Podcasts about ro1

0:00 INTRO0:30 GEORGE FACE ȘI MUZICĂ3:43 TROLL-UL ANULUI4:58 ȘOFERI BEȚI CU CHEF DE GLUMĂ6:35 TALKING BABY PODCAST7:36 PAPA ȘI ISUS10:09 ANTI BUTT CRACK JEANS11:36 SANTEHNICU13:26 IAR CAMPANIE16:00 TE GÂNDEȘTI SĂ PLECI?18:41 PREȚURI APARTAMENTE AVIAȚIEI19:47 BUCUREȘTI-UL E MAI SCUMP22:33 CINE ÎL MAI ÎNȚELEGE PE TRUMP?24:58 DESPRE SALARII ADEVĂRATE30:45 ROMÂNIA NU TRIMITE MILITARI ÎN UCRAINA32:24 CUTREMUR ÎN TURCIA33:13 HARTABLOCURI.RO36:00 CUM CONSTRUIEȘTI SĂ FIE SIGUR41:30 UE A AMENDAT APPLE ȘI META43:05 META E CHIAR NESIMȚIT45:55 HYPER FARMACIILE49.48 PREȚUL FISTICULUI A CRESCUT DIN CAUZA CIOCOLATEI DUBAI52:32 PE GRANIȚA DINTRE VIAȚĂ ȘI MOARTE - DAN BENGA #IGDLCC 27755:54 INSTA 360 X559:15 GB.RO1:02:54 WINWIN.FIT1:04:20 COFFEEHOUSE.RO1:06:14 ROBOROCK F25 ACE1:08:48 HUAWEI VA FI RIVALUL LUI NVIDIA1:12:44 INSTAGRAM O IA PE URMELE TIKTOKULUI1:14:30 DESPRE CONTENT ȘI EDITORI1:23:57 OPEN AI VREA SĂ CUMPERE CHROME?1:25:46 INSTAGRAM DETECTEAZĂ MINORII DE PE PLATFORMĂ1:27:27 O GENERAȚIE ÎN PERICOL1:28:32 AVATAR FX1:34:44 CUM UIȚI SĂ VORBEȘTI1:37:05 CE URMEAZĂ ÎN LUMEA AI-ULUI?1:39:07 MODELE AI PENTRU INSECTE1:43:27 PICIOARE BIONICE1:46:00 AVEM ROBOȚI ÎN ROMÂNIA?1:48:18 TRUMP VREA AI ÎN ȘCOLILE PUBLICE1:49:18 TERRAMIND1:50:28 CE S-A ÎNTÂMPLAT CU MAREA ARAL1:53:58 CUM STĂM CU ÎNCREDEREA?1:57:20 A FOST DESCOPERITĂ O NOUĂ CULOARE1:59:28 MAI ȚII MINTE ROLLS-UL?2:01:40 TESLA SE DUCE ÎN CAP2:03:13 BATERIILE CU SODIU2:09:23 CONTAINER-UL ANTI-FOC2:11:33 MERCEDES VLS2:14:20 OSCAR PENTRU FILME FĂCUTE CU AI2:14:36 OBLIGAȚI SA-ȘI FACĂ TREABA2:15:18 ANORA2:17:17 DAVID NEACSU - CARTEA INALTIMILOR

JCO PO author Dr. Michael J. Hall, Professor of Medicine, Chairman of the Department of Clinical Genetics, and Co-Leader of the Cancer Prevention and Control Program at Fox Chase Cancer Center in Philadelphia, PA, shares insights into the JCO PO article, “Uptake of aspirin chemoprevention in patients with Lynch Syndrome.” Host Dr. Rafeh Naqash and Dr. Hall discuss the finding that only about 1 in 3 patients with Lynch Syndrome use aspirin for cancer chemoprevention. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I'm excited to be joined by Dr. Michael J. Hall, Professor of Medicine, Chairman of the Department of Clinical Genetics and co-leader of the Cancer Prevention and Control Program at the Fox Chase Cancer Center in Philadelphia, and also the lead author of the JCO Precision Oncology article entitled, “Uptake of Aspirin Chemo Prevention in Patients with Lynch Syndrome.” At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Hall, welcome to the podcast and thank you for joining us today to explain and help the listeners understand your interesting research that was just published in JCO Precision Oncology. Dr. Michael J. Hall: Thank you so much for having me and really thanks for the interest in our work. I think it's an important subject and I hope people will also find it as interesting as we do. Dr. Rafeh Naqash: Absolutely. I think your research touches upon a few things. One, obviously, touches upon Lynch syndrome germline assessments of individuals. It also touches upon chemo prevention, prevention in general, and it also touches upon the knowledge and understanding of chemo prevention aspects. So to start off, I would like to ask you, for the sake of our listeners, many of whom who may not necessarily fully understand the length and breadth of Lynch syndrome, maybe perhaps some residents or trainees out there, could you tell us what Lynch syndrome is, what some of the mutations are, what the implications are, and then we can try to go and delve more into the research topic. Dr. Michael J. Hall: Sure, I'd be happy to. Lynch syndrome is probably, in the hereditary cancer genetics world, one of the most common hereditary risk syndromes we encounter. Recent estimates are that probably roughly about 1 in every 280 individuals in the population is a carrier of a pathogenic variant, one of the Lynch syndrome genes, there are roughly four. There's sort of a fifth gene that is also involved with Lynch syndrome, but really, we largely think about four genes in Lynch syndrome, MLH1, MSH2, MSH6, and PMS2. Over time we've begun to learn, and I'll say that the guidelines that we develop have become more specialized for each of those genes. They are not sort of all the same in the cancers they cause and the way they behave. But roughly, what is Lynch syndrome? It's a syndrome of DNA mismatch repair. So, individuals who have Lynch syndrome have some degree of deficiency in their ability to repair DNA via the mismatch repair system. Depending on the pathogenic variant that is within a family, that may be related to a more severe deficiency of mismatch repair, repair, editing, or for instance, with the PMS2 gene, we've learned over time that actually the degree of DNA repair deficiency is actually a milder phenotype. These individuals over a lifetime are at risk of a variety of different kinds of cancers, the most common being colon cancer. And the risk of that is variable by gene. With MLH1 and MSH2, it's close to 50% over a lifetime. With MSH6 and PMS2, somewhat lower. There are also risks of endometrial cancer, gastric cancer, ovarian cancer, pancreas cancer, a number of other ones. But they're all related again to the same underlying molecular deficiency, and that's this deficiency of being able to repair mistakes made in the DNA accurately. And so, mutations accumulate in the genome of cells in various tissues of the body. Dr. Rafeh Naqash: Thank you for that very simplified version of a very complicated topic otherwise. So, as you mentioned, these different genes have different implications. Perhaps some have higher risks for colorectal cancer than others. What are some of the current standardized approaches for screening or following these individuals over the course of their journey until perhaps either get detected with cancer or while they're being monitored? Dr. Michael J. Hall: Sure. It's a great question, because this is very much a moving target in this disease. I'm going to give you a quick second of history that up until maybe about six or seven years ago, we had uniform guidelines, really, that any Lynch syndrome pathogenic variant carrier should start colorectal cancer screening. Usually, we were recommending between the age of 20 and 25, and this was usually annual colonoscopy. And for years that was the standard. In more recent years, we've stuck to that tight interval, particularly in the higher risk genes, MLH1 and MSH2, although the guideline now reads every one to two years, because we recognize people need some degree of flexibility to live their lives. And there are people in the population who are more risk averse, and there are those who want a colonoscopy every year because they want to stick to that schedule. For MSH6, we recommend a somewhat later start at age 30, and that can be every one to three years for colon screening and for PMS2, similar recommendations, although I think there is a chance in the coming years, we may actually expand the screening interval even more, again, because the risks are somewhat lower. We still have ways to go in terms of screening for the other cancers in Lynch syndrome. I'll say that, for instance, endometrial cancer, which is the second most common cancer in this disease, we still struggle with what is the best way to screen women for a risk of endometrial cancer. Our guidelines in the past were always somewhat draconian, that once women sort of finish childbearing, they should immediately have a total abdominal hysterectomy and oophorectomy. And I'll say that with greater input from the gynecologic and GYN ONC community, we have somewhat softened those recommendations, especially for the endometrial cancer and also the age at oophorectomy, because we recognize that there were compensatory risks of taking the ovaries out too early in some women, risks of bone loss and cardiovascular disease. So those are the most common. For other tumors in Lynch syndrome, for instance, gastric cancer and pancreas cancer, the guidelines are still really evolving, and different groups have put out guidance for clinicians. And I'll say NCCN, which I participate in and help write those guidelines, has very good recommendations for docs. But I'll say that it is again, back to the idea that it's a moving target. And as we learn more, hopefully, we'll have better recommendations. Dr. Rafeh Naqash: I completely agree as far as a moving target is concerned, and we often look at the disconnect between the recommendations and then what's implemented or followed in the real-world setting. So I have a question in that context, and my question is, when you identify these individuals with Lynch syndrome, perhaps let's talk about academic settings, and then we can try to delve into how this might work in the real world community oncology settings, where the real world population actually exists, 60, 70% of individuals get treated in the community. So, when you talk about an academic center, what is the flow of the individual? Does the individual stay within the geneticist when they're diagnosed? Does the individual go to the primary care and the geneticist makes the recommendation and the primary care follows the recommendation? How does it work for you and what are some of the models that you've seen work best perhaps at different academic centers? Dr. Michael J. Hall: I think you get at a really great question. And I'll say there is really no one model. And I think models have to be fluid these days because people with Lynch syndrome are really being identified in more and more diverse settings, and by diverse means. I'll say at my own center, we are more of a traditional practice. So, we do the pre-test and the post-test counseling. Once we have counseled individuals identified Lynch syndrome, we will usually make referrals. If folks don't have a gastroenterologist that they have interacted with before, we keep them in our own group and follow them. But their Lynch syndrome home really sits both in a continuity clinic that I run for patients to come back and circle around every one to two years just to review guidelines and review their screening results. However, I do really make an effort to, first of all, keep primary care docs involved, because I think some of the things we recommend, it is critical that the primary care doc is aware so that patients are keeping up with some of the recommendations. For instance, we often recommend skin screening to make sure that folks have had at least one good skin exam somewhere in the 40s. And I think the primary care doc can be very helpful in making sure that happens. It is somewhat different, I think, in the community where many more patients with Lynch syndrome are being identified these days. I suspect that much more of the burden of making sure Lynch syndrome patients are well hooked in with a gastroenterologist and with a dermatologist and maybe a urologist probably does fall on that primary care doctor. In my experience, some primary care physicians have really kind of jumped up in and taken hold of this and really know their Lynch syndrome well, and I think that's amazing. I do, however, as kind of an expert in this area, I do get a lot of referrals in from the community as well, from docs who just feel that they may not have quite that expertise that they can get at a comprehensive center. So, someone may come in to me just for a consult to review what my recommendations would be, hear about research, hear about what's going on in the field, and those folks will often touch base with me again every couple year or so. Often, another thing I've started to experience is that I may meet people once or twice early on in their diagnosis, and then they go back to their primary docs and I may not hear from them again until something more profound happens in the family or into the patient and they get their screening colonoscopy and a stage 1 cancer is found. Often then, that's the patient who, after four or five years, will contact me again and say, “We haven't talked in a while, but something has happened, and can we re-consult about what would be the best way to do things?” Dr. Rafeh Naqash: Again, like you said, lots of moving targets, moving aspects to this whole care of these individuals. Do you think, in your experience, nurse navigation, maybe some centers have already implemented that perhaps you might have that, do you think nurse navigation could play a certain level of role? You know how in the multidiscipline care we have nurse navigators that coordinate care between radiation oncologists, medical oncologists, thoracic surgeons. So that's something that is being implemented. My second part of that question is telehealth in this case, maybe it's a little more difficult for somebody to drive three hours to come to you for a visit just to check in versus maybe virtually talking to you or your team getting a sense of where things are at in terms of their screening and their follow ups. Dr. Michael J. Hall: I think both are great, great questions and absolutely, we use both of those pieces in our model. And I know from colleagues that they do as well. So, in terms of navigation, we do have an embedded nurse navigator within our department. She joins and kind of helps facilitate all of our high risk follow up clinics. Mine, for GI, we have a high-risk prostate clinic, we have several high-risk breast clinics and those are populated by providers. We have a couple of nurse practitioners in my genetics group and a PA they are sort of the main provider in those clinics, but they are very much supported by that nurse navigator who, as you well point out, really helps with the coordination of the care. Telehealth as well, I do 100% support because you're absolutely right, if you look at a map of the United States and you first of all look at where there are good counseling services available, of course, there's ample counseling in the major metropolitan areas all over the U.S., but the minute you get outside of those counseling and then other management expertise, then– So we do have a model where particularly for folks who are from central Pennsylvania and sometimes more towards western Pennsylvania, I do have some individuals who've been identified with Lynch syndrome who telehealth in, again, for that follow up. A sort of side notes on telehealth, I think we learned a lot from the pandemic about how to use telehealth more effectively. And thank goodness, we've all gotten up to speed in medicine of how to be better telehealth providers. Unfortunately, I feel like with the pandemic kind of waning, there's been a little bit of a regression of the telehealth laws. So now if I want to do telehealth with someone who is from New Jersey, even though New Jersey sits very close to where I practice, it's more complicated now. Again, I have to get a license and same thing with New York and same thing with Delaware. I sort of wish we had a little bit of a better and welcoming system in the states where you could have easier ability to practice, especially when states were quite close using telehealth. But nonetheless, that's for another podcast, I think. Dr. Rafeh Naqash: Well, thank you again for some of those interesting aspects to this whole topic. But let's dive into the thing that we are here to talk about, which is aspirin in these individuals. So can you give us some context of why aspirin, what's the biology there and what's the data there, and then talk about why you did what you did. Dr. Michael J. Hall: So, we've known for many years that aspirin has preventive properties in terms of preventing colorectal cancer. Many observational studies and some interventional studies have shown us that aspirin has benefits for reducing the risk of colon cancer in an average risk population. There was even an interventional trial a number of years ago that looked at individuals who made polyps, and this looked at particularly adenomas, which we know are the precancerous polyps and adenoma prevention using aspirin. And that study clearly showed that aspirin had benefits for lowering risk of recurrent polyps and adenomas. Particularly even a lower dose of aspirin, 81 milligrams, was effective in that setting. Aspirin's also been studied in other hereditary risk syndromes, the most visible one being FAP, where data have shown that aspirin does help reduce polyp count in FAP, although is certainly not a perfect chemo prevention for that disease. So, in that background of knowing that aspirin has many benefits for colorectal cancer prevention, a study was initiated in the UK a number of years ago called the CAPP2 study, with its lead investigator being John Burn. And in this study, it was a two-arm factorial study that was not just aspirin, but they were also looking at resistant starch, which there was a lot of excitement about resistant starch back then. But in this study, they looked at using aspirin as a way of lowering risk of colorectal cancer in patients with Lynch syndrome. And that study, which was initially reported in The New England Journal, the initial outcomes did not actually show benefits in its first analyses of adenoma risk and colon cancer risk. But what they found over time was that there was a delayed effect and, in a follow, up paper looking at 10 plus years of follow up, they showed a substantial reduction in risk of colon cancer, about 40% risk reduction, which was really striking and exciting in the field to see such a large benefit from aspirin. Now, one caveat was in the analyses they performed, it was those individuals who were able to stick to the aspirin dose in that study, which was 600 milligrams a day. I always say to folks that back in the day, that was not a lot of aspirin, although I think these days we're much more skeptical about taking larger doses of any drug. So, 600 milligrams is roughly about two adult aspirin in the U.S. So those folks who were able to stick to that dose for at least two years were the ones who gained benefit from being on aspirin. And what was interesting is that benefit endured for really 10 years after those two years of being able to take aspirin. So, this was striking and it really changed our thinking about whether there may be chemo prevention options for folks with Lynch syndrome. However, and I think what formed the background of our study here was that there was a somewhat equivocal endorsement of aspirin by the major guidelines committees, mainly because, as we all know in oncology, we love one first big study, but we always really love secondary studies that solidify the finding of the first study. And so, because this was such a niche group and no one else out there was doing big aspirin studies when this result came out in 2011, we've sort of been waiting for many years for some follow up data. And the NCCN guidelines have always been a little bit equivocal that people could consider using aspirin to lower risk in their patients with Lynch syndrome, but without that kind of strong, “Everyone should do this.” And so, this has kind of formed the background of why we performed the study that we did. Dr. Rafeh Naqash: Interesting. And then you had a bunch of observations. One of the most important ones being that use of aspirin was pretty low. Could you dive into that and help us understand what were some of the factors surrounding those low implementation aspects? Dr. Michael J. Hall: Of course. So, what we were interested in then again in that background was, here's a high-risk population, docs are getting somewhat maybe ambiguous information from the guidelines, but what actually is going on out there in practice? How many patients are actually using aspirin? What doses are they using, and what are some of the factors that drive it? So, we performed a survey that actually occurred in two parts. One started at Fox Chase in our population here, and then we expanded it online to a convenience sample. Overall, we had 296 respondents. And yeah, what we found actually was the uptake of aspirin was only about roughly 30%, 35% or so among patients who were eligible to take aspirin. When you actually drill down to those people actually taking aspirin because they wanted to prevent Lynch syndrome, it was even lower. It was in the range of 25% to 30%. This somewhat surprised us. And then when we looked at the doses that people were using, of course, thinking back to that 600-milligram dose that was tested in the study, we found actually that more than half of folks were taking low dose aspirin, like an 81 milligram, and only about 8% of our study participants were using that 600-milligram range. So, again, I would say this somewhat surprised us because we thought it might be higher than this. I'll say as a somewhat caveat to this though, is that back to my comment about we always like another study that confirms our findings, and at a meeting earlier this year, there was a study performed in a New Zealand population by a medical oncologist named Rebecca Tuckey. And she actually found almost the same identical results that we did in the New Zealand population - very, very similar uptake rates of aspirin in the New Zealand population with Lynch syndrome, so kind of confirming that something we've stumbled upon appears to be true. But how do we understand why some folks use aspirin and why others don't in this condition? Dr. Rafeh Naqash: You had a very robust question there from what I saw in the paper. And some of the questions that I had around that was, did you or were you able to account for demographics, education level of the individuals? Were you also able to assess whether these individuals felt that they had been counseled appropriately when they met with either a primary care physician or of any provider on the genetic side, physician or non-physician? So how did you get an assessment of whether it was an apples-to-apples comparison or were there a lot of confounders. Dr. Michael J. Hall: Very good question. And of course, in the setting, unfortunately, we weren't interviewing people, which we could have gotten much richer data in some ways. And there were other things we were looking at in this survey as well, so our aspirin questions, we had a number of them, but perhaps in retrospect, it would have been nice to even have more. We did have some common covariates, age, sex, ancestry, marital status, which gene was affected, whether they had a history of cancer. We did not have education, unfortunately. And I think your question is a great one, but we did not actually ask folks about whether they had been counseled by their provider or their genetic counselor or someone else about whether they should use aspirin or not. We simply wanted to see whether folks were using it. We did ask them again whether they were using it because they wanted to lower their risk of a Lynch syndrome cancer or whether they were using it for another reason or a combination of both. So, yes, in retrospect, we actually do have another study plan to kind of drill deeper into these questions of is it more of a hesitancy question? Is it more of a question of just not as much awareness? Are there other reasons? I think there's a lot to answer, and I think answering these questions is really important because we both want to make sure we're talking about interventions that we think can help people, but we need to understand also some of the barriers they may face. And if people do have barriers to some forms of chemo prevention or I think about some of the vaccine research that's going on right now, if the kinds of things that we're working on to develop are actually not going to be palatable to the patient, the population, then I think we kind of need to step back and say we need to maybe understand what people want so that we can have a good meeting of what's going to work and what's going to fit the needs and lifestyles of our patients. Because these are things they might have to do for many, many years and starting maybe even in their 20s or 30s. So, it makes a difference. Dr. Rafeh Naqash: From what you learned in the study, are you thinking of any subsequent interventional approaches, whether they involve a simple phone call to the patient regularly or perhaps, even though I'm not a big fan of EMR prompts, like an EMR prompt of some sort, where they talk, where they're instructing the provider, whoever is seeing the patient physician or the APP or the geneticist that, “Hey. Did you counsel the patient?” And its sort of a metric how in the oncology side they say, “Well, your metric is you should stage all patients and you should talk about toxicities from a reimbursement standpoint and also from a quality improvement metric standpoint. “Is that something you're thinking of? Dr. Michael J. Hall: 100%. So, when we looked at the barriers, many of the kind of the things that were the strongest predictors of who used aspirin versus who didn't were really patients' perceptions of whether aspirin would cause side effects or whether aspirin would be burdensome to take on a daily basis, also, just how much benefit they thought would come from taking aspirin. So, I think there's, number one, I think an intervention and our next delve into this as an interventional study would be both education about the delta prevention benefit that you get from aspirin, the safety profile of aspirin, which is really quite excellent. And also, I think the data that are so important that in this study by Burn et al, it was actually only two years of intervention that then paid off for 10 years down the line, right? So, I think that's important. The other thing that we actually learned as an aside in this study was actually the kind of intervention that patients wanted the most was actually not a drug and was not a vaccine and was not another kind of special scope to stick somewhere. What they actually were most interested in were interventions related to diet. People really see diet as being an important part of health, or I should say diet and nutrition. And so, I think a subsequent study would perhaps wed both a nutritional intervention of some kind with a chemo prevention in some sort of time limited fashion, so that folks felt like they were both focusing on something that was more important to them, but also, something that was related to the study that we wanted to look at. So that's kind of my idea of where we're going to go in the future with this. Dr. Rafeh Naqash: Excellent. Sounds like the next big RO1 for your group. Dr. Michael J. Hall: Let's hope so. Dr. Rafeh Naqash: Well, I hope the listeners enjoyed talking about the science and learning about aspirin Lynch syndrome. The last couple of minutes are about you as an individual, as an investigator. Can you tell us what your career journey has been like, how you ended up doing what you're doing, and perhaps some advice for early career junior investigators on what this whole space looks like and how you pace yourself and how they can learn from you? Dr. Michael J. Hall: I really got interested in oncology during my residency training. I really found that I really liked oncologists. I found them to be a bit more of a science focused group. They liked research, but you're in oncology because you understand the fears and the challenges of cancer. And so, it's both a combination of that love of science, but also that real human touch of taking care of people. The thing I always tell my fellows as well is the other thing I love about oncology is if you tell people they don't have cancer, they don't want to come back to you. Now, of course, that's modified in the prevention setting. But I really like that when people come to me in my GI oncology clinic, it's because they have a diagnosis and if I say you actually don't have cancer, they go off to their life, and so you're really spending your time on real subjects. The person who really got me most interested in Lynch syndrome and this kind of prevention research was a mentor from University of Chicago, Funmi Olopade, who really has been an enormous mentor for many, many people in the field. Actually, three people in my fellowship class all went on to careers related to genetics and genomics. So, she's been highly influential and continues to mentor me even in my mid-career. I think in terms of pearls or what keeps this interesting for me, I think as much as oncology treatment and new drugs and trials is super exciting, I love being able to step away from that into my genetics and prevention population and kind of focus on treating people in a different format. Patients who are healthy but are worried about cancer because of a family history or carrying a gene or otherwise, and I feel that that's where I can have also an important impact, but on a different level in educating people and helping them understand how genetics works in an understandable and simple way, but also giving them some tools. And one reason for this study, and the reason I study preferences related to prevention is, again, I don't want to just develop something and spend 10, 15 years of my life developing some intervention that everyone looks at and is like, “I don't really want to do that.” I want to really understand what it is that is important to the patients so that we can hopefully work together to develop things that can not only have impact but have impact on a wide scale. Dr. Rafeh Naqash: Awesome. You mentioned Dr. Olopade. I crossed paths with her actually at an international medical graduate community of practice session earlier this year at ASCO where she talked about her journey as an immigrant, talked about how she started, the kind of impact that she's had. It was obvious evident in the picture that she showed with all her mentees who have kind of gone all over the world. So that was very phenomenal. And it's surprising how small of a world we live in. Everybody knows everybody else. Dr. Michael J. Hall: It's crazy. More so than anyone I think I've met in my career; she is really a huge believer in mentorship and spending that extra time with your mentees. And she has been someone who has continued to promote me as an investigator and build me up and get me involved in things. And like I said, I've been in oncology now for quite a few years. But having that person who I think is always thinking about their trainees and people who have learned and grown under them, because what it does is it gives you that fire as well as an investigator to do the same thing for the people that you are a mentor for and train. So, I try to be just as good of a mentor to my genetic counselors and the fellows who come through me and my APPs to give them opportunities to get them excited about research and when they have these big moments to do that. So, yeah, I know Funmi just has had a huge impact on the field of genetics. I still remember some of our early conversations on the wards when she said to me, “Oh, this is such an interesting case. We don't really have anyone who's studying Lynch syndrome so much right now and you should really get into this area.” And I remember thinking, “Okay, I want to develop a niche and here's a niche that's waiting.” Dr. Rafeh Naqash: Clearly it paid off big time and you're paying it forward with your mentees. So, thank you again for joining us. This was an absolute pleasure. Hopefully, the listeners learned a lot about the science and also your journey and how you're trying to impact the field. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts   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 opinion, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.      

Dr. Panigrahy is board certified in both Pediatric Radiology and Neuroradiology. He is a Professor of Radiology, Radiologist-in-Chief at Children's Hospital of Pittsburgh and Vice Chair of Clinical and Translational Imaging Research at UPMC. He has been continuously funded by the NIH since 2009 including both a K23 and current multi-center Ro1. He also has active funding from the Department of Defense, Society for Pediatric Radiology and private foundations. Dr. Panigrahy's research focuses on applying advanced MR techniques to the study of fetal/neonatal/pediatric brain development and injury in those diagnosed with congenital heart disease and its impact on neuro-developmental across the lifespan.

Ro1:18-20 The God of Foreshow and Predestination 

Krissy Dilger of SRNA was joined by Drs. Drs. John J. Chen and Elias S. Sotirchos for an “Ask the Expert” podcast episode titled “Acute Treatments and Rare Neuroimmune Disorders.” The experts began by providing an overview of treatments for an acute demyelinating attack and how they are administered. They also discussed side effects, safety concerns, and the decision process for escalation. Finally, the experts shared age considerations and upcoming research. John Chen, MD, PhD attended the University of Virginia for his undergraduate and combined MD/PhD degrees. He completed his Ophthalmology residency and Neuro-Ophthalmology fellowship training at the University of Iowa. He then took a position at the Mayo Clinic in 2014 where he specializes in Neuro-Ophthalmology. Currently, he serves as a Consultant and Professor of Ophthalmology and Neurology, and Neuro-Ophthalmology Fellowship Director at the Mayo Clinic. Among Dr. Chen's awards/honors are the AAO Achievement Award, resident and fellow teaching awards at the University of Iowa, Ophthalmology Teacher of the Year Award three times at the Mayo Clinic, 2023 Mayo Clinic Distinguished Educator Award, Top Doctors in Minnesota, and the Heed Fellowship. He is a board member for the North American Neuro-Ophthalmology Society and is on multiple committees for the AAO, co-chairs the Upper Midwest Neuro-Ophthalmology Group, is a member of the American Ophthalmological Society and American Eye Study Club, previously served as the President for the Minnesota Academy of Ophthalmology and participated in the AAO and AUPO Leadership Development Programs. He has over 200 peer-reviewed publications, has received several research awards, and is currently RO1 funded through the NIH. He has given over 200 oral presentations, including multiple named lectureships, and visiting professorships, on his interests in ophthalmic imaging, idiopathic intracranial hypertension, and optic neuritis, especially NMOSD and MOG antibody-associated disease. Elias Sotirchos, MD is a neurologist at Johns Hopkins Hospital in Baltimore, Maryland. He specializes in the diagnosis, management, and treatment of neuroimmunological disorders that involve the central nervous system, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated disorder (MOGAD). His research focuses on developing and validating novel imaging and blood-based biomarkers of these conditions, and clinical trials of experimental therapeutic agents.

Jyrell and RO1 are evangelists spreading the word of Bombasticism and the often stern love of their god XOXO.

Andrea Sikora, PharmD, MSCR, BCCCP, FCCM, is a Clinical Associate Professor at the University of Georgia College of Pharmacy and is a critical care clinical pharmacist at Augusta University Medical Center.We talk through critical care pharmacist practice models, her recently awarded RO1 grant funding, and her new book “Pay it Forward: a map to mentorship in medicine.” You can purchase the book on Amazon!

This month on Episode 38 of Discover CircRes, host Cynthia St. Hilaire highlights original research articles featured in the Jue 24th, July 8th and July 22nd issues of the journal. This episode also features an interview with the 2022 BCBS Outstanding Early Career Investigator Award finalists, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstadt.   Article highlights:   Nguyen, et al. miR-223 in Atherosclerosis.   Choi, et al. Mechanism for Piezo1-Mediated Lymphatic Sprouting   Kamtchum-Tatuene, et al.  Plasma Interleukin-6 and High-Risk Carotid Plaques   Li, et al. 3-MST Modulates BCAA Catabolism in HFrEF   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. And today I'm going to be highlighting articles from our June 24th, July 8th and July 22nd issues of Circulation Research. I'm also going to have a chat with the finalists for the 2022 BCBS Outstanding Early Career Investigator Award, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstadt.   Cindy St. Hilaire:        The first article I want to share is from our June 24th issue and is titled, miR-223 Exerts Translational Control of Proatherogenic Genes in Macrophages. The first authors are My-Anh Nguyen and Huy-Dung Hoang, and the corresponding author is Katey Rayner and they're from the University of Ottawa. A combination of cholesterol accumulation in the blood vessels and subsequent chronic inflammation that's derived from this accumulation drive the progression of atherosclerosis. Unfortunately, current standard medications tackle just one of these factors, the cholesterol. And this might explain why many patients on such drugs still have vascular plaques. In considering treatments that work on both aspects of the disease, meaning lipid accumulation and inflammation, this group investigated the micro RNA 223 or miR-223, which is a small regulatory RNA that has been shown to suppress expression of genes involved in both cholesterol uptake and inflammatory pathways in both liver and immune cells.   Cindy St. Hilaire:        The team showed that mouse macrophages deficient in miR-223, exhibited increased expression of pro-inflammatory cytokines and reduced cholesterol efflux compared with control cells. Overexpression of miR-223 had the opposite effects. Furthermore, atherosclerosis prone mice, whose hematopoietic cells lacked miR-223, had worse atherosclerosis with larger plaques and higher levels of pro-inflammatory cytokines than to control animals with normal levels of miR-223. These findings highlight miR-223's dual prompt, antiatherogenic action, which could be leveraged for future therapies.   Cindy St. Hilaire:        The second article I want to share is from our July 8th issue of Circulation Research and is titled, Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymph Expansion. The first author is Dongwon Choi and the corresponding author is Young-Kwon Hong, and they're from UCLA.   As well as being super highways for immune cells, lymph vessels are drainage channels that help maintain fluid homeostasis in the tissues. This network of branching tubes grows as fluids begin to flow in the developing embryo. This fluid flow induces calcium influx into the lymphatic endothelial cells, which in turn promotes proliferation and migration of these cells, leading to the sprouting of lymph tubules. But how do LECs, the lymphatic endothelial cells, detect fluid flow in the first place? Piezo1 is a flow and mechanosensing protein known for its role in blood vessel development and certain mutations in Piezo1 cause abnormal lymphatic growth in humans.   Cindy St. Hilaire:        This script found that Piezo1 is expressed in the embryonic mouse LECs and that the suppression of Piezo1 inhibits both flow activated calcium entry via the channel ORAI1, as well as downstream target gene activation. Overexpression of Piezo1, by contrast, induced the target genes. The team went on to show that mice lacking either Piezo1 or ORAI1 had lymphatic sprouting defects and that pharmacological activation of Piezo1 in mice enhanced lymphogenesis and prevented edema after tail surgery. Together, the results confirmed Piezo1's role in flow dependent lymphatic growth and suggest it might be a target for treating lymphedema.   Cindy St. Hilaire:        The third article I want to share is also from our July 8th issue and is titled, Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability and Progression. The first and corresponding author of this study is Joseph Kamtchum-Tatuene from University of Alberta.   Excessive plasma cholesterol and systemic inflammation are contributing factors in atherosclerosis. While traditional remedies have been aimed at lowering patient's lipid levels, drugs that tackle inflammation are now under investigation, including those that suppress Interleukin-6, which is an inflammatory cytokine implicated in the disease. Focusing on carotid artery disease, this group conducted a prospective study to determine whether IL-6 levels correlated with disease severity. 4,334 individuals were enrolled in the cardiovascular health study cohort. They had their blood drawn and ultrasounds taken at the start of the study and five years later. This group found IL-6 was robustly correlated with and predicted plaque severity independent of other cardiovascular risk factors. This study also determined that an IL-6 blood plasma level of 2.0 picograms/mls, identified individuals with the highest likelihood of plaque, vulnerability and progression. This threshold value could be used to select patients who might benefit from novel IL-6 lowering medications.   Cindy St. Hilaire:        The last article I want to share is from our July 22nd issue of Circulation Research and is titled, Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure. The first author is Zhen Li, and the corresponding author is David Lefer from Louisiana State University. Hydrogen sulfide, or H2S, is a compound that exerts mitochondrial specific actions that include the preservation of oxidative phosphorylation, mitochondrial biogenesis and ATP synthesis, as well as inhibiting cell death. 3-mercaptopyruvate sulfurtransferase, or 3-MST, is a mitochondrial H2S producing enzyme, whose functions in cardiovascular disease are not fully understood.   Cindy St. Hilaire:        This group investigated the global effects of 3-MST deficiency in the setting of pressure overload induced heart failure. They found that 3-MST was significantly reduced in the myocardium of patients with heart failure, compared with non failing controls. 3-MST knockout mice exhibited increased accumulation of branch chain amino acids in the myocardium, which was associated with reduced myocardial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance, following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism, or administration of a potent H2S donor, ameliorated the detrimental effects of 3-MST deficiency and heart failure with reduced injection fraction. These data suggest that 3-MST derived mitochondrial H2S, may play a regulatory role in branch chain amino acid catabolism, and mediate critical cardiovascular protection in heart failure.   Cindy St. Hilaire:        Today, I'm really excited to have our guests, who are the finalists for the BCVS Outstanding Early Career Investigator Awards. Welcome everyone.   Hisayuki Hashimoto:   Thank you.   Anja Karlstaedt:          Hi.   Hisayuki Hashimoto:   Hi.   Matthew DeBerge:      Hello. Thank you.   Cindy St. Hilaire:        So the finalists who are with me today are Dr Hisayuki Hashimoto from Keio University School of Medicine in Tokyo, Japan, Dr Matthew Deberge from Northwestern University in Chicago and Dr Anja Karlstaedt from Cedar Sinai Medical Center in LA. Thank you again. Congratulations. And I'm really excited to talk about your science.   Hisayuki Hashimoto:   Thank you. Yes. Thanks, first of all for this opportunity to join this really exciting group and to talk about myself and ourselves. I am Hisayuki Hashimoto, I'm from Tokyo, Japan. I actually learned my English... I went to an American school in a country called Zaire in Africa and also Paris, France because my father was a diplomat and I learned English there. After coming back to Japan, I went to medical school. During my first year of rotation, I was really interested in cardiology, so I decided to take a specialized course for cardiology. Then I got interested in basic science, so I took a PhD course, and that's what brought me to this cardiology cardiovascular research field.   Matthew DeBerge:      So I'm currently a research assistant professor at Northwestern University. I'm actually from the Chicagoland area, so I'm really excited to welcome you all to my hometown for the BCVS meeting.   Cindy St. Hilaire:        Oh, that's right. And AHA is also there too this year. So you'll see a lot of everybody.   Matthew DeBerge:      I guess I get the home field advantage, so to speak. So, I grew up here, I did my undergrad here, and then went out in the east coast, Dartmouth College in New Hampshire for my PhD training. And actually, I was a viral immunologist by training, so I did T cells. When I was looking for a postdoctoral position, I was looking for a little bit of something different and came across Dr Edward Thorpe's lab at Northwestern university, where the interest and the focus is macrophages in tissue repair after MI. So, got into the macrophages in the heart and have really enjoyed the studies here and have arisen as a research assistant professor now within the Thorpe lab. Now we're looking to transition my own independent trajectory. Kind of now looking beyond just the heart and focusing how cardiovascular disease affects other organs, including the brain. That's kind of where I'm starting to go now. Next is looking at the cardiovascular crosstalk with brain and how this influences neuroinflammation.   Anja Karlstaedt:          I am like Hisayuki, I'm also a medical doctor. I did my medical training and my PhD in Berlin at the Charité University Medicine in Berlin, which is a medical faculty from Humboldt University and Freie University. II got really interested in mathematical modeling of complex biological systems. And so I started doing my PhD around cardiac metabolism and that was a purely core and computationally based PhD. And while I was doing this, I got really hooked into metabolism. I wanted to do my own experiments to further advance the model, but also to study more in crosstalk cardiac metabolism. I joined Dr Heinrich Taegteyer lab at the University of Texas in the Texas Medical Center, and stayed there for a couple of years. And while I was discovering some of the very first interactions between leukemia cells and the heart, I decided I cannot stop. I cannot go back just after a year. I need to continue this project and need to get funding. And so after an AHA fellowship and NIHK99, I am now here at Cedars Sinai, an assistant professor in cardiology and also with a cross appointment at the cancer center and basically living the dream of doing translational research and working in cardio-oncology.   Cindy St. Hilaire:        Great. So, Dr Hashimoto, the title of your submission is, Cardiac Reprogramming Inducer ZNF281 is Indispensable for Heart Development by Interacting with Key Cardiac Transcriptional Factors. This is obviously focused on reprogramming, but why do we care about cardiac reprogramming and what exactly did you find about this inducer ZNF281?   Hisayuki Hashimoto:   Thank you for the question. So, I mean, as I said, I'm a cardiologist and I was always interested in working heart regeneration. At first, I was working with pluripotent stem cells derived cardiomyocyte, but then I changed my field during my postdoc into directly programming by making cardiomyocyte-like cells from fiberblast. But after working in that field, I kind of found that it was a very interesting field that we do artificially make a cardiomyocyte-like cell. But when I dissected the enhanced landscape, epigenetic analysis showed that there are very strong commonalities between cardiac reprogramming and heart development. So I thought that, hey, maybe we can use this as a tool to discover new networks of heart development. And the strength is that cardiac reprogramming in vitro assay hardly opens in vivo assay, so it's really time consuming. But using dark programming, we can save a lot of time and money to study the cardiac transitional networks. And we found this DNF281 from an unbiased screen, out of 1000 human open reading frames. And we found that this gene was a very strong cardiac reprogramming inducer, but there was no study reporting about any functioning heart development. We decided to study this gene in heart development, and we found out that it is an essential gene in heart development and we were kind of able to discover a new network in heart development.   Cindy St. Hilaire:        And you actually used, I think it was three different CRE drivers? Was that correct to study?   Hisayuki Hashimoto:   Ah, yes. Yeah.   Cindy St. Hilaire:        How did you pick those different drivers and what, I guess, cell population or progenitor cell population did those drivers target?   Hisayuki Hashimoto:   So I decided to use a mesodermal Cre-driver, which is a Mesp1Cre and a cardiac precursor Cre-driver, which is the Nkx2-5 Cre and the cardiomyocyte Cre, which is the Myh6-Cre. So three differentiation stages during heart development, and we found out that actually, DNF281 is an essential factor during mesodermal to cardiac precursor differentiation state. We're still trying to dig into the molecular mechanism, but at that stage, if the DNF281 is not there, we are not able to make up the heart.   Cindy St. Hilaire:        That is so interesting. Did you look at any of the strains that survived anyway? Did you look at any phenotypes that might present in adulthood? Is there anything where the various strains might have survived, but then there's a kind of longer-term disease implicating phenotype that's observed.   Hisayuki Hashimoto:   Well, thank you for the question. Actually, the mesodermal Cre-driver knocking out the DNF281 in that stage is embryonic lethal, and it does make different congenital heart disease. And they cannot survive until after embryonic day 14.5. The later stage Nkx2-5 Cre and Myh6-Cre, interestingly, they do survive after birth. And then in adult stage, I did also look into the tissues, but the heart is functioning normally. I haven't stressed them, but they develop and they're alive after one year. It looks like there's really no like phenotype at like the homeostatic status.   Cindy St. Hilaire:        Interesting. So it's kind of like, once they get over that developmental hump, they're okay.   Hisayuki Hashimoto:   Exactly. That might also give us an answer. What kind of network is important for cardiac reprogramming?   Cindy St. Hilaire:        So what are you going to do next?   Hisayuki Hashimoto:   Thank you. I'm actually trying to dig into the transitional network of what kind of cardiac transitional network the ZNF281 is interacting with, so that maybe I can find a new answer to any etiology of congenital heart disease, because even from a single gene, different mutation, different variants arise different phenotypes in congenital heart disease. Maybe if I find a new interaction with any key cardiac transitional factors, maybe I could find a new etiology of congenital heart disease phenotype.   Cindy St. Hilaire:        That would be wonderful. Well, best of luck with that. Congratulations on an excellent study. Hisayuki Hashimoto:   Thank you.   Cindy St. Hilaire:        Dr DeBerge, your study was titled, Unbiased Discovery of Allograft Inflammatory Factor-1 as a New and Critical Immuno Metabolic Regulatory Node During Cardiac Injury. Congrats on this very cool study. You were really kind of focused on macrophages in myocardial infarction. And macrophages, they're a Jeckel Hyde kind of cell, right? They're good. They're bad. They can be both, almost at the same time, sometimes it seems like. So why were you interested in macrophages particularly in myocardial infarction, and what did you discover about this allograft inflammatory factor-1, or AIF1 protein?   Matthew DeBerge:      Thank you. That's the great question. You really kind of alluded to why we're interested in macrophages in the heart after tissue repair. I mean, they really are the central mediators at both pro-inflammatory and anti-inflammatory responses after myocardial infarction. Decades of research before this have shown that inflammation has increased acutely after MI and has also increased in heart failure patients, which really has led to the development of clinical efforts to target inflammatory mediators after MI. Now, unfortunately, the results to target inflammation after MI, thus far, have been modest or disappointing, I guess, at worst, in the respect that broadly targeting macrophage function, again, hasn't achieved results. Again, because these cells have both pro and anti-inflammatory functions and targeting specific mediators has been somewhat effective, but really hasn't achieved the results we want to see.   Matthew DeBerge:      I think what we've learned is that the key, I guess, the targeting macrophage after MI, is really to target their specific function. And this led us to sort of pursue novel proteins that are mediating macrophage factor function after MI. To accomplish this, we similarly performed an unbiased screen collecting peri-infarct tissue from a patient that was undergoing heart transplantation for end stage heart failure and had suffered an MI years previously. And this led to the discovery of allograft inflammatory factor-1, or AIF1, specifically within cardiac macrophages compared to other cardiac cell clusters from our specimen. And following up with this with post-mortem specimens after acute MI to show that AIF1 was specifically increased in macrophages after MI and then subsequently then testing causality with both murine model of permanent inclusion MI, as well as in vitro studies using bone marrow drive macrophages to dig deeper mechanistically, we found that AIF1 was crucial in regulating inflammatory programing macrophages, which ultimately culminated in worse in cardiac repair after MI.   Cindy St. Hilaire:        That's really interesting. And I love how you start with the human and then figure out what the heck it's doing in the human. And one of the things you ended up doing in the mouse was knocking out this protein AIF1, specifically in macrophage cells or cells that make the macrophage lineage. But is this factor in other cells? I was reading, it can be intracellular, it can be secreted. Are there perhaps other things that are also going on outside of the macrophage?   Matthew DeBerge:      It's a great question. First, I guess in terms of specificity, within the hematopoietic compartment, previous studies, as well as publicly available databases, have shown that AIF1 is really predominantly expressed within macrophages. We were able to leverage bone marrow chimera mice to isolate this defect to the deficiency to macrophages. But you do bring up a great point that other studies have shown that AIF1 may be expressed in other radio-resistant cell populations. I mean, such as cardiomyocytes or other treatable cells within the heart. We can't completely rule out a role for AIF1 and other cell populations. I can tell you that we did do the whole body knockout complementary to our bone marrow hematopoetic deficient knockouts, and saw that deficiency of AIF1 within the whole animal, recapitulate the effects we saw within the AIF1 deficiency within hematopoietic department.   Matthew DeBerge:      It was encouraging to us that, again, the overall role of AIF1 is pro-inflammatory after MI.   Cindy St. Hilaire:        I mean, I know it's early days, but is there a hint of any translational potential of these findings or of this protein?   Matthew DeBerge:      Yeah, I think so. To answer your question, we were fortunate enough to be able to partner with Ionis that develops these anti-sensible nucleotides so that we could specifically target AIF1 after the acute phase during MI. We saw that utilizing these anti-sensible nucleotides to deplete AIF1, again, within the whole mouse, that we were able to reduce inflammation, reduce in heart size and preserve stock function. I think there really is, hopefully a therapeutic opportunity here. And again, with it being, perhaps macrophage specific is, even much more important as we think about targeting the specific function of these cells within the heart.   Cindy St. Hilaire:        Very cool stuff. Dr Karlstaedt, the title of your submission is, ATP Dependent Citrate Lyase Drives Metabolic Remodeling in the Heart During Cancer. So this I found was really interesting because you were talking about, the two major killers in the world, right? Cardiovascular disease and cancer, and you're just going to tackle both of them, which I love. So obviously this is built on a lot of prior observations about the effects of cancer on cardiac metabolic remodeling. Can you maybe just tell us a little bit about what is that link that was there and what was known before you started?   Anja Karlstaedt:          Yeah. Happy to take that question. I think it's a very important one and I'm not sure if I will have a comprehensive answer to this, because like I mentioned at the beginning, cardio-oncology is a very new field. And the reason why we are starting to be more aware of cancer patients and their specific cardiovascular problems is because the cancer field has done such a great job of developing all these new therapeutics. And we have far more options of treating patients with various different types of cancers in particular, also leukemias, but also solid tumors. And what has that led to is an understanding that patients survive the tumors, but then 10, 20 years later, are dying of cardiovascular diseases. Those are particular cardiomyopathies and congestive heart failure patients. What we are trying, or what my lab is trying to do, is understanding what is driving this remodeling. And is there a way that we can develop therapies that can basically, at the beginning of the therapy, protect the heart so that this remodeling does not happen, or it is not as severe.   Anja Karlstaedt:          Also, identifying patients that are at risk, because not every tumor is created equally and tumors are very heterogeneous, even within the same group. To get to your question, what we found is, in collaboration actually with a group at Baylor College of Medicine, Peggy Goodell's group, who is primarily working on myeloid malignancies, is that certain types of leukemias are associated with cardiomyopathies. And so when they were focusing on the understanding drivers of leukemia, they noticed that the hearts of these animals in their murine models are enlarged on and actually developing cardiomyopathies. And I joined this project just very early on during my postdoc, which was very fortunate and I feel very lucky of having met them. What my lab is now studying here at Cedars is how basically those physiological stress and mutations coming from the tumors are leading to metabolic dysregulation in the heart and then eventually disease.   Anja Karlstaedt:          And we really think that metabolism is at the center of those disease progressions and also, because it's at the center, it should be part of the solution. We can use it as a way to identify patients that are at risk, but also potentially develop new therapies. And what was really striking for us is that when we knock down ACLY that in a willdtype heart where the mouse doesn't have any tumor disease, ACLY actually is critically important for energy substrate metabolism, which seems counterintuitive, because it's far away from the mitochondria, it's not part of directly ADP provision. It's not part of the Kreb cycle. But what we found is that when we knock it out using a CRISPR-Cas9 model, it leads to cardiomyopathy and critically disrupts energy substrate metabolism. And that is not necessarily the case when the mouse has leukemia or has a colorectal cancer, which upregulated in the beginning, this enzyme expression. And so we have now developed models that show us that this could be potentially also therapeutic target to disrupt the adverse remodeling by the tumor.   Cindy St. Hilaire:        That is so interesting. So one of the things I was thinking about too is we know that, I mean, your study is showing that, the tumor itself is causing cardiac remodeling, but we also know therapies, right? Radiation, chemotherapy, probably some immune modulatory compounds. Those probably do similar, maybe not exactly similar, but they also cause, adverse cardiac remodeling. Do you have any insights as to what is same and what is different between tumor driven and therapy driven adverse remodeling?   Anja Karlstaedt:          So we do not know a lot yet. It's still an open question about all the different types of chemotherapeutics, how they are leading to cardio toxicities. But what we know, at least from the classic anti-cyclic treatments, is right now at the core, the knowledge is that this is primarily disrupting cardiac mitochondrial function. And through that again, impairing energy provision and the interaction, again, with the immune system is fairly unknown, but we know through studies from Kathryn Moore and some very interesting work by Rimson is that myocardial infarction itself can lead to an increase in risk for tumor progression. And what they have shown as independent of each other, is that the activation of the immune system in itself can lead to an acceleration of both diseases, both the cardiac remodeling, and then also the tumor disease. We don't fully understand which drivers are involved, but we do know that a lot of the cardiomyopathies on cardiotoxicities that are chemotherapeutically driven, all have also metabolic component.   Cindy St. Hilaire:        Nice. Thank you. When I prepare for these interviews, I obviously read the abstracts for the papers, but I found myself also Googling other things after I read each of your abstracts. It was a rabbit hole of science, which was really exciting.                               I now want to transition to kind of a career angle. You all are obviously quite successful, scientifically, at the bench, right? But now you are pivoting to a kind of completely opposite slash new job, right? That of, independent researcher. I would love to hear from each of you, if there was any interesting challenge that you kind of overcame that you grew from, or if there was any bit of advice that you wish you knew ahead of time or anything like that, that some of our trainee listeners and actually frankly, faculty who can pass that information onto their trainees, can benefit from.   Anja Karlstaedt:          I think the biggest challenge for me in transitioning was actually the pandemic. Because I don't know how it was for Hisa and Matt, but trying to establish a lab, but also applying for faculty position during a major global pandemic, is challenging is not quite something that I expected that would happen. And so I think saying that and looking more conceptually and philosophically at this as, you can prepare as much as you want, but then when life just kicks in and things happen, they do happen. And I think the best is to prepare as much as you can. And then simply go with the flow. Sometimes one of my mentors, Dave Nikon, mentioned that to me when I was applying for faculty positions, it's sometimes good to just go with the flow. And as a metabolism person, I absolutely agree. And there are some things that you can do as a junior investigator.   Anja Karlstaedt:          We need to have a good network. So just very important to have good mentors. I was blessed with have those mentors, Peggy Goodell's one of them, Heinrich Taegtmeyer was another. And now with this study that we are publishing, Jim Martin and Dave Nikon were incredible. Without them, this study wouldn't have been possible and I would not be here at Cedars.   Anja Karlstaedt:          You need to reach out to other people because those mentors have the experience. They have been through some of this before. Even if they have never had a major event, like COVID-19 in their life before, because none of us had before, they had other experiences and you can rely on them and they set you then up for overcoming these challenges. And the other thing I would say, is put yourself out there, go and talk to as many people as possible or set conferences, present a poster, not only talks. Don't be disappointed if you don't get a talk, posters are really great to build this network and find other people that you probably wouldn't have encountered and apply for funding. Just again, put yourself out there and try to get the funding for your research. Even if it's small foundations, it builds up over time and it is a good practice to then write those more competitive grants.     Cindy St. Hilaire:        Dr Hashimoto, would you like to go next?   Hisayuki Hashimoto:   Just my advice is that, could be like a culture of difference, but in east Asia, like in Japan, we were taught to, do not disturb people, don't interrupt people and help people. But I realized that I wasn't really good at asking for help. After I am still not like fully independent, but I do have my own group and I have to do grant writing. I still work at the bench and then have to teach grad students, doing everything myself. I just realized it's just impossible. I didn't have time. I need like 48 hours a day. Otherwise, you won't finish it. I just realized that I wasn't really good at asking for help. So my advice would be, don't hesitate to ask for help. It's not a shame. You can't do everything by just yourself. I think, even from the postdoc, even from grad school, I think, ask for help and then get used to that. And then of course, help others. And that is the way I think to probably not get overwhelmed and not stress yourself. Science should be something fun. And if you don't ask for help and if you don't help someone, I think you are losing the chance of getting some fun part from the science.   Cindy St. Hilaire:        That's great advice. I really like that, especially because I find at least, I started my lab seven years ago now. And I remember the first couple months/year, it was extremely hard to let go, right? Like I taught my new people how to do the primary cell culture we needed, but I was terrified of them doing it wrong or wasting money or making too many mistakes. But you realize, you got to learn to trust people. Like you said, you got to learn to ask for help. And sometimes that help is letting them do it. And you doing, you're being paid now to write grants and papers. That's a big brain, you're not paid to do the smaller things. That's really great advice. I like that. Thank you. Dr DeBerge, how about you?   Matthew DeBerge:      So I guess towards a bit of life advice, I think two obvious things is one, be kind, science is hard enough as it is. So I think we should try to lift each other up and not knock each other down. And along those lines as the others have alluded to as well, one of the mantras we sort of adapted on the lab, is a rising tide raises all ships, this idea that we can work together to elevate each other's science and really, again, collaborate.   Towards the career side of things I'll just touch on, because I guess one thing I'll add, there's more than one path, I guess, to achieving your goals. I've been fortunate enough to have an NIH post-doctoral fellowship and had an AHA career development award, but I'm not a K99 recipient. Oftentimes, I think this is the golden ticket to getting the faculty job, so I'm trying to, I guess, buck trend, I just submitted an RO1. So fingers crossed that leads to some opportunity.   Even beyond academia, I'm not certain how much everyone here is involved in science Twitter, it's really become a thing over the last couple years, but I think, kind of the elephant in the room is that academia, it's really hard on the trainees nowadays to have a living wage, to go through this. I mean, I'm really excited to see my, fellow finalists here are starting their own groups and stuff, but for many, that's not the reality for many, it's just not financially feasible. So I think, kind of keeping in mind that there's many, many alternative careers, whether it's industry, whether it's consulting, science writing, etcetera, going back to what Dr Hash says, find what you love and really pursue that with passion.   Cindy St. Hilaire:        I think it's something only, I don't know, five to 10% of people go into or rather stay in academia. And that means, 90 to 95% of our trainees, we need to prepare them for other opportunities, which I think is exciting, because it means it can expand our network for those of us in academia.   Anja Karlstaedt:          I think right now it's even worse because it's about 2% of old postdocs that are actually staying and becoming independent researchers, independent or tenure track or research track. And I think I second, as what Matt said, because I play cello. I do music as a hobby and people always ask me if I'm a musician. And at the beginning I felt like, no, of course not. I'm not like Yoyo Ma. I'm just playing, it's a hobby. And then I, that got me thinking. I was like, no, of course you are because there's so many different types. And what we need to understand is that scientists, like you are always a scientist. It doesn't matter if you are working at Pfizer or if you are working at a small undergrad institution and you're teaching those next generation scientists, you are still scientist and we all need those different types of scientists because otherwise, if everybody is just a soloist, you are never going to listen to symphony. You need those different people and what we need to normalize beyond having those different career paths, is also that people are staying in academia and becoming those really incredible resources for the institutions and labs, quite frankly, of being able to retain those technologies and techniques within an institution. And I think that's something to also look forward to, that even if you're not the PI necessarily, you're the one who is driving those projects. And I hope to pass this on at some point also to my trainees that they can be a scientist, even if they're not running a lab and they become an Institute director and that's also critically important.   Cindy St. Hilaire:        There's lots of ways to do science. Thank you all so much for joining me today. Either waking up at 5:00 AM or staying up past midnight, I think it is now in Japan or close to it. So Matt and I kind of made it out okay. It's like 8:00 or 9:00 AM.   Matthew DeBerge:      Thank you.   Hisayuki Hashimoto:   My apologies for this time zone difference.   Cindy St. Hilaire:        I'm very glad to make it work. Congratulations to all of you, your presentations. I forget which day of the week they are on at BCVS, but we are looking forward to the oral presentations of these and congratulations to all of you. You are amazing scientists and I know I'm really looking forward to seeing your future work so best of luck.   Matthew DeBerge:      Thank you.   Hisayuki Hashimoto:   Thank you.   Anja Karlstaedt:          Thank you so much.   Cindy St. Hilaire:        That's it for the highlights from the June 24th, July 8th and July 22nd 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 at CircRes and hashtag Discover CircRes. Thank you to our guests. The BCVS Outstanding Early Career Investigator Award Finalists, Dr Hisayuki Hashimoto, Dr Matthew DeBerge and Dr Anja Karlstaedt. 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 the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire. And this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information visit ahajournals.org.  

Sample the penultimate season one episode of “Mental Health Trailblazers, Psychiatric Nurses Speak Up,” where our host Indrias Kassaye will be interviewing Dr. Jillian Inouye: a licensed psychologist, a qualified mental health professional, a board certified clinical specialist in psychiatric nursing, and an advanced practice registered nurse. Among her many areas of research, she's presented new insights on topics such as Asian-Pacific Islanders' Health Disparities and psychiatric care, including schizophrenia, depression, substance use and abuse and more.Working hand-in-hand with politicians during an early summer internship, Dr. Inouye found her love of psychology, psychiatry, nursing and cross-cultural problems by helping to craft a bill focused on combating child abuse due to family or support system isolation within military institutions. In working to overcome both internal limitations (being reserved) and external challenges (racially based microaggressions), Dr. Inouye has been able to expand her career to regularly contribute to the scientific community.Within this conversation, Dr. Inouye and Indrias work though concepts such as how nursing can look at not just mental and social effects, but at physical and biological interactions, her expansive work within the Diabetes Prevention Project as well as her own RO1 that looked at managing diabetes and depression in ethnic groups (mainly Asian Pacific Islanders), and the importance for rising generations to mobilize in order to take action in support of future minority healthcare.If you want to gain further awareness on how legislation plays an important role in the dissemination of research, wish to receive insight on the value of mentoring (especially for Minority Fellowship Program fellows) so as to best know what key elements may arise from recent historical moments, or just have an interest in the political landscapes that can accompany various grant submission processes, then start this episode. To learn more about Dr. Jillian Inouye, visit https://emfp.org/mfp-fellows/doctoral/jillian-inouye.

Ally got to the bar first. The bar is about a mile from our house and part of a seafood restaurant. To get to the bar inside the restaurant, I had to walk the length of the Blue Crab Restaurant. The last 20 feet of the walk I had an unimpeded view of Ally sitting on a barstool facing toward me. What caught my eyes, and everyone else's eyes I am sure is that sparking lights that came from her pussy. It turned out diamonds, artificial diamonds, now adorned both sides of Ally's labia. In the right light, they caught the light and sparkled in the darkness between Ally's legs. I marveled that Ally had added this twist to her “skirt game”. To my surprise, my body did not react to the sparkling lights as I approached her. Ally got up and hugged me and then bounced back on her barstool and turned toward me, her legs slightly open. She smiled at me waiting for the view I now had of her pussy to do its magic. My body responded, but slower than normal. Was I adjusting to the madness, or was I just too tired. I sat next to her on my bar stool. Ally rotated around where we now both faced the bar. The bar only has eight stools, and we were the only two at the bar. She let her knees move apart the width of the barstool and asked me about her new diamonds, “do you like them. They are zirconia. I think they are a little big and gaudy, but they do get me attention.” On cue, before I could answer, an older gentleman, perhaps in his mid-sixties sat on the stool next to Ally. Her legs flinched inward for very brief moment then she held her position and let her diamonds shine. The man ordered a whiskey as if she wasn't there. He then asked the bartender to give us drinks on his tab. Ally was halfway through her martini, and I hadn't ordered. I asked for a seven and seven. Alfred introduced himself to Ally and me and commented on Ally's new jewelry[RO1] , “I heard you say they were too gaudy, I think they're just right[RO2] .” He turned slightly and looked down, and then looked up at the bartender, a small woman I guessed to be in her twenties[RO3] . “What do you think of her zirconia?”[RO4] [RO1]end of part 1 [RO2]on anchor part 2 [RO3]Billy Joel part 3 stand alone [RO4]On anchor part 4 --- Send in a voice message: https://anchor.fm/mchastity/message

I Am a Servant of Jesus Christ Ps101:6; Ro1:1-2

Does the thought of practicing open science give you sweaty palms? That’s a normal reaction for those of us who weren’t formally trained in the open-science methodology. The sweaty-palm reaction is really not that surprising since most of us have gotten where we are today because we’ve been meticulous in our work and tried to put out the best work we possibly could. In a nutshell, we tend to be perfectionists. But science, like life, is far from perfect. It’s messy. And it often takes unexpected twists and turns. Once we embrace this reality and view research as a conversation starter, we’ll be able to move past the sweaty-palms stage. Part of getting comfortable with open-science practices is your mindset. It’s about valuing doing rigorous science, even when it gets messy. Open science is also about creating an environment where feedback is sought and embraced. It’s about learning along the way so that you can do even better science going forward. In this episode, you’ll learn… Why Dr. Teachman felt primed to embrace open science from her grad school experience, even though she wasn’t taught open-science protocol in school How to begin embracing open-science practices The barriers to embracing open science Why open science is about more than protocols and checklists -- it’s about a culture that supports transparency and is non-defensive to feedback About the documentation process within her lab About the benefits of using GitHub in addition to OSF Why doing science according to your values can ease the sting of rejected work by publications Dr. Teachman’s suggestion of putting a pre-registration section on your CV How Dr. Teachman approaches collaborations with other researchers who are unfamiliar with open-science practices Tips from the episode On how to shift a lab towards open-science practices… Incorporate visual reminders about your lab’s open-science goals. Set concrete deadlines and expect participation from everyone in the lab. Get over the idea that “it has to be as near perfect as possible before I make it public.” On incrementalism and where to start… Just start. It won’t be perfect, and you’ll get better at it. Embrace that science is about taking risks and figuring it out as you go along. As a first step, do a pre-registration of your hypothesis or share a data set. On the documentation process for open-science projects… Use plain language for your comments within your code Include a section on deviations from the pre-registration Include a guide to open-data and materials Use an internal wiki Links from the episode: RO1 trial – Mindtrails Alan Kazdin Center for Open Science PACT lab Pre-registration templates on OSF Twitter feed on CVs incorporating open science and related materials on OSF Tutorial on integrating Github and R ReproducibiliTea open science methodology reading groups Jeremy Eberle can be found on Twitter: @JeremyWEberle, and https://www.researchgate.net/profile/Jeremy_Eberle2 or https://osf.io/nyqux/ Research Matters Podcast is hosted by Jason Luoma, who can be found on Twitter @jasonluoma or Facebook at: facebook.com/jasonluomaphd. You download the podcast through iTunes, Stitcher, or Spotify. Reach out with suggestions, questions, or comments to researchmatterspod@gmail.com

Dr. Hayes interviews Dr. Bruce Chabner on his experience with cancer drug discovery and development, phase I trials and pharmacology.   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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Welcome to JCO's Cancer Stories, The Art of Oncology, brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.ASCO.org. Today my guest on this podcast is Dr. Bruce Chabner. Dr. Chabner's is widely considered one, or frankly if not the father, of our understanding of the pharmacology principles of anti-neoplastic drugs.   And probably more importantly, the translation of these principles to the intelligent application of the agents we use in clinic every day. Among the many accomplishments that Dr. Chabner has had working with his mentor, Dr. Joseph Bertino at Yale, who developed the concept of high dose methotrexate leucovorin rescue, that was completely based on their preclinical understandings of the mechanism of action, and more importantly, resistance to this agent. Dr. Chabner was also instrumental in the development of paclitaxel when he was at the National Cancer Institute, and he was intimately involved in many of the early studies that led to better understanding of AIDS and the ways to treat it.   Dr. Chabner was raised in Shelbyville, Illinois, and I'm going to digress for a moment, because I've always had a very special soft spot in my own heart for Bruce Chabner. A, because of his science, but more importantly, because I was raised in Shelbyville, Indiana. Both of these towns were named after Colonel Isaac Shelby, who was a hero in both the Revolutionary War and the War of 1812. By the way, Dr. Chabner, I know you were a big student of history when you were in college, so I thought you'd like this.   Dr. Shelby became the first and then the fifth governor of Kentucky, and as a citizen he was a land surveyor. There were actually nine counties and 11 cities and towns spread around the Eastern and Midwest regions that are named after Colonel Shelby. And I don't know about you, Bruce, but I had this drilled into my brain in eighth grade history class. I had to learn all about Colonel Shelby.   Anyway, so he and I are brothers in Shelbyville. Dr. Chabner received his undergraduate degree of Yale, where again, he spent a lot of his time in the history department but also in the biology department. And then he got his medical degree at Harvard, where he stayed to complete his residency in internal medicine at the Peter Bent Brigham Hospital before it became the Brigham Women's Hospital.   In 1967, Dr. Chabner became a clinical associate in medical oncology at the National Cancer Institute, where he was, in succession, a senior investigator in the laboratory of clinical pharmacology, chief of the clinical branch of the clinical oncology program, associate director of the clinical oncology program, and then he succeeded Dr. Ben [? Stabida, ?] someone I have previously interviewed for this series, as director of the division of cancer therapy.   In 1995, after 25 years at the NCI, he moved to Boston as the chief of the division of hematology oncology and the clinical director of the Massachusetts General Hospital Center, where he is now the clinical director emeritus. Dr. Chabner has authored, I counted, over 500 peer reviewed papers. I think even more than that. By the way, his first was in 1969, a case report of shaking chills related to occult lymphoma, authored with Drs. DeVita and the [INAUDIBLE] of the [INAUDIBLE] syndrome. Bruce, that really shows how old you are.   He's been the editor of all five editions of the Principles and Practice of Cancer Chemotherapy and Biologic Response Modifiers, which I consider the bible of cancer pharmacology. And I'm looking at my fifth edition on my bookshelf right now. He's trained too many Fellows for me to name, but numerous of them have gone on to be cancer center directors, chiefs of division, department chairs, and other leaders of oncology in the world. He's won way too many awards me to go through, but he received a Karnofsky award from ASCO, and he served on the ASCO board of directors.   Dr. Chabner, welcome to our program.   Nice, that's a lot of history. It speaks to my name.   Well, that's the problem of interviewing all of you folks. It takes a long time to get through all the things you've done. It's a good problem to have, though. First, I want to start out, I understand you carry the flag rank of rear admiral. And I want to know, have you ever even been on a ship? And more importantly, did you and Dr. Shelby actually serve together in the Revolutionary War? I couldn't figure that out.   You know, I never bumped into him when I was on the battleship Shelbyville, but who knows. He seemed to be what I call a name dropper. He left his name on so many different things, and I think there's a Shelby County, Tennessee, which is Memphis. Plus I think the smallest thing that he ever created was Shelbyville, Illinois, which was even smaller than your hometown.   Yep, that's true. All right, that's the last joke I'm going to tell in this interview, but I like that connection. Anyway, so how did a guy from Shelbyville, Illinois get to Yale and then Harvard and NCI? And more importantly, what made you decide to be an oncologist? I know your father was a general practitioner, but at that time the field barely existed. What was your motivation?   Well, OK, I'll tell you a bit of a story. My mother came from Chicago and she had a brother who was pretty smart. And he went to Harvard. And he used to come down to Shelbyville because he liked the pies that she made. And we were 200 miles south, so it was a trip for a pie, but anyway we used to play chess together. And when he was a college student and I was like in fourth grade, I beat him in chess and he said, Jesus, you ought to go to an Ivy League school. So that put the idea in my mind.   And then my parents were not really happy with that. They wanted me to go to Washington University or University of Illinois, but I wanted to get away from home. It was a little bit confining to be around my parents for the rest of my life. So I applied to Yale, Harvard, and Princeton, and the deal was I could go to school if I got a scholarship. So I got a scholarship to Yale, so I went there. I was happy with that choice. I really-- it was sort of, you know, life changing, actually. Stayed on the east coast.   But I still have many good friends from my Shelbyville days. We all get together once a year to play golf and poker and tell life stories.   So I have to interject. My father told me I could go to any college in the United States as long as the tuition was the same as in-state tuition of Indiana University, which at the time was $400 a year. So I ended up going to Indiana University. So how did you--   That was such a great deal. Yeah, that was my--   How did you get into oncology?   Well, when I was at the Brigham, I got interested in cancer. There was not much going on there, but one of my residents was a guy named Jack [? Moxley, ?] who had been a part of the initial study with DeVita and others, George [? Kinellas, ?] of the mop treatment for Hodgkin's disease. And I got really interested in that. And actually during my internship my sister got an immediate stromal tumor during her pregnancy, and it turned out to be a thymoma. But cancer really intrigued me at that point.   And we all had to apply for positions at NIH as a way to get out of the draft, and I wanted to do research, so that really appealed to me. And I actually applied for cardiology and cancer, and I was interviewed by Gene Brown for cardiology, and he didn't seem very impressed. But the cancer people did like me, particularly George and Vince, who had come back there. And they were young and energetic and they had interesting ideas about combination therapy, so I ended up in oncology.   Yeah, I talked with some of the other people I've interviewed about the so-called era of the yellow berets and how that really transformed medicine, in my opinion. Because so many smart people went to the NIH to stay out of Vietnam. It's probably the only good thing that came out the Vietnamese war, as far as I can see, and especially the NCI. So when you went to the NCI, [? Harlan ?] and Frye and [? Freirach, ?] I believe, were gone. So you've already started to say, it sounds like Dr. DeVita and Dr. [? Kinellas ?] were the movers and shakers at the time. Is that fair, or?   Yeah, well they were really young. I mean, it was like working for, you know, contemporaries. There were no old people there. And Frye and [? Freirach ?] weren't that old at that time. They were in their 40s with Vince and George, who were in their mid 30s. And I was 28 years old, I guess, when I went down there. I loved it. We had laboratory opportunities, we had patients, we had people that believed that they could change the way cancer was treated. George and Vince, particularly Vince, were so energetic and so committed to the idea of changing therapy, and particularly combination therapy.   And then the other thing that made it such a great experience were the colleagues that I had in my first group of clinical Fellows. Bob Young was part of it, and I became very close friends with Bob Young. And in the same group, David Livingston was my next door neighbor, and we had interned together and been arrested together. So we had just constant stimulation from a lot of different people, all of them energetic and interested in research.   Who else was in your class besides Dr. Livingston and Young, then?   Phil Shine, who made a name for himself in toxicology and then in industry. And let's see--   He was director at the cancer center at Georgetown for a while.   Georgetown, right. Subsequently, there was just a long list of wonderful Fellows. When I came back, I actually spent two years at Yale between my NCI time and then coming back to NCI. And I had a wonderful time with Joe Bertino. He was, I think, very important to me, because he was really a great scientist. And I learned a lot about biochemistry enzyme purification and working in the lab.   And so when I came back to NCI I had sort of converted to being an anti-folate person from being interested in alkylating agents. And so I was always interested, I guess, in anti-metabolites. But that was a great anti-folate experience with Joe, high dose methotrexate. It was really his idea, not mine. But the thing I worked on was the clinical pharmacology and trying to figure out why it was so toxic to kidneys. So we actually did some really interesting experiments.   We gave high dose methotrexate to monkeys, and then when they died, we took the kidneys out and looked at them. And we were doing it because we thought we would see interesting pathology. What we saw were a bunch of yellow gravel in their tubules. And it turned out it was methotrexate, and it became obvious what was happening. The drug was precipitating in the acid urine environment. But that was sort of the beginning of the methotrexate studies.   And personally, I don't think we teach pharmacology very well anymore. What made you want to go to high dose methotrexate?   Well, interestingly, I was particularly interested in-- Joe was trying head and neck cancer. There was almost simultaneously an article from Frye and Isaac [? Jurassi ?] about adjuvant therapy of osteogenic sarcoma. And there were several interesting things about that. One is that it turned out that 12 patients weren't all patients with osteogenic sarcoma. But prognosis of those patients wasn't apparently obvious.   But there seemed to be some success with it, and there was a lot of toxicity that they didn't really know how to deal with. And so I started doing pharmacokinetic monitoring in patients that we had that were on the treatment. And then when they went into renal failure, they just didn't clear the drug. The drug was hanging around for many days and they were getting this horrible toxicity. So we got into this business of why the renal toxicity and the need for hydration and alkylization, particularly.   And so first of all, I have to tell you I blamed you for much of my first year as a Fellow, because we had to draw the blood. So there were no study coordinators. Dr. Frye would just run around at all times of day and night drawing blood on patients for getting high dose methotrexate. And I still mumble under my breath when I hear your name.   Well, you don't have to do all of that now, but you know, in those days we were trying to get a more complete profile, so we did. There was a woman there at the Farber that was doing similar work. I can't remember her name.   Sue Pittman I think, right?   Yeah, Sue Pittman. That's right, that's right, that's right. But that was certainly the introduction to the anti-folate. And then I got into a very interesting area of polyglutamation and how it changed the potency of the drug and led to retention, and it was an important determinant of response. That was quite an interesting area of research.   Were you the first to report amplification of DHFR? No, that happened in 1978. I was working on MTX at the time and we had noticed that you could select highly resistant cells in culture. But then we were interested in knowing why, and Joe and Joe Bertino had described the fact that increased dihydrofolate reductase activity was found in this circumstance. But the actual demonstration of amplification in mammalian cells was done by Bob [? Shimke ?] when Joe was on a sabbatical with him.   And they had a medical student working in the lab on that on that paper, and that was Dan [? Haber ?] actually. Who came back to--   Who is now the cancer center director [INAUDIBLE], right?   Yeah, he wrote a key paper. So we had, at the time when that came out, we got interested in that. And we stuck radiolabeled methotrexate in the culture with some tumor cells and found these odd migrating entities that turned out to be polyglutamate. So that led to the whole issue of what were polyglutamates and how did they change the biochemistry? And that was quite interesting, and then actually at the same time we saw a patient.   It was a young man who came to NIH with non-Hodgkin's lymphoma and was treated with high dose methotrexate. I can't remember. I think he had CNS involvement or something like this. We found evidence of gene amplification in this patient. So it was actually the first demonstration that gene amplification occurs in people on the drug. There are a lot of interesting things that were happening at that time.   How was translational medicine before it was called translational medicine?   That was the nice part of NIH, you know? The emphasis was on the labs working with the clinics, and particularly with physician scientists. So, you know, we were one of the few places where our Fellows were expected to work in labs in their second and third years, and they did, and we had a wonderful group of Fellows that came through. The first guy that worked on polyglutamation of MTX was Rich [? Shilske. ?]   Who is now the chief medical officer of ASCO, and many, many other accomplishments after that.   Right. But many--   Actually, I'd like to change gears for a minute, because I know you had a lot to do with the development of paclitaxel. And I always found that story interesting that, you know, it was in the bark of the Japanese yew tree, which had to do with ultimate supplies. But also the first phase one trials, which some of that was done at the Dana Farber when I was there. Can you just walk through the history of paclitaxel? I think our listeners would love to hear this.   Well, it was an accident of history. Believe me. The thing started in 1964, when a group at the research triangle, a chemist, isolated this compound from the yew tree. And they didn't actually know what it was, but it was cytotoxic. And it was an anti-mitotic, and it took him seven years to figure out the structure. So finally in 1971 a guy named Ronnie from that group published the structure. It was a ridiculously complicated structure, And nobody could synthesize it, at least at that point.   It hung around in the lab and nobody was interested in developing it, because it was such an odd molecule. It was insoluble. Nobody can put it in solution. So it really wasn't an attractive pharmaceutical. And the thing that happened was, in 1978 or 1979, we had a very hot drug that was called maitansine. And we were very eager to put this into the clinic. And it was an anti-mitotic also, and very, very potent drug.   And so Dr. DeVita asked me to personally shepherd this thing and he told me that he didn't want it to fail. And so I put it into patients and it was terrible. And I kept telling him, this is not going to work. He said, it's got to work. He was pretty persistent. Well, it didn't, and he was very disappointed. So was I. And the fact is, we had nothing else to put in the clinic at that time except for paclitaxel. So we said, oh, well, we'll try it.   And we put it in a lipid emulsion. It was like putting it in engine oil or something, but it went into the clinic in several places. Peter [? Wernick ?] did it. Einstein. I guess you guys did it at the Farber. And it was causing all sorts of hypersensitivity responses. It looked impossible. And it took about, I don't know, four or five years to get it into a regimen that was tolerable. And there had been responses. The first response was in melanoma, so we were all excited about that.   That was the usual circumstance in those days that, when you took a drug into the clinic, melanoma would be the first response. And no one else from melanoma. Everywhere was-- and so but then Peter began noticing responses in ovarian cancer. And a regimen was worked out with antihistamines so it was reasonably tolerable. And finally in 1991, which was eight years after it went into the clinic, we finally decided, well, it was time to license it to industry. There was no patent, but we did it under a co-operative research and development agreement.   And the only company that was interested in the US was Bristol-Myers. Everybody else said, this is ridiculous. Nobody wants this drug. And it was too hard to make it. You had to make it from the bark of plants and it was insoluble and it caused hypersensitivity. So they took it. And about a month afterward there was a report from M.D. Anderson saying that it was active in breast cancer. And at that point it just took off like a rocket. And, you know, tried in all sorts of different diseases. Was active in lung and bladder and-- I can't remember all the other things. Head and neck.   Anyway, it became the first billion dollar drug in the cancer drug industry. And I think, you know, there are two things that really set off industry to be interested in cancer. One was that, the fact that you could actually make money on it. And the second was the notion of targeted therapies, which was growing at that time.   So to my knowledge, this is the only time somebody at the NCI had to work with the US Forest Service and the Bureau of Land Management regarding a new drug. Can you tell that story?   Well, yes. The only place where you get the raw material for the drug was from the US Forest Service. And so Texas plants were being sort of cut and burned because they were considered scrub and not worth anything as lumber. So they were cooperating. And finally when we licensed it, Senator Ron Wyden, who's still in the Senate from Oregon, got interested in this whole thing. He said, why isn't the government making money on this license? Why did you license it to Bristol-Myers and you didn't you didn't ask for anything back?   And we said, well, you know, that's not the function of NIH. We didn't have a patent. I guess we could have asked for a slice of the pie, but we didn't because no one else wanted it. We really were trying to give it away. And he was giving us a really hard time at this hearing. And then the key thing that happened was a woman who was a forest ranger with ovarian cancer, we found this woman, and she testified to how much good it did for her. And that sort of stopped all the fuss about the license.   And we actually, it was the first drug where as part of the licensing agreement we had the chance to fix the price or agree to the price that Bristol-Myers fixed. And the government never has done that since that time. Of course, this was a circumstance where we sort of owned the information, so they had to listen to it. But they set the price at $2,000 a course. And we consider that pretty high, but it was sort of equivalent to what other drugs were costing at the time, so we let that go by. But ever since then, the price of drugs has just escalated remarkably.   I hope there are some young people listening, because this story, in my opinion, the story of trastuzumab again, I think people think that these things just happen because the system makes them. And my experience is they happen because the drug or the treatment gets a hero, gets a champion. Ultimately the science has to prove it works, but I'm sure lots of people wanted to walk from Taxol.   You know, everybody thought it was a dog. Because it was, you know, caused hypersensitivity, it wasn't all that active in the initial testing, and it was really hard to make the stuff.   Well, the same thing is true with platinum I did my residency at UT Southwestern with Donald Sullivan, who's the chair of medicine. He was a renal guy, and a patient with metastatic-- and I had gone to Indiana. So Dr. [? Einhardt ?] taught me how to give it. So I had a patient come in with widespread testicular cancer, I wanted to give him cisplatin, and Dr. Sullivan wouldn't let me do it because it would hurt his kidneys. I said, Dr. Sullivan, he's going to die if we don't do this. And he said, he'll die anyway.   And so I did it behind Dr. Sullivan's back and I got a complete response. Fortunately in those days the residents didn't have a lot of oversight so I could do what I wanted to do. There were a lot of people that thought these drugs should be shut down, and it took the courage that you guys had back at the NCI and other places to push them out.   Don Sullivan was very anti cancer chemotherapy for the rest of his life. And it was odd for me, because I actually had a relative who was on his faculty and I went down there a couple times to talk. And I always felt very uncomfortable telling him that we were accomplishing something. Because his concept of success in science was getting an RO1 in your lab.   Yeah. He finally came to terms because [? Shelfke, ?] myself, Fred [? Lemaitre, ?] and a number of us went into oncology and had been reasonably successful. And I think he decided that it was worthwhile after all. But it wasn't easy for him. We lost him a year ago. I still miss him.   Yeah, he was an amazing guy, but he really did have a hard time believing in cancer.   So the other question, I wanted to change gears a little bit, because I know just about the time you became the director of the DCT was when the AIDS epidemic was exploding in the early 1980s. That must have been a very confusing situation about who should be in charge of this at the NIH, which institute, and how you approach it. Can you give us some background on that?   Again, it was really a crazy time. Because I remember one of the first patients that was identified as having AIDS was a person admitted to the immunology branch at the NCI. Not the medicine branch or the clinical branches. It was a patient who had disseminated tuberculosis and it had no CD4 cells. And, you know, everybody said, oh my god, what is this? This is really a weird, weird circumstance. And then other people began reporting this from San Francisco and New York.   So we actually, DCT, the reason we got involved was because of Bob Gallo. Bob Gallo had discovered the HTLV1 virus, which was causing this lymphoma in T cells. And we suspected that this might be a syndrome caused by a T cell virus. So in 1981, really quite early, we convened I think the first meeting about the biology of what was called HTLV2, I think, at the time, or three. I can't remember which one it was. But at any rate, there were a cadre of people at NIH that felt that it was caused by inhaling gases or, I don't know, their various weird theories about it.   But this theory that made sense to us was that it was caused by a virus. So Sam [? Brodeur ?] was collecting samples from patients and brought them over to Gallo's lab. And of course Gallo mixed those samples with the French sample and found virus and then made a test kit for the virus, which was really a key event in beginning to control the epidemic. And because of all that work going on at NCI at the time, we were asked-- we had the only drug development system at NIH.   We were asked to, well, look, can you set up a drug development system for this? And Sam [? Brodeur ?] set up assays in infected T cells and showed that certain nucleocyte analogs could stop the virus from replicating. The first one was ADT. And his first study was, I think, was 16 patients with AIDS in which he showed that the T cell counts recovered and people didn't die. And from that point on, we were getting significant funding for doing research on treatment development. And it was it was done in conjunction with NIAID and Tony Fauci.   What Tony did is he delegated a fellow to work with us and sort of be the liaison. And the first fellow that did that was Margaret Hamburger, who became [INAUDIBLE] FDA subsequently. And, you know, subsequently, four other people from our division-- well, actually one from NGH, became directors of FDA. Ned Sharpless most recently, and then Steve Hahn, who was a Fellow in the medical oncology group at NCI.   Yeah, he's just been named.   It was, you know, an unusual breeding ground for people interested in therapeutics.   That's interesting. You know, I was a third year resident at UT Southwestern. I was at the VA in March and a young man was admitted to our service. He had been a Vietnam veteran and he had red splotches all over him, so I called a dermatologist who biopsied it. And I got a page from the pathologist and I called him back and he said, you have mislabeled the samples. And I said, what do you mean? He said, well, this says it's a 37-year-old man. This is something I've never seen before, but I looked it up and it's called Kaposi sarcoma, and that only happens in old men or people from Africa.   And I said, I don't think we mislabeled things. And I think he was probably the first man in Dallas to be diagnosed with this. Because just as the MWR and the new journal paper came out a few months after that. So again, for the young folks listening to this, and we've already hit this a couple of times, it's one or two patients that pique your interest that often change the world in terms of, gee, I wonder why that happened.   Yeah, absolutely. I mean, you know, a lot of this is an outcome of the fact that you have research people as physicians who are working with patients, and then they ask questions.   Yeah. One of the things I've carried forward, Dr. Frye used to always say, think like a scientist. Think like a doctor. And ask yourself, so what? And I know you do that, because again, you've already told us today and I've seen you do that in other places. You know, so what? Why did this happen to this patient?   Why did that happen, yeah.   What in my lab actually will change that? And you guys did that in spades, I think, 40, 50 years ago. It's pretty amazing.   Yeah. Well, I [INAUDIBLE].   [INAUDIBLE]. Go ahead. Go ahead.   No, it's really happening a lot now, you know, in terms of recognizing subsets of diseases. We used to think that non-small cell lung cancer was just one disease. Now it's 20 diseases. It's amazing, you know? It's amazing, you know, as science progresses, you begin to understand the complexity of cancer. And then therapies become meaningful.   Yes, I agree.   It's so nice. And so I wish, you know, we were curing people. But we are making a difference, and least we're understanding it a little.   I agree. Anyone who has not heard or read Bruce Johnston's ASCO presidential address should do so. Because he did point out exactly what you just said. He had a pie chart, and 10 years ago the entire pie chart was chemotherapy for metastatic non-small cell lung cancer with little or no success. And now the pie chart is well over half the patients getting some kind of targeted or immunotherapy. Yeah, it's pretty amazing.   It is quite [INAUDIBLE] for young people that are listening to this, is that there are enormous opportunities for doing even better than we did. So we just made a start in this whole thing.   OK. With that inspiring message, which I'm glad you said it, we've run out of time. Actually we come at the end of our time. But Dr. Chabner, I want to thank you on behalf of all of us who trained after you, who've learned so much from what you've done, and more importantly, the patients who have benefited from the stuff that you've contributed to the field. It's pretty remarkable and inspiring. I don't use that word too often, but it is. So thank you, and thank you for taking time today. I hope folks listen to this and say, I'm going to go back and make a difference here.   Thank you, Dan. I have enjoyed it. It's been a wonderful time in this career.   Yeah. Well, my pleasure. Until next time, thank you for listening to this JCO's Cancer Story, the Art of Oncology Podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.ASCO.org.

Shannon Wiltsey Stirman, PhD, of the Department of Psychiatry and Behavioral Sciences at Stanford University Medical School and is Acting Deputy Director, Dissemination and Training Division, National Center for PTSD. She’s a leading researcher in the area of disseminating evidence-based therapies. As part of this, she juggles two RO1 research grants from NIMH, working with multiple teams, and having team members scattered across the US and Canada who are conducting research in various settings. She balances all of that with being married with three kids…and carves out time to keep up her running. In today’s episode, we dive into how stays organized with her various projects and how she deals with the messiness of dissemination research that involves intense involvement with front line providers and sites. She also talks about how to vet collaborating organizations in the community and how to look for win-win collaborations for those you work with. We also discuss her perspective on open science and the need to stay nimble when it comes to data collection. You’ll also hear Dr. Wiltsey shares tips for squeezing in time for writing, her tips for finding work-life balance, being led by what is exciting for you, and her advice for graduate students. The opinions expressed by Dr. Stirman on this podcast are solely her own and do not express the views or opinions of her employers.  Some abbreviations mentioned in the episode: CPT – cognitive processing therapy IPV – intimate partner violence DBT – dialectical behavior therapy CBT – cognitive behavioral therapy In this episode, you’ll learn… How Dr. Wiltsey manages various groups and teams across multiple settings How she deals with bureaucracies from multiple organizations How to form teams and foster win-win collaboration How to determine if a site is a good match for your study How to deal with the messy realities of research Wiltsey’s perspective on open research Tips for getting your writing done Tips on work-life balance Wiltsey’s advice for grad students   Tips from the episode On how to how to stay organized across project and teams… Distribute the work. Host once-a-week team calls. Take detailed notes and document all decisions made. Reach out when you need something. Don’t be afraid to tap into the expertise of others. Respect team members’ time. Only pull them in when they’re really needed. On writing... Utilize time on flights. During your writing time, don’t turn on Wi-Fi. If you need to look something up, make a list or leave a comment and do it later. Utilize time in the evenings if the rest of the family is occupied or asleep. Take advantage of the times in the margins of your day.  On work-life balance... Prioritize family dinner. In general, don’t schedule activities for the kids around dinner time. Carve out time for exercise. Only work on weekends if the rest of the family is busy. Take a day or a half-day off Delegation is critical.

Dr. Panigrahy is board certified in both Pediatric Radiology and Neuroradiology.  He is a Professor of Radiology, Radiologist-in-Chief at  Children’s Hospital of Pittsburgh and Vice Chair of Clinical and Translational Imaging Research at UPMC. He has been continuously funded by the NIH since 2009 including both a K23 and current multi-center Ro1. He also has active funding from the Department of Defense, Society for Pediatric Radiology and private foundations.  Dr. Panigrahy’s research focuses on applying advanced MR techniques to the study of fetal/neonatal/pediatric brain development and injury in those diagnosed with congenital heart disease and its impact on neuro-developmental across the lifespan.

Cindy S.H.:                         Hi. Welcome to Discover CircRes, the monthly podcast of the American Heart Association's journal Circulation Research. I'm your host, Cindy St. Hilaire, and my goal is to bring you highlights of articles published in the Circ Research Journal as well as have in-depth conversations with senior scientists and the junior trainees who have led the most exciting discoveries in our current issues. Today is our premier episode, so I want to take some time to introduce myself, give you a little bit of background about the history of the journal, and then have a conversation with our new editor in chief, Dr. Jane Freedman, and my social media editor partner in crime, Dr. Milka Koupenova. Cindy S.H.:                         First, a little bit about me. I'm an assistant professor of medicine and bioengineering at the University of Pittsburgh. My lab is part of the division of cardiology and we're also a member of the Pittsburgh Heart, Lung and Blood Vascular Medicine Institute. I'm still a relatively new PI. I'm still learning as I go. One of the strengths of being a new PI in the current time is the amazing network we have through social media, whether it's through listening to podcasts or through Twitter or through select groups like one of my favorites, New PI Slack. Really one of my personal goals of starting this podcast for Circ Research is to have a career development angle. Because career development is so fresh in my mind and it's really something I want to incorporate into this podcast, we're hoping we can reach out to more junior trainees through these mediums. Really that's the impetus for Dr. Freedman wanting to have specific social media editors at the Circulation Research Journal. Cindy S.H.:                         I'm very honored to be the first host of this podcast and I'm very excited for this opportunity. As a team, Milka and I hope to expose the larger community to not only the most current and exciting discoveries in cardiovascular research but also a behind-the-scenes look of what it takes to get high-impact research done and published and planned and funded, and also talk about some of the maybe the non-bench aspects of this job, the networking, the behind-the-scenes look that really you learn on the fly as you go. Hopefully we can expose more people to these on-the-fly things in a slightly more rigorous manner. Cindy S.H.:                         Before I go into the articles summarized in this week's podcast, I want to give a very big thank you to Ruth Williams. Ruth is the person who writes the content of the In This Issue which is featured in every issue of the journal Circulation Research, and that content is extremely helpful in deciding which articles we're going to focus on in this podcast and also for helping me form the conversations and discussions. Thank you, Ruth, for all your hard work. Cindy S.H.:                         Now I'm going to highlight three articles that were featured in the June 21st issue of Circulation Research. The first is entitled Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality: A 30-Year Prospective Cohort Analysis. The first author is Jiaqi Huang and the corresponding author is Demetrius Albanes , who are both at the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, which is at the NIH in Bethesda, Maryland. Alpha-tocopherol is the more formal name for vitamin E, and vitamin E is an essential fat-soluble vitamin. By essential, that means that while your body absolutely needs it, it does not produce it itself. Therefore we need to consume products containing vitamin E. We do that by eating vegetable oils, nuts, seeds, whole grains and certain fruits and vegetables. Previously, population-based studies have shown inconsistent associations between circulating vitamin E and risk of overall death or death due to specific diseases such as cancer and cardiovascular disease. Cindy S.H.:                         To look more closely at cause-specific mortality, Huang and colleagues studied a cohort of close to 30,000 Finnish men, which is a huge study. Added to that, these men were in their 50s and 60s at the start of the study and then continued for the next 30 years of their life to be in this study. It's frankly an amazing achievement to keep that many individuals enrolled. From approximately 24,000 deaths, so about 80% of the original cohort, the authors adjusted for factors such as age and confounding things like smoking. They found that vitamin E levels were inversely associated with the risk of death from a variety of causes. What that means is that higher levels of vitamin E associated with lower risk of death. All of those causes of death that they found were cardiovascular disease, heart disease, stroke, cancer, and respiratory disease. This large prospective cohort analysis provides very strong evidence that higher vitamin E levels means greater protection. Cindy S.H.:                         It's really interesting to note though that this data did not seem to associate with a reduced risk of death by diabetes or, for that matter, injury and accidents, which I guess kind of makes sense. The authors say these results indicate that vitamin E may influence longevity, but they also highlight the need for further studies, specifically in more ethnically diverse populations and of course in women, because we all know a major limiting factor of a majority of cardiovascular studies is the fact that often there are just not enough women in these studies. But really that's a push now to include not only women but more ethnically and geographically diverse populations. Cindy S.H.:                         The second article I want to highlight is titled Mitochondria Are a subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells . The first authors are Florian Puhm and Taras Afonyushkin , and the senior author is Christopher Binder. All three are in the Department of Laboratory Medicine, the Medical University of Vienna, in Vienna, Austria. This group is also part of the Research Center of Molecular Medicine of the Austrian Academy of Sciences. Cindy S.H.:                         I want to talk about this paper because I found that title extremely provocative. Extracellular vesicles or microvesicles are small particles that can be released from cells. These particles can act as cell-cell communicators. They can hold a variety of substances such as proteins and micro RNAs and minerals and all sorts of things that are derived from inside the cell. The matrix vesicle is then budded off. Matrix vesicles released from monocytes after bacterial LPS stimulation, so a stimulus that induces an inflammatory response, these matrix vesicles have been shown to contain mitochondrial proteins. Mitochondrial DNA-containing matrix vesicles have been reported in the mouse model of inflammation. From this premise, from these prior studies, Dr. Puhm and colleagues hypothesized that the mitochondrial content of matrix vesicles might actively contribute to pro-inflammatory effects. Cindy S.H.:                         What they then did was show that monocytic cells release free mitochondria and also matrix vesicles that contain mitochondria within them. These free and matrix vesicle-encapsulated mitochondria were shown to drive enothelial cells to induce inflammatory cytokines such as TNF-alpha and interferon. These circulating matrix vesicles were collected also in human volunteers that were injected with this same inflammatory substance, LPS. These circulating matrix vesicles isolated from humans also induced endothelial cell cytokine production. Very interestingly, inhibition of the mitochondrial activity drastically reduced the pro-inflammatory capacity of these matrix vesicles. Cindy S.H.:                         Together, this result suggests that the released mitochondria, whether it's free or whether it's encapsulated in a matrix vesicle, may be a key player in certain inflammatory diseases. This study shows that in addition to their central role in cellular metabolism, mitochondria, whether encapsulated or free, can actively participate in an inflammatory response in a cell other than the cell it was native in, which is just intriguing to think about. This work provides new insight to the contribution of mitochondria to the content and biological activity of extracellular vesicles. It also might suggest that perhaps targeting mitochondria and their release may represent a novel point for therapeutic intervention in inflammatory pathologies. Cindy S.H.:                         The last article I want to highlight is titled Macrophage Smad3 Protects the Infarcted Heart, Stimulating Phagocytosis and Regulating Inflammation . The first author is Bijun Chen and the senior author is Nikolaos Frangogiannis . When tissues are injured, there is localized increase in the cytokine TGF-beta. However, depending on conditions, this TGF-beta can function to stimulate macrophages to adopt either pro-inflammatory or anti-inflammatory phenotypes. To complicate matters more, the signaling pathway for both the pro- and anti-inflammatory phenotypes involves activation of the intracellular signaling protein Smad3. Inflammation, whether too much or too little, can influence the outcome of injuries, including injuries such as myocardial infarctions. An infarction, for those of you unfamiliar with the term, is a localized area of dead tissue and that results from a lack of blood supply. In this case, an infarction, a myocardial infarction, is essentially a heart attack that stops blood flow through the coronaries and causes death in the cardiac tissue and cells. Cindy S.H.:                         The authors hypothesized that in the infarcted myocardium, activation of TGF-beta and Smad signaling and macrophages may regulate repair and remodeling. They had a very specific question about a very specific cell type in the context of the whole heart. To address the role of Smad3, they utilized mice that were engineered to lack Smad3 in the myeloid lineage which produces macrophage cells. They found that these mice with myeloid cell-specific deletion of Smad3 had reduced survival compared to control mice. Additionally, the hearts from the animals with the myeloid cell-specific deletion of Smad3 exhibited increased adverse remodeling and greater impairment of function. That's a really interesting finding. The heart tissue itself was the same. All that was different were the cells of the myeloid lineage. Then to dig after what cells were mediating this effect, the investigators moved on to in vitro studies. They found that Smad3-lacking cells themselves showed reduced phagocytic activity, sustained expression of pro-inflammatory genes, and reduced production of anti-inflammatory mediators when compared with control macrophages. Cindy S.H.:                         In summary, these results suggest Smad3 is necessary for macrophages in the area of the infarction to transition to an anti-inflammatory phagocytic phenotype that protects against excess remodeling. However, we cannot go after global inhibition of Smad3 as a potential therapy post myocardial infarction, and that's because inhibition of Smad3 in cardiomyocytes is actually protective against the infarction. Inhibition in a macrophage is bad, but inhibition in a cardiomyocyte is good. Any potential Smad3-modifying therapies really needs to be designed to be cell type-specific and be able to be deployed to activate that cell type. Cindy S.H.:                         In addition to science, I love history. I thought I would take this opportunity of the first podcast to share with you a little bit of history about the Journal of Circulation Research. Circulation Research is now in its 66th year, but its origins can be traced to 1944. That was when the AHA established a council that was attempting to organize its research arm and its professional program arms. The AHA journal Circulation was already in existence, but in 1951 the executive committee decided to launch a basic research supplement, and it was called just that: Circulation Basic Research Supplement. But a few years later, Circulation Research was to be its own publication because of the interest and the excitement around the basic research supplements. The quote that I'm going to read is from that first executive committee meeting and there they wanted Circulation Research to be the authoritative new journal for investigators of basic sciences as they apply to the heart and circulation. Cindy S.H.:                         It's a fun little subgroup that they list after that. They list in anatomy, biology, biochemistry, morphology, which I just think is so neat to think about, pathology, physics, pharmacology, and others. It's interesting to think about what that would be today if we were now finding this journal. Biochemistry, genetics, molecular biology. It's fun to think about how much science has changed since they began this journal. Really the broader goal was to integrate and disseminate new knowledge. Leading that was Dr. Carl Wiggers, who was the first editor in chief of Circ Research. At the time, he was the head of physiology at Western Reserve University, and he's often referred to as the dean of physiology, as his research really provided much of the fundamental knowledge regarding the pressures in the heart and the vessels of the body and how they interact. Cindy S.H.:                         I actually went back and looked at some of the first titles in Volume One, Issue One, of Circ Research. It's really kind of neat. Some of them could be completely relevant today. I'm just going to read a few. Nucleotide Metabolism and Cardiac Activity, Fundamental Differences in the Reactivity of Blood Vessels in Skin Compared to Those in the Muscle. That was at the VRIC the other day. Haemodynamic Studies of Tricuspid Stenosis of Rheumatic Origin. Reading these for the first time I actually got chills because my two themes of my lab are both in that first Volume One, Issue One, of that journal. I study the extracellular nucleotide aCD73 and its impact on vascular homeostasis. I also study calcific aortic valve disease and are hugely curious about the role of inflammation and things like rheumatic heart disease in the progression of the disease. It's amazing how much science has changed, but yet how so much has stayed the same. Cindy S.H.:                         Dr. Wiggers wrote a few gems, a few quotes in his biography that I want to share with you. I find them inspiring and also humbling. The first is, "Research is a gamble in which the laws of chance favor the loser. The loser must remain a good sport," which I think is perfect to think about in science. I really wish I had read that after my first RO1 was triaged. The next two are more about the science writing and I think they're great not only for when we're thinking about papers but also grants. The first is, "Readers are greatly influenced in their judgment of a research project by literary style. A poor presentation can easily damage the best investigation," which is so true. No matter how good your science is, if you can't communicate it, it doesn't matter. And lastly, "A good paper, like a good glass of beer, should be neither largely foam nor flat. It should have just the right amount of head of foam to make it palatable." Cindy S.H.:                         With these nuggets of wisdom, we're now going to talk with Drs. Jane Freedman, who's now the editor in chief of Circ Research, and Dr. Milka Koupenova, who is the social media editor. Before I really introduce Jane, I want to recognize all of the former editors in chief of Circ Research, Dr. Carl Wiggers, Dr. Carl Schmidt, Dr. Eugene Landis, Dr. Julius Comroe, Dr. Robert Berne, Dr. Brian Hoffman, Dr. Francis Abboud, Dr. Harry Fozzard, Dr. Stephen Vatner, Dr. Eduardo Marbán, Dr. Roberto Bolli, and now Dr. Jane Freedman. Welcome, Jane. Thank you so much for this opportunity and congratulations on your new position. Dr. Freedman:                   Thank you very much. Cindy S.H.:                         I was wondering if you could just introduce yourself to the listeners and give us a little bit about your background. Dr. Freedman:                   Sure. I am the Budnitz Professor of Medicine at the University of Massachusetts, and I originally became interested in a scientific career while attending Yale University where I was both an architecture and geology major. Cindy S.H.:                         Interesting. Dr. Freedman:                   Yes, very interesting. Then, not exactly knowing what I wanted to do, I worked for a year as a research assistant for my later-to-be mentor Dr. Joe Loscalzo at Brigham and Women's Hospital. There one day he sent me up to the intensive care unit and said we need to get a tube of blood from someone who was in the throes of having a myocardial infarction. Really at that point I became hooked. Why was that person having a heart attack, and using their blood how could I figure out whether they would live, die, do well, not do well, or yield new things that might help us cure or diagnose people with heart attacks later on? After that. I went to Tufts Medical School. I did my residency and cardiology fellowship at Brigham and Women's Hospital and the Massachusetts General Hospital. After working at several different places, I have wound up at the University of Massachusetts where I am in the Division of Cardiology and where my laboratory currently resides. Cindy S.H.:                         Excellent. As the new editor in chief, what do you see as your vision for the journal? Dr. Freedman:                   I'm in a very fortunate position to be taking over a wonderful journal from an incredibly dedicated group of editors and associate editors and other supportive editors. Scientific pursuits and reporting and publications are really evolving at a rapid clip, so we hope to have several things happen over the next few years to survive and thrive. The first thing is we hope to define and expand Circulation Research's scientific identity. We want to extend its already outstanding portfolio of science that really demonstrates how elegant basic and translational mechanisms and pathways are part of a greater web of cardiovascular disease and stroke. This will include an increasingly diverse group of basic and translational sciences and they'll touch on both fundamental studies as well as how they translate to human disease. We also want to continue to pursue the excellence that Circulation Research already epitomizes and we want to extend its brand both to an increasingly diverse group of members, both nationally and internationally. Dr. Freedman:                   Circulation Research already has really wonderful publication metrics such as turnaround time, time to review, and we hope to maintain that so as to be a journal of choice for an increasingly growing number of investigators. We would also very much like to have greater interface with the American Heart Association. A lot of the research on our pages is funded by the American Heart Association, and the majority of science that the American Heart Association currently funds is basic cardiovascular science. We hope to have greater interface and help our users of the journal understand what the American Heart Association can do for them and for their scientific pursuits. Dr. Freedman:                   Last and very importantly, we really want to attract early and mid-career investigators to the journal. We already have some really nice programs that the previous editorship has started, such as Meet The First Author, but we would also like to be a site for education of how you can review papers, have a junior editor program and other types of programs that will help early and mid-career investigators in their future. One of the ways we're going to be doing that is to have enhanced social media programs. Cindy S.H.:                         Great. I really like that idea of having the junior editors because I think the best learning experience I had about how to write a grant did not happen until I actually served on a study section, because it was there you actually can understand all of those comments you got on your first grant that was triaged and why they were said. I think that is a key and really important aspect. Dr. Freedman:                   That's a perfect analogy because you want to remove the black box that people think is happening when they send their manuscripts in. There's so many reasons why manuscripts succeed and don't succeed, and we really do want to be as transparent as possible and we do want to educate investigators as much as possible about the process. Cindy S.H.:                         Actually, could you maybe tell us a little bit about that process? I made all my figures, I formatted my paper according to the instructions, I hit submit. Black box. What happens? What's the next step? Dr. Freedman:                   What's the next step? Cindy S.H.:                         What do you do? What does an editor in chief actually do? Dr. Freedman:                   I do have to say that none of this would happen, especially in the incredibly quick turnaround time, if we didn't have amazing support and help in our office that happens to be in Baltimore. The people there are just incredible. They make sure that papers move through. It's really 24/7. Our group has not been at it for very long, but I know Dr. Bolli's group as well as our group, people are handling manuscripts as fast as they really come in. We see the manuscript, they get quality checked. We try not to be too onerous with the first steps. Then typically they go to one of the associate or deputy editors who will handle them to send out for review. Cindy S.H.:                         Is that based on keywords or the title or how is that decided? Dr. Freedman:                   Sometimes it's based on keywords, so careful with your keywords. A lot of times, because each of the associate editors has an area of expertise that hopefully covers what your science is interested in, they will know experts in the field. We very heavily rely on our editorial board. We have an amazing editorial board at Circulation Research, and amazing contributions from the BCBS council. These individuals have over the years and currently provided just tireless and unsung, devoted help to making the journal run smoothly. It's a pretty quick turnaround time. Then the decision made based on the reviews of the article. Occasionally articles come in and they're not suitable for the journal because they're not what we perceive as what our readers would be interested in. Sometimes those articles don't go up for review. We don't want to keep them caught up, so we send them back right away. Dr. Freedman:                   When the articles come back in with the reviews, we're going to be discussing them at a weekly meeting. Other viewpoints will weigh in, and then we make a decision whether it's an accept, whether it's a revise, whether it needs a lot more science. That's called a de novo. Sometimes we think it's more suitable for one of the other 11 American Heart Journals and we might suggest that you consider sending it to that journal and we consult with that journal's editor. Cindy S.H.:                         Interesting. All that happens with about 14 days. Dr. Freedman:                   That's supposed to happen with 14 days. Cindy S.H.:                         It does pretty regularly based on the stats. That's amazing. One of the initiatives you mentioned was really the role of social media. Now I would like to introduce Dr Milka Koupenova, who is the co social media editor alongside me. Before I let Milka talk, I really have to be honest and say that my graduate school days were some of the best of my life. It was in part because Milka I were both in the same lab. We overlapped by a couple of years under the amazing mentorship of Dr. Katya Ravid. Every time we get together, all we'd talk about was how can we be like Katya? Maybe someday we'll actually have a podcast where we can get Katya in here and actually record all her nuggets of wisdom. Dr. Koupenova:                 I think the same thing about Katya. Cindy S.H.:                         How can it be more like Katya? But for now, Milka, welcome. Thank you. If you could just introduce yourself and give us a little bit about your background. Dr. Koupenova:                 Hi, everybody. My name is Milka Koupenova. I am an assistant professor at University of Massachusetts Medical School. Briefly about me, as Cindy mentioned, I did my PhD at Boston University and I studied at that time metabolism in atherosclerosis. Then I had this great opportunity to join this lab in thrombosis that studied these little cell fragments called platelets, which I knew something but not that much about. I joined Dr. Freedman lab as a postdoctoral fellow, and actually my interest evolved to be very much in platelet immunobiology and how platelets may contribute to thrombotic disease during viral infections. Luckily for me, I had two angels that I wanted to be. One of them was Katya Ravid, as you mentioned, and the other one was Dr. Freedman. Both set up a great example of scientists and how to do science in life. Cindy S.H.:                         Wonderful. Excellent. Thank you. I won't lie. I don't know if you feel this way. I definitely feel a little nervous about being a social media editor. I'm talking in a room to a box with a microphone on me and I don't know who's going to be listening. That's also exciting for me too. I get to disseminate all this cool knowledge and share our basic research with this huge audience. What are you most nervous about and excited about? Dr. Koupenova:                 You're doing the podcast, so I don't have to worry about that, that that particular part. I am quite excited actually about everything that's going to surround popularizing the science at Circulation Research. I think in the time that we live in and when social media is a huge part of our life, we definitely need to engage the community, scientific or lay, and communicate our ideas. I'm super excited about the creative part behind how we are going to achieve this via various social medias. Cindy S.H.:                         Can you talk about the platforms that you plan on using? Dr. Koupenova:                 We currently are using Twitter and Facebook. Please follow us on Twitter and Facebook. And we are going to launch Instagram. Find us, follow us, engage us. That will be great. You can always send us messages and like us, retweet whatever you decide. Cindy S.H.:                         Give podcast feedback on Twitter. Nice comments only. Dr. Koupenova:                 We'd like to hear your comments and we'd like to hear what you envision in certain cases when it comes to your Circulation Research, because this is your journal as much as it is ours. We're here for you. In addition to popularize and advertise the wonderful science that we're publishing in Circ Research, we want you to be engaged. We want you to be able to advertise in your own work and to think of it as something that you own and something you need to communicate to the rest of the world. That is one of the things that we want to do. Dr. Koupenova:                 Finally I'm going to echo on what Dr. Freedman said, is we want to attract truly early career and young investigators and help them be involved, help them own their science and help them communicate their ideas. That's pretty much what our social media platform is and we are going to evolve with you. That is perhaps one of the challenges. Cindy S.H.:                         I think one of the most interesting aspects, at least in academia as I see it, is really the role of self-promotion. It's something you're never taught and it's something that you don't really appreciate until you go to that conference. I remember my first conference as a new PI, I was standing there and I'm just like, "Okay, these are all other PIs. How are they all in groups? How does everybody know each other? Why are they all friends already?" It takes a lot of guts and you have to inject yourself. "Hi. I'm Cindy St. Hilaire and I'm new. Please be my friend," essentially, essentially. But it's important and I really liked the fact that when your journal is published you have that little button, share on Twitter, share on Facebook. I think that's really important. It helps you practice that self-promotion and can help really allow you to embrace your extrovert when you know how to. Dr. Koupenova:                 That's exactly what I was going to point out. Scientists or physician scientists, or physician scientists perhaps are a bit better. But as scientists we're very much introverted. But social media gives you a platform that it's not cheesy to popularize and communicate. Then you see those people on conferences and then you have your little group without- Cindy S.H.:                         It's amazing how many Twitter friends I have. "Oh, I met you on Twitter. It's so nice to meet you in real life." Dr. Koupenova:                 It's a new generation. We at Circ Research want to evolve with it. Is that correct, Dr. Freedman? Dr. Freedman:                   That is correct. Thank you very much. Cindy S.H.:                         It's exciting times. I guess maybe this is a question for all of us to talk about, but how do you think we can, number one, attract people to science, attract diverse people to science, and then really keep them in science and how do you think we can use Circ Research and also the social media aspects of Circ Research to do that? Dr. Freedman:                   I think, first of all, people have to see themselves in the journal. The journal, I think the first point I talked about, about being inclusive, inclusive types of people, way people consume science, types of science. We really want people to feel like Circ Research isn't just a journal that puts out scientific papers, but is a forum. It's a forum for them to exchange ideas and it's a forum for them to understand better about their scientific careers. Cindy S.H.:                         Great. Thank you. This has been an amazing first podcast. I'm so happy to share it with the two of you and I'm super excited for this opportunity. Again, Jane, I want to congratulate you on your new position as editor in chief and I can't help but mention as the first female editor in chief. That's a wonderful, wonderful thing. Cindy S.H.:                         You can find us on Twitter. The handle is @CircRes, at C-I-R-C-R-E-S. We're also on Instagram using the same name, C-I-R-C-R-E-S. We hope to hear from you there. Cindy S.H.:                         Thank you for listening. I'm your host, Cindy St. Hilaire, and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.

Nietzsche’s classic line was “what doesn’t kill me makes me stronger.” It’s a nice sentiment, but is it true? Don’t people who were born with advantages do better in life? Isn’t it better not to suffer setbacks? Why would someone want to experience disadvantages or difficulties?Those questions were answered in a recent paper published by Cornell University. Researchers looked at RO1 grant application for the National Institutes of Health, focusing on individuals who just missed receiving funding (“near-misses”) and individuals who just succeeded in getting funded (“near-winners”). Comparing the two groups over the ten years following first submission, results found that near-misses produced work that garnered substantially higher impacts than their near-win counterparts. Researchers concluded,“For those who persevere, early failure should not be taken as a negative signal—but rather the opposite, in line with Shinya Yamanaka’s advice to young scientists, after winning the Nobel prize for the discovery of iPS cells, ‘I can see any failure as a chance.’”It’s beautiful proof that getting what we want isn’t always what we need. Coming up short, getting stuck, getting passed over—this can be fuel. That’s what Marcus Aurelius was saying when he talked about the impediment to action being an advancement to action, how the obstacle can be the way.There’s another study that shows that college basketball teams down a point or two at half-time were actually more likely to win than the team with the lead. Again, because it made them hungry. The struggles gave them something to prove.In any endeavor—creative, business, or grant proposals—we rarely achieve the result we hope for on our first go. Many great artists, entrepreneurs, and scientists have all admitted some version of Einstein’s, “It’s not that I’m so smart, it’s just that I stay with problems longer.” We must adopt and keep that mindset. We cannot let one obstacle, one “near-miss” turn us off the path. Keep at it. Persist. Resistance is futile.

Emeran A. Mayer, MD, Ph.D., David Geffen School of Medicine at UCLA, delivers an informative overview of the brain to gut connection. Dr. Mayer serves as director,G. Oppenheimer Center for Neurobiology of Stress and Resilience (CNSR); co-director, CURE: Digestive Diseases Research Center; and is an experienced professor of medicine, physiology, and psychiatry. Dr. Mayer attended the Ludwig Maximilian's University in Munich, Germany where he received his MD/ Ph.D. Dr. Mayer completed his residency at the Vancouver General Hospital in Vancouver, Canada and his GI fellowship training at the UCLA/VA Wadsworth Training Program. With a lifelong fascination for research, Dr. Mayer has applied his extensive knowledge toward a career studying the clinical and research aspects of brain-body interactions, with a particularly intensive focus on bidirectional communication between the brain and the gut in regard to health and disease.  Dr. Mayer discusses his long career and findings that led to the decision to write his new book, The Mind-Gut Connection. He details particular studies that influenced the material that is discussed in-depth in his books, such as one study that involved testing of individuals who were given a probiotic cocktail and then observed regarding their symptoms and brain function. His surprising findings in this study pushed him to include the gut microbiome in all of his studies thereafter. Dr. Mayer is considered to be one of the world's top expert investigators of the many brain-gut microbiome interactions in GI disorders, with specific regard to functional and inflammatory bowel disorders as well as obesity. Dr. Mayer's exceptional work has been noted worldwide and as such he has enjoyed continual funding for his important research from the National Institutes of Health (NIH) since 1989. The digestive research expert reveals his findings on multitudinous studies of microbial function. He details the use of interventions such as cognitive behavioral therapy (CBT) in his studies, specifically regarding gastrointestinal maladies such as irritable bowel syndrome (IBS) and others. His findings indicated that the CBT was instrumental in improving symptoms for IBS significantly. Dr. Mayer's work concluded that the brain has incredible influence on microbial composition. Dr. Mayer relates how the autonomic nervous system affects the environment of the gut, thus stressors in our lives have a direct impact on our digestive system's functioning, from secretions to peptides, to blood flow, and beyond.  Dr. Mayer speaks about causality and the models that they have studied to explain microbiome disorders. He discusses the circular process in which the brain sends signals to the gut, the back and forth signaling that impacts functioning. Further, he discusses in detail gene expression profiles, proteins, metabolites, etc., and the connections between various elements of his research, as well as the collective research, being done globally in regard to these brain/gut issues.  The neurobiology researcher provides some background on other studies that focus on teaching the brain to send different signals, as well as diet in regard to gut microbial function. Dr. Mayer states that plant-based diets are by far the best diets for functioning, and the microbiome in general, according to epidemiological studies. He discusses how metabolites are affected by diet, and how gut function will revert when special diets are changed or discontinued. He provides detailed information on specific diets and his thoughts regarding them. As Dr. Mayer states, exposure to antibiotics and dietary patterns of pregnant mothers, etc. all impact microbiomes. He explains the differences that exist in the microbiomes of various and diverse populations of people, and how diet can impact our gut functioning rather quickly once changes are made, for example switching from fast food to a Mediterranean diet, etc.  Dr. Mayer is the director of the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, and is currently PI of a NIH Center grant on the sex differences in functional GI disorders, on a consortium grant of brain-bladder interactions, and a RO1 grant on brain imaging in IBS. As a leading expert in microbiome studies, Dr. Mayer seeks to continually dig deeper into the connections between the brain and the gut in his quest to find new ways to improve health for everyone. 

Jane Ferguson:                Hello, I'm Jane Ferguson and you are listening to Getting Personal: Omics of the Heart, the podcast from Circulation: Cardiovascular genetics, and the functional genomics and translational biology council of the AHA. This is episode ten, from November 2017.                                            November is always a big month for AHA and the annual Scientific Sessions were held in Anaheim, California, November 11th through 15th. For those of you who were able to attend, hopefully you came away feeling refreshed and invigorated and with your desired level of Disney merchandise. For those of you who could not attend, or who didn't make it to all of the genomic sessions, this month's episode should catch you up.                                            For the past several years, the FGTB Council has been organizing boot camps at AHA sessions to give people a chance for hands on learning in a flipped classroom model. This year was no exception and in addition to a clinical genomics boot camp focused on patient centric genomics including single gene testing, whole genome sequencing and pharmacogenomics there was also a new boot camp focused on tackling big data network systems analysis for high input data interpretation.                                            These boot camps are always very well attended and popular, so if you're interested in attending one next year, make sure to get in early and sign up during registration. There was also a hands on session in collaboration with the AHA's Precision Medicine Institute to teach people how to use the precision medicine platform to further their research.                                            In addition to this, there was a full day of programming related to precision medicine in the precision medicine summit, which is held on the Tuesday of Sessions. That covered topics ranging from big data, electronic health records, collaborations and the All of Us initiative to rapid fire reports from ongoing consortium, large scale analysis to disease specific approaches in cardiomyopathy.                                            We were planning to have an in depth focus on the Institute for Precision Cardiovascular Medicine in a future podcast episode, so stay tuned for more on that coming soon. There were a number of individuals who were recognized for their contributions to science and we would like to congratulate all of these outstanding individuals.                                            The FGTB medal of honor was awarded to Stuart Cook from the Duke National University of Singapore. The FGTB mentoring award was awarded to Robert Gerszten from Beth Israel Deaconess Medical Center. The FGTB distinguished achievement award went to Sekar Kathiresan from the Broad Institute. And the functional genomics and epidemiology mid-career research award went to Kiran Musunuru from the University of Pennsylvania. Congratulations to all of these.                                             One of the highlights for the FGTB council at sessions is the FGTB young investigator award. This award celebrates early career investigators and recognizes outstanding research in basic science, populations science, genetic epidemiology, clinical genetics and translational biology. Four finalists presented their research on the Sunday afternoon sessions and I had the chance to chat with all four of them before and after their presentations. So listen on for a behind the scenes over view of the finalists research and the announcement of the winner.                                            Mark Benson is a cardiology fellow at Brigham and Women's Hospital and is working on post-doctoral research at the Beth Israel Deaconess Medical Center in Boston with Dr. Robert Gerszten. His talk was entitled "The Genetic Architecture of the Cardiovascular Risk Proteum." Mark Benson:                  My name's Mark Benson. I'm just finishing up a cardiology fellowship at Brigham and Women's Hospital and am in the middle of post doc in Robert Gerszten’s lab at Beth Israel. Jane Ferguson:                Great, and congratulations on being chosen as a finalist for the FGTB Young Investigator Award. We would love to hear a little bit more about what you’re working on and what you're gonna be telling us. Mark Benson:                  Yeah, absolutely. So the goal of the project was really to integrate proteomic data with genomic data, with the idea that we may be able to use the overlap between those data sets to identify potentially novel biological pathways that underlie very early cardiovascular disease risk.                                            And the thinking behind that was that the lab had just finished up applying DNA-aptamer-based proteomic platform to profile over 110 proteins and the Framingham-Offspring Cohort and from that work, we had identified a very specific signature of 156 proteins in plasma that were each very strongly associated with cardio-metabolic risk.                                            The idea was while those associations were very strong, it was unclear if we were capturing cart or horse or how these associations were fitting together. We wanted to incorporate the genomic data to try to get a better handle on that, to try to connect those pathways to see how these proteins might actually associate with the end phenotype of risk. Jane Ferguson:                It's a sort of Mendelian randomization-esque. Mark Benson:                  Exactly, yeah. So what we were able to find in doing this, we were able to use peripheral blood samples from participants at the Framingham-Offspring study. With a validation in participants of the Swedish Malmo Cancer and Diet Study. Then we did protein profiling using commercial DNA aptamer platform, soma scan. What we were able to find is we were able to detect very strong associations between these circulating cardio metabolic risk-proteins and genetic variance.                                            What was fascinating was we were able to see many things. We were able to start mapping where are these associations, where are these genetic variance in relation to, for example, the gene that's coding the protein that we're measuring. That had some interesting implications because for about half of the protein that had significant associations, we could track those genetic variance back to the gene. It was coding the protein that we were measuring, which was interesting because it's validating the specificity of the proteomic platform that we're using. Jane Ferguson:                Right that's nice, because so often you found a gene that's nothing related to what you think it's going to be so it's nice actually the gene you expect. Mark Benson:                  Yeah, it's very reassuring too when you're looking at rows and rows and rows of data. When the top association of the p value of 10 in the minus 300 is the actual gene you thought would be coding the protein that you're measuring. So that was very reassuring, but we also found dozens and dozens and dozens of associations that were totally unexpected and that may point to completely unexplored biological pathways in cardiovascular disease. So that was obviously very exciting.                                            That actually led us to do two things. One was to make all these data available publicly on dbGaP because as a resource for cardiovascular research there is just way too much data for one group or a handful of groups to digest. The other thing that was fun about the project, is we were able to take one association that was particularly interesting for a number of reasons and experimentally validate it in a tissue-culture model. Jane Ferguson:                So how did that work? Mark Benson:                  So this was an interesting challenge where we all of a sudden got all of these hits back, which was probably to be expected, but to try to figure out which of these dozens and dozens and dozens of new, unexpected hits, what do you do? There was one hit, one association, that was particularly strong and it was between several variance around this gene. That's a phosphatase called PPM1G. It's a transcription factor.                                            These variants, which was interesting, were associated with several different circulating cardio metabolic risk proteins. So our idea was, isn't that interesting? Is it possible that this is mapping to some central regulator? And so it fit that that would be ... that the nearest gene to these variants was a transcription factor and could be a central regulator.                                            What made it more interesting to us was that several variants in the GLGC had recently been described that were highly associated with circulating levels of total cholesterol and triglycerides and they were located around this PPM1G locus as well. The association between those variants and circulating cholesterol didn't have a clear biological connection.                                            So what our work had shown is that those same variants were associated with circulating levels of apolipoprotein E. So wouldn't that be interesting if these variants mapped to PPM1G, the transcription factor, this PBM1G in turn regulated circulating apolipoprotein E and that would provide some insight into the biology behind the GLGC findings.                                            So sure enough we were able to knock down PPM1G using SRNA and hepatocytes and then see that that led to a significant down regulation of the transcription of Apo-B and extra-cellular presumably secreted Apo-B in this model, which is kind of a nice proof of principal that this idea of integrating proteomics and genomics may lead to some novel biological pathways. Jane Ferguson:                Yeah, it's really interesting. So what's next. There are probably a lot more associations that you're going to have to go after? Mark Benson:                  Yeah, I think that what this showed us is that this seems like a powerful tool. Joining these orthogonal data sets to find new pathways and so we're continuing to pursue that with an increasing number of proteins for example, so we're doing genome-wide association studies and x-gamma rays. We've gone from 156 to 1100 to 1300 and are now going beyond that and so as those numbers get higher, you start to see these central nodes come together and more interesting targets and potential pathways. It's also interesting to use these data to find new associations or new tools that you would never think to look for as ways to modulate protein levels.                                            So you can imagine, for example, one thing that we've been exploring for the last few months is can we identify, for example, SNP associated with an interesting circulating protein. That SNP maps to an enzyme or some other druggable mechanism and very preliminary studies, it seems like the answer is probably yes, but there is still a lot of work to be done. Jane Ferguson:                Well that's cool. That sounds really interesting. Mark Benson:                  Yeah, I think the key thing is that all these data will soon be out there and so it's a very rich data set and I think there are many ways that we could use the data. Jane Ferguson:                So is that the genomic data and all the proteomic data or it's the summary of the those associations? Mark Benson:                  All the genomic data, all the proteomic data and the associations as well. You can do the associations yourself if you'd like to. Jane Ferguson:                We can find that  dbGaP. Awesome, well thank you for talking to us. Mark Benson:                  Thank you. It's been fantastic. Jane Ferguson:                Congratulations again. Mark Benson:                  Thanks so much. ... Jane Ferguson:                Jenny Lin is an instructor at the University of Pennsylvania, working with Dr. Kiran Musunuru. Her presentation was entitled, "RNA binding protein A1CF Modulates Plasma Triglyceride Levels through Transcriptomic Regulation of Stress-Induced BLDL Secretion".                                            Jenny, can you take a moment to introduce yourself? Jenny Lin:                          Yes, hi. Thank you for this opportunity to participate. I'm Jenny Lin. I'm an instructor of medicine at the University of Pennsylvania, a nephrologist by clinical training, but training in cardiovascular research in Kiran Musunuru's lab. Jane Ferguson:                So congratulations for getting selected as a finalist for the Young Investigator Award. We'd love to hear a little bit more about what you've been presenting and what you've been working on. Jenny Lin:                          Thank you. So basically, what I've been working on over the past year is functional follow-up of this A1CF locus, which is a novel locus for triglycerides. So say Sek Kathiresan's group recently published in Nature Genetics and x and y association study on plasma lipids involving more than 300,000 individuals.                                            One of the key findings from that study is this strong association between a lo-frequency coding variant and elevated plasma triglycerides. So we wanted to delve more deeply into the biology for why we have that genotype/phenotype connection. One of the key things that we wanted to do was ... A1CF is not a stranger to lipo-protein metabolism, but we wanted to see what else it may be doing outside of its canonical role of facilitating the editing of Apo-B messenger RNA.                                            It really took us on a little bit of a wild journey using different unbiased approaches to try to figure out some of the mechanisms that could be behind it. Jane Ferguson:                So you had to do a lot of different types of experiments to really get at this question. Jenny Lin:                          Yeah. So again, one thing we wanted to see was: if you lose A1CF function, whether or not you would have differences in Apo-B 100-B48. We actually found that A1CF isn't even needed for that editing reaction and that our mice that we were able to create with crispr cas9 genome editing, so knocking in the mutation and knocking out the gene, actually have the phenotype even though they don't have changes in editing.                                            But what surprised us was that we know that A1CF as an RNA binding protein binds Apo-B transcript, yet it somehow does not alter transcriptional abundance of the Apo-B messenger RNA. And it has nothing to do with Apo-B synthesis so we basically had to think, what is A1CF doing outside of Apo-B biology?                                            We found that you have A1CF loss of function, you have increased triglycerides secretion. There is more Apo-B secretion, but that seems to be a downstream effect of other processes going on in the cell and to really try to figure out what those processes are, we had to take an unbiased approach using enhanced clipseek to figure out binding targets and also doing some transcriptional profiling with RNA sequencing and found that it's not necessarily regulating that transcriptum on a differential expression level, but there are some key alternative splicing events as well as messenger RNA binding to affect translational efficiency of some key targets that could be driving the biology. Jane Ferguson:                That's really interesting and you wouldn't have been able to find that by just looking at levels of protein or levels of mRNA, you really had to do these additional clipseek and some experiments to really get at this splicing. Jenny Lin:                          Yeah, so it's been interesting. Clipseek is not as commonly performed method, so we had to collaborate with some brilliant people over at UCSD, to help us facilitate this. But again, finding that A1CF binds many more transcripts than Apo-B itself is a novel finding and the fact that it can regulate alternative splicing is also a very novel finding as well. Jane Ferguson:                So what was the most challenging part of this whole project? Jenny Lin:                          I think the challenging part was that when we saw there wasn't necessarily a direct effect on Apo-B abundance and having to then cast this wide net and then figure out from all of the different unbiased data we have and integrating it find different pathways that may be relevant. In this case, it may all be relevant to ER stress, which is a field that is a little bit controversial in VLDL secretion in terms of directionality, but certainly is important in the biology. Jane Ferguson:                So is that something that you're going to have to start doing in the future? Are you going to start looking at ER stress or what kind of other experiments do you think you're going to keep doing to move this project forward? Jenny Lin:                          Yeah, so actually, I think focusing in on A1CF as an RNA-binding protein and pursuing some of these additional targets will also be relevant, so I think in terms of ER stress, we could be looking at different targets, but there other processes going on in the cell that's mediated by A1CF, that could contribute maybe doing some isoform specific studies just to really prove that these alternative-splicing changes are driving some of the biology.                                            There's a lot of work to do as I would joke to anyone on study section listening to this, perhaps four to five years of work for an RO1. Jane Ferguson:                Sounds very appropriate. Jenny Lin:                          Yeah, there's a lot of exciting work to do. A1CF is actually also a locus for other cardio-metabolic relevant traits such as uric acid, gout and kidney function so there could be something very interesting going on. There could be cross talk among cellular processes that could lead to these different phenotypes. Jane Ferguson:                Really interesting project and a lot of really great work. Congratulations again on being selected as finalist and on this really interesting paper. Jenny Lin:                          Thank you. Jane Ferguson:                Thanks.                                            Sarah Parker is based in Cedar Sinai Medical Center in LA and her mentor is Dr. Jenny Van Eyk. The title of her presentation was "Identification of Putative Fibrous Plaque Marker Proteins by Unsupervised Deconvolution of Heterogeneous Vascular Proteomes ". And I apologize in advance for the quality of this recording. The background noise wasn't that noticeable at the time, but that recording really gives you that full immersive audio experience of a busy hotel lobby.                                            Hey Sarah. Thank you for joining us. Could you just take a few moments to introduce yourself to the audience? Sarah Parker:                   So I'm Sarah Parker. I'm a project scientist at Cedar Sinai Medical Center where I'm doing work to study the basic mechanisms of vascular biology of various indolent conditions. Jane Ferguson:                So congratulations on being selected as a finalist for the Young Investigator Award. It's a great achievement. I'd love to hear a bit more about your project, how that started and what you found. Sarah Parker:                   The work that I did was under the overarching umbrella of a project called the Genomic and Proteomic Architecture of Atherosclerosis. So with this project, we're using tissues that we're able to obtain from individuals who are young and have passed away from traumatic and violent and so non-cardiovascular causes of death. Because of the presence of atherosclerosis in the population, we get this range of lesion, both fatty streak and fibrous-plaque lesions in these asymptomatic or non-diseased individuals and this gives us this opportunity to do some molecular profiling to really try to find protein-signatures of early stage plaque formation, that could ultimately and hopefully be used for biomarker development. Jane Ferguson:                That's really cool and that's such a valuable sample resource. Sarah Parker:                   Yeah so we've essentially, in this project I was able to set up a pipeline that enabled us to do these proteomics on such a large scale, because that's actually really difficult in label free quantitative proteomics and to use other forms becomes very expensive and cost-limiting.                                            So we were able to find a panel of proteins that we think are a putative early set of fibrous plaque markers and with this panel, we took them to see if any of these tissue derived markers would then be detectable and informative in plasma, because that's the next really big translational leap with these discovery-type data sets. Of our 58 initial candidates, we were able to detect 39 of them and about a handful 10-13 are showing informative behavior in the plasma of initial cohort of women with known coronary-artery disease. Jane Ferguson:                So out of the 58 that you first found, how many of them were potentially known to be involved in disease and how many were novel? Sarah Parker:                   I would say, going through the list, it was probably about 50/50 in terms of background data that shows role as a biomarker, so there are a lot of apolipoproteins, which have all been characterized as potential biomarkers. There were a lot that could feasibly be linked through the literature to atherosclerosis. Most of them made a lot of sense, but having been proposed as potential biomarkers, some of them were more rare. Jane Ferguson:                Were there any of them that were sort of in different directions, let's say were elevated in tissue, but then were lower in plasma? Sarah Parker:                   Funny you should ask. That actually has us scratching our heads a little bit right now. There were a couple of apolipoproteins that are more associated with HDL biology that we saw as being elevated in the tissue but then lower in the plasma [inaudible 00:23:34] so that's a really interesting observation so something about the role of these proteins to scavenge cholesterol and then once they're in the blood, they're cleared really quickly relative to normal, or something. So we're really trying to figure out what that biology means. Jane Ferguson:                Maybe if they're building up in the tissue, that's bad. But while in circulation, they're fine. Sarah Parker:                   Yeah, maybe they're trapped in the circulation. We have a lot of exciting hypotheses to test along that front. Jane Ferguson:                So what's next? Are you following up some of these proteins? Sarah Parker:                   Yep, so we have a huge discovery arm to the project where we're looking for more molecular mechanisms like why do we have these things in the tissue versus plasma and then we are working to really validate and optimize these multi-plexes in much more generalized large-scale populations to determine whether this strategy of instead of one or two biomarkers, more of a signature-style panel can be informative, especially as we try to press towards a precision medicine approach where different substratum might be informed by different protein signatures. Jane Ferguson:                Right, so you might have to have a specific panel based on sex or age or race or some other demographic. Sarah Parker:                   Yes and to find those signatures, it's going to be very big numbers, with very accurate, careful quantitation. Jane Ferguson:                So you have a lot of work to do. Sarah Parker:                   Yes. Jane Ferguson:                Alright, well thank you for talking to us and congratulations again.                                            Louie Wang, a cardiologist and PhD student came all the way from the Victor Chang Cardiac Research Institute in Syndey, Australia. His mentor is Dr. Diane Fatkin. The title of his talk is "A novel zebrafish model of human A-band truncated titan exhibits alternated ventricular diastolic compliance in vivo and reveals enhanced susceptibility to the effects of volume overload in mutation carriers.                                            So thank you for joining me. Could you take a few minutes to introduce yourself? Louie Wang:                     So I'm Louie Wang. I'm a cardiologist based in Australia. I work and live in Sydney. I'm a PhD student at the Victor Chang Cardiac Research Institute and I'm an NHMRC (National Health and Medical Research Council and National Heart Foundation of Australia post-graduate scholar). I have previously been based at St. Vincent's Hospital. Jane Ferguson:                Great. So we'd love to hear a little bit in advance of what you're working on and what you're planning to present. Louie Wang:                     So basically what I'm presenting is what I think is a different form of functional of genomics. What we're actually looking at is the impact of genetic changes, specific genetic change on function of the heart at an organ level. So there is a problem out there that is very common in cardiology and it's a big problem in cardiology and that is there are mutations in the sarcomere protein titan, truncating variants which actually are associated with dilated cardiomyopathy.                                              Now they're pretty common in idiopathic dilated cardiomyopathy, present in about 15-20% of the cases depending on which cohort study you look at. But they're also widely prevalent in the general population. Somewhere between 0.3 to 1% of the general population carries this truncating variants or various forms of this truncating variant.                                            So it's not sure whether these are disease-causing in their own right or if it's just a genetic susceptibility factor for heart failure and so what our work involves is that we actually, by chance, at St. Vincent's Hospital and at Victor Chang Cardiac Institute, two families who had the identical genetic truncation in the A-band region of his human titan gene where the individuals in the family, typically who carried the gene, typically developed systolic heart failure, which is a mild phenotype and occurred at middle age, but in two individuals, they developed severe onset accelerated disease trajectory in a very severe phenotype when exposed to conditions associated with chronic volume overload.                                            We suspect and this was a hypothesis, not only was this genetic-truncation disease-causing, but at volume overload was disease-modifying and given that volume overload is a very common condition present in birth, a lot physiological processes like lung endurance, exercise, pregnancy as well as a lot of pathological disease states in cardiovascular disease, this was actually a very important modifiable factor.                                            So what we did, was we created a novel zebrafish model of this human A-band truncated variant. We then studied the animals when they became adults to look at their heart structure and function and we used zebrafish echocardiography. So reversed translated all the techniques you can do in human echocardiography so they can be used in the zebrafish.                                            What we found was, yes, this animal, or heterozygotes developed dilated cardiomyopathy but also the volume overload exacerbated this condition. So this is a phenomenon that has conserved this by four hundred million years of vertebrate evolution so this is a pretty important mechanism. Jane Ferguson:                So what kind of next steps do you see for this project? Louie Wang:                     So one thing is that we obviously have shown that there is an association with volume overload in precipitous disease. The corollary of our work is that perhaps interventions that could reduce volume load in these genetic susceptible individuals or alternatively in people who can't avoid volume overload. Because a lot of volume overload conditions can be modifiable and perhaps this could be protective and that would have wide-ranging population benefits. Jane Ferguson:                Thank you for sharing that soundbite of your work and good luck. Congratulations again on becoming a finalist. Louie Wang:                     Thank you. ... Jane Ferguson:                Each of these four finalists gave compelling presentations of their research and the judges were highly impressed of the quality of the research and level of accomplishments of these early career investigators.                                            Just getting selected as a finalist for this award is a huge accomplishment. But there did have to be one winner. I'm delighted to announce that Jenny Lin was selected as the 2017 FGTB Young investor award winner. Congratulations, Jenny, and thanks to all four finalists for agreeing to appear on this podcast.                                            And that's all for this month. We'll be back at the end of December with a new episode. Subscribe to the podcast through iTunes or your favorite podcast app. to get new episodes delivered automatically and thank you for listening.

1st Podcast of 2nd SeriesThis could be considered the rebirth of my podcast. I talk about stuff like how I was able to continue my podcast. Not super exciting, but I say that about all of them.