you, Eric, they deserve credit. PCF, and the PCF involvement, was one of the things that changed. There's many things that are constant that haven't changed, even though the science clearly has evolved dramatically. And I'm wondering if you guys can comment on things that are the same. One thing that stands out for me: I had the opportunity to look through the agenda for the 2005 meeting. And right there, very prominently, was a special lunch session that we had designed for mentorship and career development for trainees and early career investigators, and that's still ongoing and others have modeled it. And I think that was one amazing feature of this. One of you, I think Anthony mentioned that we invited a lot of young people to speak and to be the path blazers, but we also did this career development piece, and it was a wonderful event. I wonder if either of you or both of you could comment on other things that you think are constants and you anticipate will always be there. Dr. Anthony Zietman: I think to me that constant is that every time I go, I hear speakers I've not heard before. Often very senior speakers, I've never heard them before. But it is the practice of GU ASCO to invite people that are outside your sphere of experience, which is very challenging. Dr. Eric Klein: Two things strike me. I think one is the international nature of the faculty. We tried very hard (and subsequent program directors have) to be very inclusive and to bring the work that was the most cutting-edge to the stage. There are lots of things that are done in Europe that started there sooner. PSMA treatment, for example, and many other ProtecT trial and many other things. And the debates on stage and how that gave the opportunity for every subspecialty to have the opportunity to share its perspective on particular case management issues and case management conferences, I think have been around forever. And maybe, the most valuable part of it all is to hear people's perspective on how to manage a particular patient. Dr. Eric Small: I think the other comment you made Anthony that resonated and still goes on, was it was a conscious decision to have a single session in one room where everyone attended. And not to do the usual small breakouts and concurrent sessions, but sort of the philosophy being, is we all need to hear the same thing, we all need to be in the same room at the same time. And it really fostered this transdisciplinary approach; it was truly educational for us. Now, it's sort of part of what we do, and part of what our patients expect of us. I think that bringing us all together into one room was really great. Dr. Anthony Zietman: But it's now so part of what we do, but it's difficult certainly for younger faculty and for residents to believe we ever did it any other way. But we did, and I don't know whether ASCO GU led that or reflected that, but that was the zeitgeist among young individuals like us. And it's really become the culture of contemporary practice. Dr. Eric Small: So, given that that's the culture now, which it is, and I think sure, we should take credit for it, at least in GU: why then is it important for people to continue to attend GU ASCO today if it's now our culture to do that? Dr. Anthony Zietman: For me, it's because we share information as equal partners in a multidisciplinary team. And our practice is so multidisciplinary and multi-modality these days that we can't exist alone, we no longer try to. Dr. Eric Klein: Nor can we. The amount of knowledge that's being generated in each subspecialty and it's spinoffs is so great. It's impossible for a busy surgeon to stay on top of that. And this is sort of one-stop shopping for everything that's really current and appropriate to know about. And again, I always look at these things from the patient perspective, and my ability to counsel patients about what their best treatment options might be, I thought more and more dependent, and I think today more and more depends on being knowledgeable about everything that's going on, and not just one narrow field that you happen to be an expert in. And that's why I think it's so important for youngsters to attend and even oldsters like us to attend to stay current. Dr. Anthony Zietman: Yeah, and also, multidisciplinary means so much more these days. It does mean oncologists and radiologists, information technologists. I mean, who knows what it'll mean in the future, but it's always expanding. Dr. Eric Small: And I think it's interesting, back when we did this, when we started it, we were worried about being able to fill one meeting with prostate cancer information - we did easily. It was not immediately clear that there was a role or room for additional GU cancers. And then there was an explosion both in kidney cancer work at first, and then bladder cancer. And now it's unbelievable how much is there. And perhaps, this meeting needs to be twice as long. So, I agree with you guys. I think that it's the best way to stay current. The other thing that I really appreciate about this meeting and others have a hard time doing it, is that it provides, as Eric indicated, for the busy clinician. It integrates sort of the important information that's coming in terms of more basic science and makes it readily available and digestible, which isn't always the case at pure science meetings and may or may not be apparent in other meetings. I, again, was looking at the preliminary agenda in 2005, we had asked Bill Nelson to talk about molecular targets or prevention, how forward-thinking. And that's continued to be the case that this is a meeting where you get that integration from the laboratory. Dr. Anthony Zietman: Well, and I would add to that, not just the integration of it, it's where now you get to hear things first. I mean, it used to be that, you went the AUA or ASTRO or ASCO to hear things. Now, everyone one wants to present it first at GU ASCO. Dr. Eric Klein: Yes, that's correct. Dr. Anthony Zietman: And I think we actually made it permissible in the early days that you could present at GU ASCO and at your specialty meeting. Dr. Eric Small: What are the challenges in the field that are going to likely shape the content of future meetings? And we've all alluded to the fact that the meeting is evolving and has done a really good job of staying current with the clinical science. But beyond that, what do you two feel are important areas that this meeting is likely to continue to address? Dr. Eric Klein: So, biomarker development has always been an important part of this meeting, and I think we need to broaden our view of what biomarkers are now, and in the AI era, digital pathology and AI-based models that predict treatment response and outcome. My hope is that they will be studied in a rigorous fashion, and that they will end up outperforming the kind of single biomarker approach that we've used in the past. And we need to understand that; we need to understand the science behind AI to a certain level, and we need to understand what questions AI can address, and how that might be useful. But I'm particularly excited about digital pathology where sampling error becomes less of an issue and the number of potential inputs you're looking at that are related to the output should increase exponentially. Dr. Anthony Zietman: And I would add on the AI side of things, as a former journal editor, when AI papers came into the journal, we actually didn't have enough people who could review them, who had the understanding to review these papers and tell us, "Is this a good paper or a bad paper?" So, we're going to need to increase our understanding of AI, Eric, as you said. So, I think that will be a push in the years to come. Also, on a very practical level, it is such a popular meeting, keeping us all under one roof and in one room, will become just difficult. But it's part of the culture of the meeting, and I think it's what people want. Dr. Eric Small: It's a good challenge to have. Dr. Eric Klein: Feeding everybody too. I recall one constant has always been really good breakfasts and lunches. Dr. Eric Small: Right, that has been a standard of ours. One of the interesting things that I think has changed, we saw glimmers of it back in 2005, but it was early on and it was, I think very early on in sort of a good understanding of social determinants of health and equitable access to healthcare and the challenges posed by incredible technology development and making sure that that doesn't increase disparities. And I think that that focus has increasingly been present in meetings and is not going to be lost. And it also speaks, one of you spoke to our international audience, that increasingly, I think this meeting is going to address urologic oncology and how we address it not only in developed countries, but in lower- and middle-income countries. And I think that will be a focus as well. I'm excited with what the future holds for ASCO GU. It has been an incredible run. I'm hoping that we'll be able to perhaps catalog some of the salient presentations that have been done at this meeting over the years, but there's no question as both of you have pointed out, this has become the venue. Well, thank you both for sharing your insights with us today on the ASCO Daily News Podcast. Really wonderful to see you both and talk with you. Dr. Eric Klein: Great to be here. Thanks. Dr. Anthony Zietman: Great to be here. Looking forward to the next 20 years. Dr. Eric Small: That's right. Dr. Anthony Zietman: If I'm still around. Dr. Eric Klein: Yeah, let's do this again in 20 years. That'd be great. Dr. Eric Small: We will. And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you. 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 and the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Eric Small Dr. Eric Klein @EricKleinMD Dr. Anthony Zietman Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Eric Small: Stock and Other Ownership Interests: Fortis, Harpoon Therapeutics, Teon Therapeutics Honoraria: Janssen Consulting or Advisory Role: Janssen Oncology, Teon Therapeutics, Fortis Dr. Anthony Zietman: Leadership: Elsevier Dr. Eric Klein:No relationships to disclose
This month on Episode 51 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the August 4th and August 18th issues of Circulation Research. This Episode also includes a discussion with Dr Eric Small and Dr Xiaoyi Liu from the University of Rochester Medical Center about their article p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricular Pressure Overload, published in the July 21st issue of the journal. Article highlights: Régnier, et al. CTLA-4 Pathway Is Pivotal in Giant Cell Arteritis Zarkada, et al. Chylomicrons Regulate Lacteal Permeability Schuermans, et al. Age at Menopause, Telomere Length, and CAD Bayer, et al. T-cell MyD88 Regulates Fibrosis in Heart Failure
Hometown Radio 05/22/23 3p: Guest host Bill Ostrander talks with Eric Small The Writer's Strike is the first to battle AI for wages. The future is here
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
As part of the 2022 Prostate Cancer Patient Conference, Dr. Eric Small discusses androgen deprivation therapy and prostate cancer. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Education] [Show ID: 38561]
A candid conversation with Dr. Eric Small, renowned Pediatric Sports Medicine expert at Mount Sinai Hospital, about physical and mental concerns in our young athletes.
Steven Spielberg. Robin Williams. Dustin Hoffman. Julia Roberts. The 1990's. All of the pieces for a great movie, and somehow still a devastating 29% on Rotten Tomatoes. This week, my guest is my friend Eric Small, a nurse here in West Virginia. We discuss his deep abiding love for this "not-as-bad-as-it-seems" movie and where we could shave 20 minutes off to make it more manageable. Was Spielberg too ambitious? Did the critics bring too much baggage with them about the cast? Is this actually a bad movie? Is this movie the spiritual predecessor to Our Flag Means Death? Eric and I discuss all of this and more.
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37272]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37272]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37272]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37272]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37272]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37274]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37274]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37274]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37274]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37274]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This session: Eric Small, MD, UCSF. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37263]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
Some patients with prostate cancer will show signs of recurrence at some point in their lives. Eric Small, MD; Hala Borno, MD; Peter Carroll, MD, MPH; Matthew Cooperberg, MD, MPH; Mack Roach III, MD; Thomas Hope, MD discuss recurrent prostate cancer cases. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37276]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
In localized prostate cancer, the cancer has not spread outside the prostate. The California Prostate Cancer Coalition (CPCC) and The Helen Family Diller Comprehensive Cancer Center present the 2021 Patient Conference on Prostate Cancer. This panel features: Matthew Cooperberg, MD, MPH; Felix Feng, MD; Mack Roach III, MD; Eric Small, MD and Stan Rosenfeld. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37264]
Eric Small, MD, and Merel Nissenberg, Esq, introduce the 2021 Prostate Cancer Patient Conference. Series: "Prostate Cancer Patient Conference" [Health and Medicine] [Show ID: 37255]
Eric Small is quizzed about this topic. Tom gets confused between York and Leeds.
This month on Episode 25 of Discover CircRes, host Cindy St. Hilaire highlights the topics covered in the June 11th Compendium on Peripheral Vascular Disease, as well as discussing two original research articles from the May 28th issue of Circulation Research. This episode also features an in-depth conversation with Drs Eric Small and Ryan Burke from the University of Rochester Medical Center about their study Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin. Article highlights: Ghosh, et al. IAP Overexpression Attenuates Atherosclerosis Dörr, et al. Etelcalcetide for Cardiac Hypertrophy Compendium on Peripheral Vascular Disease Cindy St. Hilaire: Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting articles presented in our May 28th and June 11th issues of Circ Res. I'm also going to speak with Drs Eric Small and Ryan Burke from the University of Rochester Medical Center about their study Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin. Cindy St. Hilaire: The first article I want to share comes from the May 28th issue and is titled Over-Expression of Intestinal Alkaline Phosphatase Attenuates Atherosclerosis. The first author is Siddhartha Ghosh, and the corresponding author is Shobha Ghosh, and they're from VCU Medical Center. The Western diet is a colloquial term that is used to say a diet that is high in fats, sugars, refined grains, and red meat. A diet consisting of these foods can cause intestinal inflammation, which weakens the gut lining and facilitates transfer of the bacterial toxin lipopolysaccharide, or LPS. Once in the blood, LPS causes systemic inflammation. Cindy St. Hilaire: Patients with diseases such as diabetes and atherosclerosis, in which inflammation is a major contributor, have increased levels of LPS in the blood. In the gut, the enzyme, intestinal alkaline phosphatase, or IAP, is a critical barrier for the intestine. It regulates the integrity of epithelial cell junctions and helps to detoxify LPS, both of which limit intestinal inflammation. Clinical trials of oral IAP have hinted at its potential to treat patients with ulcerative colitis. In this study, Dr Ghosh and colleagues investigated whether over-expression of IAP can reduce systemic LPS and help to prevent atherosclerosis. They fed atherosclerosis-prone mice engineered to over-express gut IAP, a Western diet for 16 weeks and found that the animals had improved gut integrity, reduced plasma levels of LPS, reduced gut lipid absorption, lower body weight, and decreased aortic plaque burden as compared to normal controls. Together, these results indicate that improving gut barrier integrity by boosting IAP, either by diet choices or pharmacologically, may help to slow atherosclerosis. Cindy St. Hilaire: The second article I want to share is titled Randomized Trial of Etelcalcetide for Cardiac Hypertrophy and Hemodialysis. The first author is Katharina Dörr, and the corresponding author is Rainer Oberbauer, and they're from the Medical University of Vienna. In chronic kidney disease, or CKD, loss of renal function leads to systemic mineral imbalances. These imbalances trigger further physiological problems, such as the excess production of parathyroid hormone and growth factor, FGF23. The former can cause muscle and bone weakness, and the latter has been implicated in left ventricle hypertrophy. Hyperparathyroidism can be treated with calcimimetics or with vitamin D, but while both approaches lower parathyroid hormone levels, calcimimetics also lower FGF23. Cindy St. Hilaire: This study investigated whether CKD patients treated with a calcimimetic, etelcalcitide, had any measurable improvements in left ventricle mass, as compared to patients given a vitamin D analog, alfacalcidol. In a single blind randomized study, 32 CKD patients were treated with etelcalcitide and 30 were treated with alfacalcidol for a year. At the end of the study, left ventricle mass measured by magnetic resonance imaging, was found to be significantly lower in the etelcalcitide group. FGF23 levels had also declined in this group, but had risen in the alfacalcidol group. The results indicate that calcimimetics reduce the risk of cardiac hypertrophy, as well as treating hyperthyroidism, and thus, might be a preferable treatment option in CKD. Cindy St. Hilaire: The June 11th issue of Circulation Research is the Peripheral Vascular Disease Compendium, and in this compendium, we have 14 articles that are written by the leading experts who present an update on the state of the field of peripheral vascular disease research. They discuss current research and also current therapeutic options. Drs Nick Leeper and Naomi Hamburg serve as the guest editors of this compendium. Drs Derek Klarin, Phil Tsao, and Scott Damrauer discuss the genetic determinants of peripheral artery disease. Drs Kunihiro Matsushita and Aaron Aday present a Review on the epidemiology of peripheral artery disease and polyvascular disease. Cindy St. Hilaire: The potential of leveraging machine learning and artificial intelligence to improve peripheral artery disease detection, treatment, and outcomes is covered by Drs Alyssa Flores, Falen Demsas, Nicholas Leeper, and Elsie Ross. The benefits of walking as exercise therapy and its benefits on lower extremity skeletal muscle is presented by Drs Mary McDermott, Sudarshan Dayanidhi, Kate Kosmac, Sunil Saini, Josh Slysz, Christiaan Leeuwenburgh, Lisa Hartnell, Robert Sufit, and Luigi Ferrucci. Drs Marc Bonaca, Naomi Hamburg, and Mark Creager discuss medical therapies currently available to improve outcomes in patients with PAD. In a similar vein, Drs Joshua Beckman, Peter Schneider, and Michael Conte cover the recent advances in revascularization for peripheral artery disease. Cindy St. Hilaire: Racial and ethnic disparities in PAD is discussed by Drs Eddie Hackler, Naomi Hamburg, and Khendi White Solaru. Drs Tom Alsaigh, Belinda Di Bartolo, Jocelyne Mulangala, Gemma Figtree, and Nicholas Leeper present their thoughts on optimizing the translational pipeline for patients with peripheral artery disease. New directions and therapeutic angiogenesis and arteriogenesis in PAD is covered by Drs Brian Annex and John Cooke. Drs Esther Kim, Jacqueline Saw, Daniella Kadian-Dodov, Melissa Wood, and Santhi Ganesh review sex-biased arterial diseases with clinical and genetic pleiotropy, focusing in on multi-focal fibromuscular dysplasia and spontaneous coronary artery dissection, which have a much higher prevalence in women. Cindy St. Hilaire: Drs Matthew Fleming, Ling Shao, Klarissa Jackson, Joshua Beckman, Anna Burke, and Javid Moslehi cover the vascular impact of cancer therapies and focus on how cardiac and vascular sequelae of novel targeted cancer therapies can provide insights into cardiovascular biology. Epidemiology and genetics of venous thrombosis and chronic venous diseases is presented by Drs Richard Baylis, Nicholas Smith, Derek Klarin, and Eri Fukaya. Dr Stanley Rockson reviews advances in our understanding of lymphedema and the compendium concludes with an article by Drs Yogendra Kanthi, Meaghan E. Colling, and Benjamin Tourdot, which reviews, inflammation, infection, and venous thromboembolism. This comprehensive compendium on peripheral vascular disease is found in our June 11th issue. Cindy St. Hilaire: So today, Drs Eric Small and Ryan Burke from the University of Rochester Medical Center are with me to discuss their study Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin. This article is in our May 28th issue of Circ Res. So thank you both for joining me today. Eric Small: Thanks Cindy, for having us. Excited to talk about our research with you. Ryan Burke: Yeah, thank you very much for having us. Cindy St. Hilaire: Absolutely. So fibrosis, it's essentially a wound healing mechanism, it's where connective tissue replaces the innate tissue of the organ system that it's happening in. It's really a component of many disease states. As far as I know, treatment options are pretty limited or really non-existent except in a couple rare cases, and in particular, your study, as it's in Circ Research, is focused on cardiomyopathy and the fibrosis related to that. But before we dig into your findings, which is really focused on a great therapeutic angle, I really want to take a step back and ask about what we know about fibrosis or the fibrotic process itself, maybe in the context of the heart, and despite why it's relatively common, it's been so difficult to target in terms of either therapies or really just understanding some of the basic processes. Eric Small: Sure, I'd be happy to discuss this. So as you know, and you alluded to already, pathological fibrosis contributes to progression of many debilitating human diseases. So in injury response in many tissues or organs, including the heart, kidneys, lungs, even the skin, leads to a wound healing process and that wound healing process is meant to repair the tissue and that includes an inflammatory response and secretion of extracellular matrix that fortifies the structural integrity of the tissue. But you can imagine in the context of a heart, that has to beat 60 plus times per minute, any alterations to the biomechanical properties of that tissue can alter the function. Eric Small: So extracellular matrix, which is meant to improve the structural integrity of an injury, even in the heart, ultimately can lead to reduced cardiac function. So this extracellular matrix, and in the context of disease, this extracellular matrix is called fibrosis, can reduce the contractility and the relaxation of the heart. The relaxation of the heart is actually an important aspect in insufficient relaxation called diastolic dysfunction, is becoming a more prevalent disease phenotype and it is called heart failure with preserved ejection fraction. What we're finding and what some investigators are alluding to is that fibrosis is a major component of this disease, and so understanding how extracellular matrix is secreted, why it is deposited in the context of injury, especially in the context of the heart, why does that process not stop sufficiently and revert once the injury is repaired, is a really important basic science and clinical question. Cindy St. Hilaire: So why, specifically, has fibrosis or cardiac fibrosis been so difficult to target therapeutically? Eric Small: From my point of view, one of the reasons that fibrosis, organ fibrosis in general, and especially within the heart, is hard to target is because I think we're understanding now that one of the major cellular sources of extracellular matrix in disease is the fibroblast. This cell type has been sort of underappreciated for many years and is coming to the forefront now of biomedical research. So fibroblasts until maybe 10 or 15 years ago were thought to be more of a structural component. Of course, they contribute to wound healing, but it was thought that they contribute mostly to structural integrity and homeostasis of the injury. It's becoming more apparent now that resident cardiac fibroblasts contribute to extracellular matrix deposition in disease. But these cell types are really plastic, phenotypically plastic cell, they respond to a lot of biomechanical stimuli, especially that are induced in the context of tissue injury or disease, and so they respond to mechanical stretch or cellular deformation, and they can respond to many secreted factors, especially the canonical factor that has been studied extensively, TGF-beta. Cindy St. Hilaire: Which itself is extremely complicated, to say the least. Eric Small: Absolutely, and so it does so much, and they respond to factors that are really high up on this hierarchy, that do so many things that I think obviously targeting TGF-beta is not going to be really an efficacious therapeutic option. So understanding what's more downstream and much more specifically related to the fibroblast, I think is really important to come up with new therapeutics. Cindy St. Hilaire: So in your quest to identify novel therapeutics, or even really understanding that below the surface signaling you just talked about, you developed a high-throughput screen. I think this is a term that we often use, but we don't really know the details of that term, like what does high-throughput actually mean when you're doing it with cells and disease models? Dr Eric Small: Sure. So I think in our case, we really let the science lead the way when it came to the high-throughput screen. So I'm not a chemical biologist, I have never, before now, developed a high-throughput screen and the science just pointed me in this direction. So the basic science research related to fibroblast plasticity and what induces fibroblasts to secrete extracellular matrix in the context of disease, all culminated in this one reporter that I thought would be good for the assay. So maybe as a way of a little bit of background, one difficulty in understanding fibrosis and fibroblast plasticity is that there are no really unique specific markers for an activated fibroblast. So most of the markers that people say are myofibroblast markers, which is the term for an activated ECM-secreting fibroblast, are expressed in other tissues or cells. Probably the most used and best characterized marker of a myofibroblast, is the smooth muscle alpha-actin gene, which encodes the smooth muscle actin protein, which is highly up-regulated in myofibroblasts, but obviously is expressed in a lot of other cell types, including smooth muscle cells. Eric Small: So it is a good marker of a myofibroblast, but it's not unique to myofibroblasts. But, this smooth muscle alpha-actin gene allowed us to make inroads into better understanding how fibroblasts respond to different stimuli. So what we did was, in the lab, one of the earlier things that we did when I set up my lab as an independent investigator, was to try to develop a stable cell line that expressed this reporter in a way that we could easily assay. So we could do it with GFP or a luciferase reporter or something like that. We made a luciferase reporter of this smooth muscle actin myofibroblast, alpha-actin gene. So one important aspect of a screen is, especially in our screen, which we were looking for chemicals that would inhibit our reporter, that we would hope would be anti-fibrotic Eric Small: Our hope was that this reporter would actually, in some cases, lead to an anti-fibrotic compound, but an important aspect of this screen, which was, I think the original question, was to not come up with factors that would just kill fibroblasts, but come up with factors that would specifically inhibit smooth muscle actin and myofibroblast activation without being too toxic. We don't want to inject a toxic chemical into a person; we want to inject a chemical that would be specific to an activated myofibroblast. So that was the first consideration, is to make sure that these were not toxic compounds, but were acting specifically on the smooth muscle actin report. Cindy St. Hilaire: So with this system, you were able to screen over 2000 compounds, it was like 2300 or something like that. From that 2000 compounds screen, you zeroed in on salinomycin and two other compounds that are in the same family, I think, of chemicals like polyether ionophores they were called, I think it was the top three were all this similar class. So that's probably unsurprising that similarly-structured chemicals have a similar function or phenotype, but it's also intriguing. So I'm wondering, what's known if anything, about this class of chemicals, have they been used in therapy or is there some kind of naturopathic history to salinomycin or these other compounds that maybe if we read more carefully, we would have got a hint before? Ryan Burke: Salinomycin has a pretty storied history in the literature, but it's an odd history. It's a veterinary antibiotic. So it's actually used primarily in livestock management and it had really no approach in human science at all. Then it was discovered that salinomycin, its earliest contribution, was that it is a compound that is actually very selectively targeting cancer stem cells. So salinomycin has a very extensive literature in cancer. It affects a lot of relevant signaling pathways, it's actually where we got a lot of our insight as to what we should be evaluating in fibroblasts. Both, in terms of ... This is probably going to be a charged statement; but there's a lot of similarities in how ... Cancer cells, when they're metastasizing and activating and moving around, there's a lot of EMT involved in that, there's a lot of things that are very analogous to how fibroblasts activate in heart failure. Ryan Burke: I'm not saying they're the same, that's the charge portion of it, but the pathways are often conserved. What we found is that salinomycin had been studied extensively in various models of both solid and blood tumors, and it was found that it was affecting a whole ton of signaling pathways and sparing others, which was actually some of the insight that we had about AKT signaling. In the heart, it seemed very easy to just apply that and say, "Well, activation of fibroblasts is largely dependent on signaling pathways like SMADs and p38 signaling, so let's see what salinomycin does to these pathways in fibroblasts," and it turned out that that wound up being a very fruitful avenue for exploration, because it does behave very similarly in fibroblasts to the way it behaves in cancer cells. We didn't really find a lot of discordance in those results. Ryan Burke: This study was very iterative, right? So do the high-throughput screen, find the drug, then try a preclinical model in animals. Then when it worked quite well in the angiotensin, hypertension-induced remodeling, that's a pretty mild model, right? Give the mouse an MI, see if it works in that, because that's a much more serious remodeling and when it performed well there, it's like, "Wow, you really actually probably have something here." Cindy St. Hilaire: Yeah, and that's a perfect segue for my next question really, was I wanted to ask about these different murine models. Like you identified this compound, now you want to test it. Could you maybe give us a little brief background on why you chose the models you did and the treatment regimens that you also tried? Ryan Burke: Sure. When we began, we began with angiotensin infusion because it's a fairly mild remodeling. You get some hypertrophic remodeling of the heart, you get some proliferation and some mild fibrosis in the mouse model. We figured this would give us the best chance to see a signal versus noise. It turned out that the results were really striking. Even the mice that were given the condition that we expected to see nothing in, is the drug with a saline infusion, even that had effects that were consistent with the effects that were seen. Consistent in direction in terms of the overall morphology and function of the heart, consistent with what you were seeing with the normalization of that hypertrophic remodeling in the angiotensin model that also got the drug. So that was really interesting to us. It was just consistent all the way through. Ryan Burke: We wound up having a meeting about it and we were like, "All right, we've done the preventative regimen. We've preloaded them and then run them through with the drug. Now let's see if we can reverse established remodeling." So we did that study and when that worked out okay, there was yet another discussion where it was like, "All right, are we doing this?" And it was a myocardial infarction study. Myocardial infarctions, that's really extensive remodeling with huge changes, both the macro and microstructures of the heart. There's a lot more of an inflammatory component involved in that. Ryan Burke: So we weren't sure how this would perform and it turns out that it performs exactly as it performs in pressure overload. You see normalization in physiology. I think that's part of the power of this study is that you're looking at non-ischemic and ischemic heart failure models, you're looking at preventative and interventional regimens, and it's just consistently performing at a level. We wanted to check all of our boxes, really, with this. Cindy St. Hilaire: Sure. Yeah, maybe salinomycin's going to be the new aspirin we pop when we're over 50. Ryan Burke: I doubt it, it's worth $7 a kilogram. I very highly doubt anyone's licensing that. Eric Small: But I think it's interesting you say that because understanding the mechanism after you understand that it's efficacious is sort of a similar idea here. We don't necessarily know precisely what it's targeting to act as an anti-fibrotic in this case, and so there's a lot of work to be done on this compound. I'd like to reiterate something that Ryan actually said is that really interesting, at least in cells and in the animal models, that salinomycin doesn't have a huge impact on the heart or on cultured fibroblasts in the absence of, for example, TGF-beta stimulation or a disease mechanism. It's really when we have a disease that salinomycin blocks the activation of the myofibroblasts and prevents that from contributing to the disease. Cindy St. Hilaire: Interesting. So that can really, at least in the case of maybe cardiomyopathy, would help target it to the heart. Eric Small: That would be the hope, yeah. Cindy St. Hilaire: Yeah, that's great. Wow. Speaking of the heart, and you mentioned this in that first answer that you had about the fibroblast being kind of the forgotten child of the heart and the focus is really more the cardiomyocyte, but did this drug have any impact on the cardiomyocytes itself that are also probably exposed to this TGF-beta signaling, in the context of an injury? Eric Small: So this is where we have some interesting, but not anticipated, results. So we obviously performed a screen in fibroblasts to look for specific anti-fibrotic compounds and when we put this into animals into ischemic or non-ischemic models, especially in the ischemic model, we found a much better outcome than we would have expected from simply an anti-fibrotic. So for example, we saw that pretreatment of mice with salinomycin prior to myocardial infarction, almost completely abrogated, not completely, but highly significantly abrogated necrotic tissue formation. So when Ryan went back and looked at the percentage of heart that became necrotic, or ischemic, after myocardial infarction, it actually reduced the necrotic core significantly. So we do think it's acting on cell types other than the fibroblasts in the context of ischemic remodeling, and it does seem to induce potentially protective signaling pathways in cultured myocytes. So that's definitely an area that we'd be interested in pursuing in more detail. Ryan Burke: So of course the question there is, and this is a totally fair question for people to evaluate, we're looking at an organ in which all the cell types are talking to each other. We know we've affected the fibroblasts in a certain way, and we know to a certain extent, from what we found, what we've done for the fibroblasts, and we know what that looked like as a result in myocytes, but who initiated that, right? Did we affect the myocyte and then fibroblasts changed? Or did we affect fibroblasts and myocytes changed? But those are important type questions. We've shown the changes, but how do we show the connections? I think that's the really interesting work that we're still doing. We even extended it a little bit to endothelial cells in the heart, because we were showing that there was sort of a preservation of vascularization in the MI model that was associated with salinomycin, and we wouldn't rule out that we were affecting endothelial cells as well. I mean, I think this is a subject for discussion in the field, in the future. Groundwork is there, it's time to move forward. Cindy St. Hilaire: Yeah, that is so exciting, and it's also I guess the classic chicken and egg question of science. What's causing what? That's excellent. So what's next for this project? I mean, you just highlighted some other angles, endothelial cell, but is there plans to translate it to a clinical setting, especially because it's already used in humans, so there's all that safety data out there? What's the plan? Eric Small: So that's a really interesting question. So our collaborators here at the University, Colin Woeller, Patricia Sime, Rick Phipps, they have been involved in the study with us and they are interested in fibrosis in other aspects as well. So they're interested in lung fibrosis, idiopathic pulmonary fibrosis, ocular eye fibrosis, and they've found that in other situations, salinomycin can inhibit fibrotic disease remodeling, for example, in the eye and in the skin. So branching out into other animal models of fibrotic disease is one area that we'd like to pursue. One area that I'm really interested in looking at salinomycin would be, for example, in models of HFpEF to see whether salinomycin might be efficacious in limiting the progression of animal model HFpEF. These are now becoming more prevalent and so it'd be great to test that there. Eric Small: So I think probably with some of these small animal studies, it would lay the groundwork for larger animal studies as collaborations or with other investigators. Absolutely, I think that's where this could definitely go next. Ryan Burke: Also, it's a high-throughput screen, right? It wasn't the only hit and so extending the screen outwards both ... So the screen was designed to pick up both anti and pro-fibrotic drugs. So pro-fibrotic drugs have applications in wound healing. It also gives us a hint as to if a drug has some unexpected side effects in large clinical populations, then we can look at that and say, "Oh, maybe we have mechanistic understanding of why this might be the case." I think you'll see some future explorations down that path as well in that study. Cindy St. Hilaire: Well, I look forward to seeing all of them. This was a wonderful study. I'm more vascular biologist, but obviously being on Circ Res, I'm learning so much more about the heart, but this one, I just particularly love that you started with this crazy complex question of what the heck is going on and this high-throughput screen was just designed in such a way that it really narrowed down what was a huge amount of options to start with. So it was really elegantly done and I just love the story, so congrats to you both and I look forward to future publications. Eric Small: Thank you. I'm especially proud of this one because as a basic scientist and as a trained in graduate school as a developmental biologist, I was following the science and when this opportunity arose to try to make this high-throughput screen work, I mean, this was as clinically relevant as I could ever have imagined my lab becoming. I'm really proud that we're able to do that. Cindy St. Hilaire: Absolutely. I know, it's something we always talk about, and this research can be translated to humans eventually, and you're almost there. That's great. Well, congrats again. Thank you both for taking the time today and I look forward to your future studies. Eric Small: Thank you, Cindy. Ryan Burke: Yeah, thanks Cindy. Cindy St. Hilaire: That's it for the highlights from the May 28th and June 11th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Drs Eric Small and Ryan Burke. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.
LaFern Cusack speaks with Eric Small, celebrity fitness specialist, American Ninja Warrior contestant and founder of ConfusedMuscles.com about health, fitness and maintaining your core foundation.
LaFern Cusack speaks with Celebrity Fitness Trainer Eric Small of ConfusedMuscles.com about getting focused and fit for life not just the new year.
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