Podcasts about pdgf

In this episode, Dr. Kristen Herzog demystifies PRP (Platelet-Rich Plasma), PRF (Platelet-Rich Fibrin), EZ Gel, and PDGF (Platelet-Derived Growth Factors) - explaining the pros and cons of each treatment. You will learn about the history of the treatments and where the ideal injection sites are. The star of this episode is PDGF, as it's been shown to be multiples above your natural growth factor concentration and thus much more effective than traditional PRP/PRF. However, if you're looking to get your lips injected, Dr. Herzog still believes that traditional filler is the way to go. Timestamps00:00 Intro01:05 Life Update03:04 Biostimulators are Trending Up04:31 PRP - Platelet-Rich Plasma06:35 PRF - Platelet-Rich Fibrin07:53 EZ Gel09:31 Comparing EZ Gel, PRP, and PRF10:01 Injecting - Which Ones for What?10:38 "Can You Put EZ Gel in the Lips?"12:32 Choosing Fillers14:16 EZ Gel Challenges15:29 Undereye Filler16:28 PDGF - Platelet-Derived Growth Factors18:25 THIS Is Why PDGF Is Best20:04 The Current Uses of PDGF21:08 "Off-Label" Treatments?22:16 TakeawaysDon't forget to follow Dr. Herzog on Instagram @the_perfectdose for more skincare tips!--------------

Join Jon and Nicole as they delve into the latest trends in aesthetics, and dive deep into the world of PDGF (platelet-derived growth factor). This episode covers the benefits, usage, and comparative advantages of PDGF over PRP and PRF, and includes personal experiences with the treatments. Learn about treatment stacking, the science behind PDGF, and the evolving field of aesthetics and wellness.On Fill Me In: An Aesthetics Podcast, Jon LeSuer NP-C and Nicole Bauer FNP-BC dive deep in the world of aesthetics. As aesthetic nurse practitioners with their own medical practices, Jon and Nicole fill you in on everything in their field.Follow Fill Me In on Instagram!https://www.instagram.com/thefillmeinpod/Follow Nicole on Instagram:https://www.instagram.com/aestheticnursenicole/Follow Jon on Instagram:https://www.instagram.com/injectorjon/Exhibit Medical Aesthetics website:https://exhibitmedicalaesthetics.com/Tox and Pout Aesthetics website:https://toxandpout.com/Jonathan LeSuer, MSN, NP-C Jonathan LeSuer graduated from Le Moyne College with his Bachelor's in Nursing in 2014 and a Family Nurse Practitioner degree in 2017. He began his career at St. Joseph's Hospital as a Registered Nurse on a cardiac medical-surgical unit. He transitioned to the Nurse Practitioner role in 2017, working for Hospitalist Medicine, where he became the coordinator for the team's Physician Assistants and Nurse Practitioners. In 2020, he started his career as an Aesthetic injector and quickly found out that this was his passion. On March 15th, 2022, he opened Tox & Pout Aesthetics. He is now a Master trained injector & National trainer for Allergan Aesthetics, offering Botox, Dysport, Hyaluronic acid fillers, Kybella, SkinViVe skin booster, and Sculptra. Jonathan is known for his empathy, profound bedside manner, and outgoing/warm personality. He has a deep love for aesthetics, and his patients' confidence is his main priority. Nicole Bauer, MSN, APRN, FNP-BC. Family Nurse Practitioner Nicole graduated with her Associates in Applied Sciences and began her journey as a registered nurse 10 years ago in 2014. She worked hard to combine her love for beauty with her passion for caring and healing others, attending aesthetics school while working as a hospital night nurse. After graduating as a licensed aesthetician, Nicole left the hospital where she had been for 3.5 years and began working as a registered nurse for a plastic surgeon. An experience of over 6 years that would leave her with so much knowledge and respect for the aesthetic world. It was during those 6 years that she pursued her Master's Degree and obtained her license as a Family Nurse Practitioner, leading the way for where she is now; owning a state of the art medical aesthetic practice and being a national Allergan Trainer. Nicole takes pride in treating her patients holistically, focusing on facial balancing and enhancing one's natural beauty. She believes education stands as the cornerstone of aesthetics and is why she is dedicated to both training others while always focusing on expanding her own knowledge as well.  Producer of Fill Me In: Joseph Ginexi#RegenerativeMedicine #PDGF #Skincare #Microneedling #injector #Aestheticmedicine #aesthetics #aestheticnurse #SkinRejuvenation #botoxcosmetic #filler #PRF #PRP

Join us for an in-depth conversation with William V. Giannobile, interviewed by Sejal Thacker, as he reflects on his key publication, Platelet-derived growth factor stimulates bone fill and rate of attachment level gain. Giannobile discusses the groundbreaking development of recombinant human platelet-derived growth factors (PDGFs) and their pivotal role in oral tissue regeneration. He traces PDGF's journey from discovery to clinical application, sharing insights into the science, trials and regulatory steps that brought this innovation to patients. From early tissue culture studies to regenerative therapies for periodontal disease, Giannobile details the research process and rigorous trials required to develop safe and effective treatments. This is a must for anyone interested in the latest developments in oral tissue regeneration!

In this Five Min Friday, we discuss how advanced microneedling techniques can enhance results when combined with other treatments like platelet-rich plasma (PRP), platelet-derived growth factors (PDGF), exosomes, and more! We'll cover key considerations for achieving optimal results and reducing risks. Tune in to discover why microneedling remains a top choice for facial rejuvenation!

In this episode, Dr. Rohrich is joined by Dr. Sam Lynch to discuss what's new in PDGF.

Platelet Derived Growth Factors, Microneedling, Hair Restoration - Join us in this week's Five Minute Friday as Dr. Kay dives into one the latest advancements in regenerative aesthetics, focusing on the revolutionary Platelet Derived Growth Factors (PDGF)! We explain the science behind PDGF, a powerful protein involved in wound healing and tissue regeneration, and how it compares to other platelet-based treatments such as PRP and PRF. Learn how PDGF enhances skin health by stimulating collagen production, promoting angiogenesis, and facilitating cell migration, leading to firmer, more youthful skin! Tune in to discover the clinical applications of PDGF, from microneedling to laser procedures and its potential in hair restoration. This is a product you will be wanting to incorporate into your practices!  

Lynn Carson is the President of LRM Aesthetics, a subsidiary of Lynch Regenerative Medicine.  After 32 years at Allergan, the maker of Botox, Lynn came out of retirement to help launch ariessense pure PDGF+.  Let's Connect! * Instagram https://www.instagram.com/premierderm/* Facebook https://www.facebook.com/premierdermatology* Website: https://premierderm.netPremier Dermatology is located in Bentonville, Fayetteville, & Bella Vista, Arkansas!

Founded by Dr. Lynch, LRM Aesthetics is a new, advanced skin care company that aims to revolutionize skin care, including skin rejuvenation to achieve optimal aesthetics results. Their first product, ariessense pure PDGF+, is the purest, most highly concentrated PDGF product ever available to the aesthetics market!  Let's Connect! * Instagram https://www.instagram.com/premierderm/* Facebook https://www.facebook.com/premierdermatology* Website: https://premierderm.netPremier Dermatology is located in Bentonville, Fayetteville, & Bella Vista, Arkansas!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.23.550235v1?rss=1 Authors: Tsutsumi, R., Ueberheide, B., Liang, F.-X., Neel, B. G., Sakai, R., Saito, Y. Abstract: Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538102v1?rss=1 Authors: Guan, Y., Fang, Z., Hu, A., Roberts, S., Johansson, P. K., Heilshorn, S. C., Enejder, A., Peltz, G. Abstract: Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. To overcome this barrier, we engineered a live cell imaging system that identifies collagen producing cells in a human multi-lineage hepatic organoid. This system was adapted for use as a microwell-based platform (i.e., microHOs) where exposure to PDGF or TGFb1 induced the formation of thick collagen fibers. Transcriptomic analysis revealed that TGFb1 exposure converted mesenchymal cells into myofibroblast-like cells with a significantly altered pattern of production of proteases and anti-proteases, which contribute to the development of liver fibrosis. When pro-fibrotic intracellular signaling pathways were examined using pharmacological probes, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates that their antifibrotic efficacy would be limited to fibrotic diseases that were solely mediated by that growth factor. In contrast, GSK3b or p38 MAPK inhibitors could prevent TGFb1- or PDGF-induced fibrosis in microHOs because they block intracellular signaling pathways that are commonly utilized by the TGFb1 and PDGF receptors. Hence, these studies identified GSK3b and p38 MAPK inhibitors as potential new broad-spectrum therapies for liver fibrosis, and it is likely that other new therapies could subsequently be identified using this microHO system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.27.534488v1?rss=1 Authors: Li, T., Shi, W., Ho, M. S., Zhang, Y. Q. Abstract: Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein that Drosophila adults exhibit a defective blood-brain-barrier (BBB), elevated innate immune responses, and hypertrophy of astrocytes upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase (RTK)), adaptor protein complex 1 (AP-1, a transcription factor complex of the c-Jun N-terminal Kinase (JNK) pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1-Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr-AP-1-Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies of TBI. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week, please join author Xuerong Wen, Associate Editor Sandeep Das, and Guest Host Mercedes Carnethon as they discuss the article "Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, Director of the Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm so excited about today's feature paper. It deals with the important condition where atrial fibrillation exists in patients with chronic liver disease and what do we do for anticoagulation in these patients. It's a comparative effectiveness and safety study of direct oral anticoagulants compared with warfarin in these patients. A huge, wonderful, important study that we're going to discuss. But before we get there, I'd like to tell you about some papers in this issue and I'd like you to tell me about some too. You got your coffee? Dr. Greg Hundley: Absolutely. Dr. Carolyn Lam: All right. I'll go first In this paper that describes a quantitative prognostic tool for the mitral valve prolapse spectrum and it's derived from the new mitral regurgitation international database quantitative or MIDA-Q registry, which enrolled more than 8,000 consecutive patients from North America, Europe, Middle East. And these were patients all diagnosed with isolated mitral valve prolapse or MVP in routine clinical practice of academic centers, all of which also did prospective degenerative mitral regurgitation quantification. The MIDA-Q score was calculated based on characteristics collected in routine practice combining the established MIDA score, which integrated guideline based markers of outcomes like age, New York Heart Association status, atrial fibrillation, LA size, pulmonary artery pressure left ventricular and systolic, I mentioned, and ejection fraction. Integrating that with scoring points based on the degenerative mitral regurgitation quantitation that is measuring effective regurgitant orifice and volume. Dr. Greg Hundley: Very interesting Carolyn. So a scoring system that combines clinical information with what we might assess with echocardiography like regurgitant volume or regurgitant orifice area. So how well did this mortality risk score perform? Dr. Carolyn Lam: So the new score was associated with an extreme range of predicted survival under medical management and that ranged from 97% to 5% at five years for the extreme score ranges. And it was strongly, independently and incrementally associated with long-term survival over all the markers of outcomes. So the authors concluded, and these by the way were authors led by Dr. Maurice Serrano from Mayo Clinic, Rochester, Minnesota. These authors concluded that the score should allow integrated risk assessment of patients with mitral valve prolapse to refine clinical decision making in routine practice and ultimately reduce degenerative mitral regurgitation under treatment. Dr. Greg Hundley: Wonderful description Carolyn. Well I'm going to switch to the world of electrophysiology, Carolyn. And so as you know, the Brugada syndrome is an inherited arrhythmia syndrome caused by loss of function variants in the cardiac sodium channel gene SCN5A and that occurs in about 20% of subjects. And these authors led by Dr. Dan Roden at Vanderbilt University School of Medicine identified a family with four individuals diagnosed with Brugada syndrome, harboring a rare missense variant in the cardiac transcription factor, TBX5, but no SCN5A variant. And upon identifying these individuals, their objective was to establish TBX5 as a causative gene in Brugada syndrome and to define the underlying mechanisms by which it would be operative. Dr. Carolyn Lam: Oh wow. So a new gene variant. So what was the relationship? Dr. Greg Hundley: Right Carolyn? So using induced pluripotent stem cell derived cardiomyocytes from members of the affected family, multiple electrophysiologic abnormalities were detected in these cardiomyocytes including decreased peak and enhanced late cardiac sodium current. In these cells these abnormalities were entirely corrected by CRISPR/Cas9 mediated editing of that TBX5 variant and transcriptional profiling and functional assays in unedited and edited pluripotent stem cell derived cardiomyocytes showed direct SCN5A down regulation caused decreased peak sodium current and that reduced PDGF receptor expression and blunted signal transduction to phosphoinositide-3-kinase. And interestingly, PDGF receptor blockade markedly prolonged normal induced pluripotent stem cell derived cardiomyocyte action potentials. And also Carolyn interestingly in this study they did a separate analysis. It reviewed plasma levels of PDGF in the Framingham Heart Study and they found that they were inversely correlated with the QT corrected interval. And so Carolyn, these results established decrease SCN5A transcription by the TBX5 variant as a cause of Brugada syndrome and also reveal a new general transcriptional mechanism of arrhythmogenesis of enhanced late sodium current caused by reduced PDGF receptor mediated phosphoinositide-3-kinase signaling. Dr. Carolyn Lam: Wow. Wow, that's significant. Thanks Greg. So this next paper is also really important and could change the practice in the field of cardiac resynchronization therapy or CRT. You see, it suggests that the practice of what we do now, which is combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we select patients for CRT, that this may not be the way to go. So let's go back a bit and remember that benefit from CRT varies with QRS characteristics and individual trials are actually underpowered to assess the benefit for relatively small subgroups. So the current authors led by Dr. Friedman from Duke University Hospital and colleagues, therefore performed a patient level meta-analysis of randomized trials of CRT to assess the relationship between QRS duration and morphology with outcomes. Dr. Greg Hundley: Very interesting Carolyn. So another wonderful paper from the world of electrophysiology in trying to understand optimal mechanisms to resynchronize the ventricle in patients with differing bundle branch blocks or intraventricular conduction delays. So what did they find? Dr. Carolyn Lam: They found that patients with intraventricular conduction delays and a QRS duration of 150 milliseconds or more, CRT was associated with lower rates of heart failure hospitalizations and all cause mortality. The magnitude of CRT benefit among these patients with the interventricular conduction delay of 150 milliseconds or more and those with the left bundle branch block of 150 milliseconds or more were similar. In contrast, there was no clear CRT benefit for patients with a right bundle branch block of any QRS duration, although the authors could not rule out the potential for benefit at a markedly prolonged QRS duration. So they concluded that the practice of combining right bundle branch block with intraventricular conduction delay patients into a single non-left bundle branch block category when we make patient selections for CRT is not supported by the current data. And in fact, patients with an intraventricular conduction delay of 150 milliseconds or more should be offered CRT as is done for patients with a left bundle branch block of 150 milliseconds or more. Dr. Greg Hundley: Wow, Carolyn, so really interesting point. No clear CRT benefit for patients with right bundle branch block regardless of the QRS duration. Well we've got some other articles in the issue. I'll describe a couple from the mail bag. There's a Research Letter from Professor Lassen entitled "Risk of Incident Thromboembolic and Ischemic Events Following COVID-19 Vaccination Compared with SARS-COV2 Infection." Also Bridget Kuhn has a wonderful Cardiology News piece entitled "Collaborative Care Model Helps Heart Failure Patients Meet End-of-Life Goals." Dr. Carolyn Lam: There's an exchange of letters between Doctors Donzelli and Hippisley-Cox regarding that risk of myocarditis after sequential doses of COVID-19 vaccine, there's an AHA Update by Dr. Churchwell on continuous Medicaid eligibility, the lessons from the pandemic. There's an On My Mind paper by Dr. Parkhomenko on Russia's war in Ukraine and cardiovascular healthcare. Wow, what an issue. Thanks so much, Greg. Shall we go on to the feature discussion? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Well welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, associate editor of the journal Circulation and Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine. I'm very excited to be here today with Xuerong Wen and Sandeep Das, my fellow associate editor here at Circulation to talk about a wonderful piece by Dr. Wen and colleagues from the University of Rhode Island. So welcome this morning Xuerong and thank you so much for sharing your important work with us. Dr. Xuerong Wen: Thank you Dr. Carnethon. It was great meeting you all and I'm the Associate Professor of Pharmacoepidemiology and Health Outcomes at the University of Rhode Island. I'm happy to introduce my study to everyone. Dr. Mercedes Carnethon: Well thank you so much and thank you as well Sandeep for identifying this fantastic article and bringing it forth. Dr. Sandeep Das: Thanks Mercedes. It's great to be with you. Dr. Mercedes Carnethon: Great. Well let's go ahead and get into it. There's so much here to talk about. So Dr. Wen and colleagues studied the comparative effectiveness and safety of direct oral anticoagulants or DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So this is such an important topic. Can you tell us a little bit about what your study found? Dr. Xuerong Wen: So our study is a comparative effectiveness and the safety analysis using a national health administrative data from private health plans. So we compared the risk of hospitalized ischemic stroke, systemic embolism and major bleeding between DOACs and warfarin in patients with atrial fibrillation and chronic liver disease. So we also had to had compare to these primary outcomes between apixaban and rivaroxaban in the study population. So our studies show that among patients with atrial fibrillation and chronic liver disease, DOACs as a class was associated with lower risk of hospitalization of ischemic stroke and systemic embolism and major bleeding, compared with warfarin. And when compared risk outcomes between individuals apixaban has lower risks as compared to rivaroxaban. So that's our study results. Dr. Mercedes Carnethon: Well thank you so much. This seems like such an important question. We hear a lot about DOACs and some of their risks as well as their considerable benefits. I think what leaves me the most curious is why did you choose to pursue this question and in particular in patients with both atrial fibrillation and liver disease. So why was the intersection of these two particular conditions of interest to your study team? Dr. Xuerong Wen: That's a great question. So the liver actually plays a central role in both the synthesis of coagulation factors and the metabolism of anticoagulant drugs. And the clearance of the anticoagulants in liver ranges from 20% to 100% for DOACs and warfarin. So in clinical practice anticoagulation abnormalities and elevated risk of spontaneous or unprovoked venous thrombotic complications have been reported in patients with liver disease. While these patients with cirrhosis were excluded from the clinical trials of DOACs and also population based, the real world experience is very limited. So that is why we initiated this retrospective cohort study and based on the real world data in this specific population. Dr. Mercedes Carnethon: Oh, thank you so much for explaining that. I definitely learned a lot and really enjoyed reading the piece. I think it was very well organized and well written and I know that our readership will appreciate it. It obviously stood out to you as well, Sandeep. Can you tell me a little bit about why you thought that this would be an excellent piece for circulation? Dr. Sandeep Das: Yeah, absolutely. Thanks for the question. So in the broad field of what we call observational comparative effectiveness research, so basically that's using large observational data sets to try to answer important clinical questions and it's a really challenging thing to do. I mean we're all very familiar with the idea of using randomized trials to assess important clinical questions because of the structure of that design allows you to mitigate some of the effects of confounding. Here, it has to be done analytically. So what's the important factor that really drives you towards a great observational comparative effectiveness piece? So first the clinical importance. I feel a little guilty because I'm old enough to remember when warfarin was the only option available, but really as a clinician, or every patient, I really prefer DOACs over warfarin just for ease of use and lifestyle. So there's a huge sort of importance to the question. Second, the patients with chronic liver disease were excluded from the larger RCTs and the DOAC trials. So really we don't have the answer to the question already. It's an important question. Obviously the bleeding risk is tied up with the liver, warfarin directly antagonizes vitamin K, so there's real questions about safety and so this is the perfect storm and then on top of it was a really well done and well executed study. So when this came across my desk, the very first thing I thought was not, "Is this something that we're interested?" But rather, "How do we make it better? How do we make it more useful to the reader?" This had me from hello. Dr. Mercedes Carnethon: Well thanks so much. We rarely have the opportunity when we read an article to be able to ask the authors questions. So Sandeep, I know that you had mentioned that you had some follow up questions as well. Dr. Sandeep Das: Yeah. So the real thought that I have then is would you argue based on this that we know enough that we should change our practice? And that do you feel comfortable advocating that people now prescribe DOACs to these patients? Dr. Xuerong Wen: I would say yes. Okay. Although this is not a clinical trial, but our study is actually systematically compare the effectiveness and safety between DOAC users and also the warfarin users. And if you look at our table one, we compare with so many variables between these two users and we use the propensity score adjustment and we after propensity score weighting and the two control group almost balanced. And I know right now FDA actually suggested that emulate the trial using the large real world data to do the emulated trial. So our study actually conducted is based on the large population using large data and we use the propensity score weighting to control all this potential compounding factors. Although there are still some limitations in this study. I think we mentioned that in the discussion section and we discussed all potential compounding factors that still may exist. And also there are some misclassifications and out of all this limitations and we still found the two drugs performed differently in this specific population. So we feel that comfortable to say that a DOAC drug performs better than warfarin. And also I think based on other studies that based on the clinical trial in the general population, DOAC drug is performs much better than warfarin and considering that the clearance in liver for DOAC is less than warfarin. So plus all this information together, I think DOAC may be safer than wafarin in the patients with AF and chronic liver disease. Dr. Sandeep Das: Yeah, I would say that I agree that these data, even if you're skeptical about observational CT generally, which I admit that I tend to be, these are really reassuring data that at least the DOACs are... There's absolutely nothing that suggests that they're any worse than warfarin and all of the sort of soft indications for ease of use and patient happiness really would seem to favor DOACs. So I think this is the sort of rare observational CT paper that may actually change my practice. Dr. Mercedes Carnethon: I have a follow-up question, Xuerong, related to the design and as well your strategy to address differences between the groups. So inverse probability weighting is certainly a standard in the field to be able to manage differences between groups when you have a situation where can't, where it's not a randomized trial. Do you as well, and educate me, I admit I'm an epidemiologist whose methodological skills are sometimes challenged. Do you have the opportunity using this design and with inverse probability weighting to evaluate subgroup effects? So my specific question is were you able to determine whether or not these associations were similar based on age and gender in particular? Dr. Xuerong Wen: That's a great question. We did conducted a lot of subgroup study but not by age or gender. We conducted I think this study in a lot of subgroups using the propensity score weighting, but the subgroup that I think we did a subgroup like a patient with a different chronic liver disease. So that's what we did. And we also tested different methods inverse probability score weighting. So we did trimming and we used a different percentage of trimming and to see how that affect the study results. So we have done a lot of subgroup studies. We did not check the age and the gender, but that's a very good point. Maybe later, well I'll ask my student to do that. Dr. Mercedes Carnethon: Well, you're a good mentor. So I think that is a really certainly an appropriate approach. Sandeep, did you have additional questions? Dr. Sandeep Das: No, I wish I had thought of yours before you did. I think exactly the older age, women, racial ethnic groups that are underrepresented historically in trials. I think that that's really, again, the sweet spot of this observational research. We definitely, and NH definitely working on trying to increase enrollment of all these groups in our CTs. However, while we wait for that, I think that's exactly what we should be doing. Dr. Mercedes Carnethon: Well that's great. And Xuerong, you really alluded to really, I think what is one of my final questions related to what do you think based on what you have observed in this study, what do you see as the next steps in the research field for your team, your students, or other people who are carrying out this type of work? Dr. Xuerong Wen: Well, that's a great question. We currently have a couple of more manuscripts ongoing in this field, and we will continue conducting the comparative effectiveness and analysis to compare drugs head to head as well as developing and implementing new methodologies to this field. And we hope our study provides real world evidence for clinical decision making, prescribing anticoagulants to patients with atrial fibrillation and chronic liver disease. We also expect the physicians and researchers more and more value the real world data studies, especially when clinical trials are not feasible or ethical. Dr. Mercedes Carnethon: Well, thank you so much. That was such an excellent vision that you provided us with and we're just very grateful that you submitted this fantastic work to the journal Circulation. I know that our readers will enjoy really digging in. The podcast is meant as a teaser to bring you to the journal so that you can read about this wonderful work by Dr. Wen and colleagues. So again, thank you. I'm Mercedes Carnethon, joined with my associate editor partner here, Dr. Sandeep Das. And thank you very much for spending your time with us today, Dr. Wen. Dr. Xuerong Wen: Thanks for this great opportunity to disseminate my study with us, thank you. Dr. Sandeep Das: Thanks Mercedes. Dr. Mercedes Carnethon: Thank you for joining us for this episode of Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2023. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

2.18 Digital Clubbing Pulmonary system review for the USMLE Step 1 Exam Digital clubbing is the enlargement of the ends of fingers and toes due to growth of connective tissue between the nail matrix and the distal portion of the digit. It is defined quantitatively as an increased angle between nail bed and nail plate (> 180°). Digital clubbing is caused by an interaction between platelets, megakaryocytes, and the growth factors platelet derived growth factor (PDGF) and vascular endothelial growth factors (VEGF). Diseases associated with digital clubbing include lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis, bronchiectasis, and an empyema. Digital clubbing is usually not associated with asthma or COPD.

Hyperbaric Oxygen Therapy (HBOT) is a treatment in which a patient breathes air or varying amounts of oxygen while inside a pressurized chamber, the pressure being anything above 1 atmosphere. The healing power of oxygen is not something new. The use of hyperbaric therapy dates back nearly 350 years. The very first hyperbaric chamber was created in 1662 with the clinical use of hyperbaric oxygen therapy starting in the mid 1800s. During the 1960s, studies began to show a wide variety of beneficial uses for HBOT therapy. Today, there are over 150 internationally approved conditions for which hyperbaric oxygen therapy has been shown to be effective and beneficial. Under normal circumstances, oxygen is absorbed into circulation when we breathe and transported throughout the body only by red blood cells.  Under pressure, oxygen can be dissolved into all of the body's fluids, the plasma, the lymphatic system, the central nervous system fluids, and the bone. This allows us to dissolve, transport and deliver many more times the normal oxygen to our tissues and cells. It has long been known that healing many areas of the body cannot take place without appropriate oxygen levels in the tissue. In many cases, such as circulatory problems and non-healing wounds, adequate oxygen cannot easily reach the damaged area. Oxygen can be carried to areas where circulation is diminished or blocked. In this way, extra oxygen can reach the damaged tissues helping the body to support its own healing process. The increased oxygen enhances the ability of white blood cells to kill bacteria, reduces swelling and allows new blood vessels to grow more rapidly into the affected areas. Hyperbaric Oxygen Therapy is safe and effective and provides this extra oxygen absorption with minimal side effects. 10 PRIMARY BENEFITS OF HBOT Increased oxygen perfusion- (Immediate increase in free floating oxygen available for tissue use) Neovascularization- Angiogenesis (new blood vessel growth) Increased white blood cell function (improved neutrophil and macrophage activity) Nerve healing factors (increases in VegF, BDNF, HIF1) Wound healing Increased capacity for healing (PDGF, VegF, collagen production circulatory healing) Stem cell release (up to 8-fold increase in mesenchymal and CNS stem cells) Vasoconstriction (decrease edema and swelling from damaged tissues) Mitochondrial healing (increase in size, shape and number of mitochondria) Anti-inflammatory (reduction of inflammatory cytokines, increase in anti-inflammatory cytokines) Anti-microbial/microbiome balancing (reduction in anaerobic pathogens and increase in aerobic probiotics) This and more in this latest episode of The Doctor Dads Podcast

A new research paper was published in Oncotarget's Volume 13 on October 19, 2022, entitled, “Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.” Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. Previously, researchers Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Amrendra K. Ajay, Larissa Camila Ribeiro de Souza, Minghua Cao, Yueming Luo, Petra Hoegger, Carmen M. Ribas, Jurandir M. Ribas-Filho, Osvaldo Malafaia, Reinhard Lissner, Li-Li Hsiao, and Ana Maria Waaga-Gasser, from Harvard Medical School, Shenzhen Traditional Chinese Medicine Hospital, University of Wuerzburg, and Mackenzie Evangelical Faculty of Paraná, recently provided evidence for upregulation of PDGF expression in UICC stage I–IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. In their new study, the researchers sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. “Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors.” Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. The team then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression. They found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. “Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.” DOI: https://doi.org/10.18632/oncotarget.28281 Correspondence to: Ana Maria Waaga-Gasser - awaaga@bwh.harvard.edu Keywords: PDGF, VEGFR, EGFR, bypassed signaling, colorectal cancer About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter - https://twitter.com/Oncotarget Facebook - https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram - https://www.instagram.com/oncotargetjrnl/ LinkedIn - https://www.linkedin.com/company/oncotarget/ Pinterest - https://www.pinterest.com/oncotarget/ LabTube - https://www.labtube.tv/channel/MTY5OA SoundCloud - https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com. Oncotarget Journal Office 6666 East Quaker Str., Suite 1A Orchard Park, NY 14127 Phone: 1-800-922-0957 (option 2)

This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway. Dr. Carolyn Lam: Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we? Dr. Greg Hundley: Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom. New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination. Dr. Peder Myhre: Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find? Dr. Greg Hundley: Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population. Dr. Peder Myhre: Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners. Dr. Greg Hundley: Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings. Dr. Peder Myhre: Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs. Dr. Greg Hundley: So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but- Dr. Carolyn Lam: Way to go, Peder. Way to go. Dr. Greg Hundley: Yeah. Well, the good news is, I can just say yes. I did know that. Dr. Peder Myhre: That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline. Dr. Greg Hundley: Oh, wow, Peder. So what did they find? Dr. Peder Myhre: So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59. And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline. Dr. Greg Hundley: Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension. Dr. Peder Myhre: Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg? Dr. Greg Hundley: Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung. They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag? Dr. Peder Myhre: So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag? Dr. Greg Hundley: Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.” Dr. Peder Myhre: And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn. Dr. Carolyn Lam: Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found? Dr. Hanna-Kaisa Nordenswan: Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis. The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up. Dr. Carolyn Lam: Great. What did you find? Dr. Hanna-Kaisa Nordenswan: So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis. Dr. Carolyn Lam: Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings. Dr. Jukka Lehtonen: Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis. So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients. So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases. Dr. Carolyn Lam: Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk. Dr. Mark Link: Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid. Dr. Carolyn Lam: Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah? Dr. Jukka Lehtonen: I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well. Dr. Carolyn Lam: Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD? Dr. Hanna-Kaisa Nordenswan: Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up. Dr. Carolyn Lam: That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark? Dr. Mark Link: Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data. Dr. Carolyn Lam: Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first? Dr. Jukka Lehtonen: Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference. I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group. Dr. Carolyn Lam: Thank you, Hannah? Dr. Hanna-Kaisa Nordenswan: Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography. Dr. Mark Link: Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue. Dr. Carolyn Lam: Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Bu soğuk kış gününde belki de spordan biraz olsun uzaklaştığımız bu zamanlarda, sizlerle yeniden bir spor travmalarına yaklaşım yazısıyla karşınızdayım. Önceki yazılardan farklı olarak bugün travma çeşitlerinden çok tedavi modalitelerinden biri olan PRP tedavisi hakkında bilginlendirme yapmak amacındayım. Sosyal medya üzerinden yapmış olduğum ankete katılımlarınız için hepinize teşekkür ederim. Ankette de görüldüğü üzere yazımızın konusu olan PRP hakkında çok fazla bilgimizin olmamasıyla birlikte acilci.net'e olan güven bizleri gururlandırmaktadır. Bilinenleriyle ve bilinmeyenleriyle gelin hep birlikte PRP'yi tanıyalım. Keyifli okumalar ve bizzat seslendirdiğim podcast ile takip etmek için keyifli dinlemeler. Kahveler hazırsa başlayalım. Giriş PRP (trombositten zengin plazma); tendon, bağ, kıkırdak ve kemik dokuyu içeren spor yaralanmalarının tedavisinde kullanılan biyolojik bir tedavi yöntemidir​1​. PRP hastadan alınan tam kanın santrifüje tabi tutularak trombosit içeriği yoğunlaştırılmış plazma komponenti olarak tanımlanmaktadır​2​. İlk olarak 1950 yılında oral ve maksillofasiyal cerrahi tedavilerinde kullanılmaya başlanmıştır​3​. Sonraki yıllarda ise kemik ve yumuşak doku yaralanmalarında da uygulanması yaygınlaşmıştır​4​.  Bu tedavinin spora geri dönüşü hızlandırdığı düşünülerek elit sporcularda akut kas ve bağ doku yaralanmalarında kullanılmaktadır. Bu avantaj nedeniyle aslında Dünya Dopingle Mücadele Ajansı (WADA) 2010 yılında PRP tedavisini yasaklı listeye dahil etmiş fakat daha sonra 2011 yılında listeden çıkarmıştır​5​. Son dönem yapılan çalışmalar, medyanın ilgisi ve sporcularda yaygın kullanımı nedeniyle PRP uygulamaları giderek artmıştır. Neden PRP? Aslında bu başlığın adı neden trombosit olarak ta düzenlenebilir. Çünkü artık hepimiz biliyoruz ki PRP dediğimiz tedavi trombosit kökenli bir biyolojik tedavi yöntemidir. Peki trombositin yara iyileşmesindeki rolü nedir? Trombositler megakaryositlerin parçalanmasıyla elde edilen ve iyileşme sürecinin ilk günlerinde en erken pik yapan periferik kandaki hücrelerdir​6​. Trombositler dokuların yenilenmesi de dahil olmak üzere onarım sürecini düzenleyen yüksek konsantrasyonda sitokin ve bir grup büyüme faktörünün kaynağıdır​7​. Bu faktörlerin başlıcaları şunlardır: IGF-1, TGF-B, PDGF, VEGF ve b-FGF. Trombositlerdeki dens granüllerde bulunan serotonin, adenozin, dopamin, kalsiyum, histamin, ADP, ATP ve katekolamin de doku yenilenmesinde rol alırlar​8​. PRP Nasıl Hazırlanır?  Tam kandan 3-5 kat daha yüksek oranda trombosit ihtiva eden PRP'nin hücre göçü, hücre proliferasyonu, anjiogenez ve matriks sentezini uyararak iyileştirmeyi başlattığı gösterilmiştir​2​. Hastadan alınan belirli miktardaki tam kana sitrat eklenerek iyonize kalsiyum bağlanır ve santrifüj öncesi pıhtılaşma önlenir. Böylece kan 3 tabakaya ayrılır. En alt tabaka eritrosit, orta tabaka trombosit ve lökosit ve en üst tabakada ise plazma bulunur. PRP hazırlama süreçleri iki ana sorunu beraberinde getirmektedir. İlk olarak kişiye özgü olarak periferik kandaki trombosit sayısı ve içerdikleri faktörlerin değişiklik göstermesidir. İkinci olarak ise alınan kan miktarı, kullanın antikoagülan madde, santrifüj sırasında uygulanan G kuvveti, dönme süresi ve çevirme sayısına bağlı olarak PRP'nin içeriğinin değişebilmesidir. Yukarıda bahsi geçen handikaplar bazı güncellemeleri de beraberinde getirmiştir. Örneğin, PRP'ye içindeki trombositleri aktive etmek amacıyla çeşitli aktivatörler eklenmektedir (kalsiyum klorid, trombin gibi). Aktivatör kullanımıyla beraber faktörlerin salınımı 1 saat gibi kısa bir sürede sağlanabilmektedir. Sektörde yer alan birçok markaya ait birden fazla kit olup, bu kitler ile ilgili çalışmalarda her birinin farklı konsantrasyonlarda farklı faktörleri içerdiği görülmüştür. Durum böyle olmuşken yapılan çalışmalarda tam olarak kabul görmüş PRP hazırlama protokolü net olarak ortaya konulamamıştır​9​. Standart protokolün olmaması,

W naszym organizmie często dzieje się tak, że albo coś się nie chce goić i chcemy zrobić coś, aby gojenie wreszcie nastąpiło, rozpoczęło się, albo co prawda goi się, ale chcielibyśmy to gojenie przyspieszyć lub jakoś poprawić jego jakość. Czy coś takiego jest w ogóle możliwe?Będzie o tym dlaczego tkanki się uszkadzają - błędy treningowe i chorobyDlaczego dieta jest ważna?Przybliżę temat czynników wzrostu. Możesz też posłuchać w sposobach wspomagania gojenia kości w odcinku 25. Wszystkie materiały o tym na www.drmick.pl/025

This month on Episode 8 of the Discover CircRes podcast, host Cindy St. Hilaire  speaks with Nikki Purcell and  Sean Wu, the chair and vice-chair of the BCVS Early Career Committee. The episode also features an interview with the 2019 BCVS Early Career Finalists, Dr Luigi Adamo, Dr Swati Dey, and Dr Jihoon Nah. In addition, we highlight three featured articles from the January 3 and January 17, 2020 issues of Circulation Research.   Article highlights:   Souza, et al. Upregulation of Plasma SPM by Enriched Marine Oils   Paredes, et al. Metabolic Control of VSMC Phenotype   Ritterhoff, et al.  ACC2 Deletion Prevents Aspartate Synthesis Transcript Dr St. Hilaire: Hi. Welcome to Discover CircRes, the podcast of the American Heart Association Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. The goal of this podcast is to share with you highlights from recent articles published in the Circulation Research Journal. But today, we're going to have a special edition focused on early career. The American Heart Association has 16 different councils. One of which is basic cardiovascular sciences,  or BCVS. The BCVS Scientific Sessions is held annually and brings together basic and translational cardiovascular scientists from around the world. It has become the go-to meeting for intra and interdisciplinary cross fertilization of ideas in basic cardiovascular research. The overarching goal is to integrate molecular, and cellular, and physiological approaches to address problems relating to functional genomics, cell signaling, myocardial biology, circulatory physiology, pathophysiology, and peripheral vascular disease. In addition to highlighting new approaches and discoveries from the general scientific community, the BCVS Council also plays a pivotal role in training the next generation of junior scientists and trainees. At the recent meeting in Boston, I had the opportunity to interview the chair and vice chair of the BCVS Early Career Committee, Dr Nicole Purcell from UCSD, and Dr Sean Wu from Stanford University, as well as the three finalists of the Outstanding Early Career Investigator Award competition, Dr Luigi Adamo, Dr Swati Dey, and Jihoon Nah. Hope you enjoy. Before we get to our interviews with the BCVS early career committee chairs, and the finalists of the BCVS Outstanding Early Career Investigator Award, I want to give you a few highlights from three articles that were published in the January 3rd and January 17th issues of Circulation Research. The first article I'd like to highlight is titled Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study. The first authors are Patricia Souza and Raquel Marques, and the corresponding author is Jesmond Dalli, and they are from Queens Mary University of London. So, this study is attempting to answer the longstanding question of whether I should or should not take fish oil supplements. Once ingested into the body, essential fatty acids, which is a group that includes those that are found in fish oils--those fatty acids are converted into molecules called specialized pro resolving mediators, or SPMs. SPMs can reduce inflammation and can also promote a process called phagocytosis where immune cells can essentially eat up dead cell debris and also micro-organisms like bacteria. While these actions are beneficial, whether ingesting fish oils translates to beneficial cardiovascular effects in humans, is unclear. Some studies show the oils reduce inflammation, while others have shown no effect. And part of the lack of clarity on this is that in previous studies there was no impartial measure of the clinical efficacy of the supplements. So to combat this, Souza and colleagues performed a double blind, placebo-controlled crossover study to determine the effects of marine oil supplementation, which by the way was tested at three different concentrations on both SPM levels and on immune cell function. Now for those of you who are unfamiliar with the clinical trial lingo, that means that both the patients, and the scientists, and the doctors did not know who got what pill, whether they got the placebo or the fish oil, and each patient was tested with both the placebo and with the fish oil so that they could be somewhat used as their own control at the end of the study. The scientists then obtain the blood from the patients before and then during the experiment at several time points. Blood samples from the subjects revealed a dose dependent increase in SPMs that was significant in the two high dose groups. Meaning the more fish oil they took, the more beneficial effects we're seeing. These effects peaked a few hours after they ingested the fish oil. Further, they found that high dose blood samples, monocytes and neutrophils, so those are inflammatory cells, those cells had increased phagocytic activity, while leukocyte activation, which is a sign of inflammation, was decreased. These beneficial effects persisted after SPM levels returned to baseline. These results suggest that SPMs are not only likely mediators of fatty acid-induced immune effects, but perhaps they could be useful efficacy indicators for future trials. The second article I want to share with you is titled Mitochondrial Protein Poldip2 Controls VSMC Differentiated Phenotype by O-Linked GlcNAc Transferase-Dependent Inhibition of a Ubiquitin Proteasome System. The first author is Felipe Paredes and the corresponding author is Alejandra San Martin, and they are located at Emory University in Atlanta, Georgia. So, I've said it before and I'll say it again, we all learned in elementary school that the mitochondria are the powerhouse of the cell. The nuclear encoded protein, Preliminaries Interacting Protein Two or Poldip2, is required for the activity of the TCA cycle, which is called the tricarboxylic acid cycle. It's also known as the citric acid cycle, and it's also known as the Krebs cycle. So interestingly, this nuclear protein, Poldip2, has effects on mitochondria, which as we also know have their own DNA encoding some of their proteins. So, Poldip2 deficiency reduces the activity of the citric acid cycle, which then induces a shift in the metabolic reprogramming, which leads to a lower rate of oxidative metabolism, and a higher glycolytic rate. So previously, this group found in mice that were heterozygous knock-outs for Poldip2, that these mice exhibited no avert phenotypes at baseline, but after an injury they actually showed protective effects. This was done with a wire induced injury that causes neointima formation, and also in an experimental aneurysm model. In normal healthy vessels, smooth muscle cells reside in a quiescent state. However upon injury, they can be induced to lose their fully differentiated smooth muscle cell phenotype, and acquire a more plastic, undifferentiated state. And in that state, these cells can migrate, proliferate, and in some cases even transdifferentiate where they acquire non-smooth muscle cell-like markers. The investigators, because of these phenotypes in response to injury, decided to look at the role of Poldip2 in metabolism in the phenotypic switching of smooth muscle cells. They found that reduced levels of Poldip2 in vascular smooth muscle cells in vitro induced the expression of transcription factors that are necessary for the expression of smooth muscle specific markers. And further, repressed the transcription factor KLF4, known to promote the loss of the smooth muscle contractile phenotype. Poldip2 deficient mouse aortas expressed high levels of contractile proteins, and more significantly did not de-differentiate or acquire macrophage-like characteristics when exposed to known stimuli, cholesterol, or PDGF. These effects are caused by inducing the enzymes that perform protein glycosylation, which helps to stabilize smooth muscle specific transcription factors yet repress the differentiation factor KLF4. Altogether, this work suggests that mitochondria metabolism and mitochondria-induced signaling plays a main role in the maintenance and phenotypic switching of vascular smooth muscle cells, and that this access could be targeted to modulate smooth muscle phenotype during vascular diseases. Sticking with the metabolism theme, the last article I want to share with you before our interviews is titled Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis. The first author is Julia Ritterhoff, and the corresponding author is Rong Tian, and the work was completed at the University of Washington School of Medicine in Seattle, Washington. Cells of hypertrophied hearts switch from using fatty acids for energy production to glucose. This is less efficient. It has been shown that preserving fatty acid oxidation prevents the pathological shift of substrate preference, which then preserves cardiac function, and improves energetics, and reduces cardiomyocyte hypertrophy. While the effects of preserving fatty acid oxidation are well known, it remains unclear whether substrate metabolism regulates cardiomyocyte hypertrophy directly, or whether this metabolic shift is a secondary effect of improving cardiac energetics. So to that end, the investigator sought to determine the mechanisms of how preservation of fatty acid oxidation prevents the hypertrophic growth of cardiomyocytes. They went about this in two ways, in vitro and in vivo. And so for in vitro, they took some cultured adult rat cardiomyocytes, and they grew them in a medium that contained glucose and mixed chain fatty acids and induced pathological hypertrophy by supplementing these cells with Phenylephrine. This hypertrophy in a dish caused increase glucose consumption and higher intracellular aspartate. Interestingly, adding aspartate alone was enough to promote hypertrophy. In vivo, they found that fatty acid oxidation prevented the metabolic shift to anabolic energy production, which further prevented cardiac hypertrophy, and overall improved myocardial energetics. Together their data shed new light on the contribution of intermediary metabolism, specifically aspartate to the hypertrophic growth of the heart. They found that aspartate synthesis is a rate limiting step, and they found that specific mechanisms for aspartate production support growth and proliferation of postmitotic cells, and these studies now provide potential therapeutic strategies to target for reducing cardiac hypertrophy. Okay, well I'm here with the BCVS Vice Chair and Chair of the Early Career Committee, Nikki Purcell and Sean Wu. Thank you for coming. Nikki Purcell: Thank you for having us. Sean Wu: Yeah, thank you. Dr St. Hilaire: Yeah. I was wonder if you could just introduce yourselves and maybe a little bit about where you are in your career. Sean Wu: I'm Sean Wu. I'm at Stanford University. I'm part of the Stanford Cardiovascular Institute. I do both clinical work as a general cardiologist, and I also work on research in stem cell and developmental biology. Dr St. Hilaire: And how long have you had your lab? Sean Wu: I have had my lab for about 10 years now. Dr St. Hilaire: That's good. Success story. How about you, Nikki? Nikki Purcell: All right. I am at the University of California, San Diego, in the Department of Pharmacology. I'm an Associate Professor there. My research deals with phosphatases in the heart and their role in cardiac hypertrophy and heart failure. And I've gotten my position as a professor for about eight and a half years now. Dr St. Hilaire: Excellent. So, my lab just had its fourth birthday, so we're still on the, okay, we're moving up. We're moving up. Nikki Purcell: Congrats. Dr St. Hilaire: Yeah. Sean Wu: Congrats, yeah. Fantastic. Dr St. Hilaire: Yeah. Thank you. So, what is the role of the BCVS Early Career Committee? Nikki Purcell: So, the real role of the Early Career Committee is to support early career investigators. And our role in the AHA is, one, to keep the early career investigators engaged in the AHA and BCVS, but also to help them with their questions as they transition from either their predoc to their postdoc, or getting their first faculty position. So, we try to make events where they can network, and get the mentorship they need, and help them along the way. Sean Wu: And also, the Early Career Committee serve as a connector between the early career and the bigger AHA with all the different activities that we have. But it also connects the early career member with each other because we feel like having an opportunity for them to be able to meet people in their similar stages of training, they can share stories with each other, and build a network of scientists themselves as they grow up into being full faculty. Dr St. Hilaire: Great. So, what kind of events are these that you use to either help bring them together or help them move along? Nikki Purcell: We've done multiple along the years. One of the ones that is really popular is probably our mentor lunches where we actually have established PIs from all different fields come in, and the one that's worked we've done the speed dating, but that's hard to get everybody in. And the last one we did was we had 12 to 13 people around a table with two PIs and that worked amazing. And they had that chance because a, early career sometimes don't like to talk as much- Dr St. Hilaire: You're a little shy. Nikki Purcell: ... but other people are going to ask questions they want to hear. So, it was a great opportunity. And for network we had a mentoring talk. So, that's one of the things we do is to try to connect people with other people in their field that maybe they are afraid to normally just go up to. But it's a much more relaxed setting I would say. Sean Wu: We also have some of the mainstream session, so having well known people come up and talk about their career, like the ones that we just now have with Litsa Kranias describing her long and distinguished career as a scientist with some of the lessons that she's learned along the way. But we also like to offer people opportunity to experience what the careers of people who have not necessarily done in academic, but into industry, in the legal world, or into the venture world to give the trainees some ideas of what they could do with their career. So, that's one of the sessions that we have this time called, Oh, The Places That You'll Go, so that they can actually see what the opportunities that they have as they complete their training in science and looking forward to the next stage of their career. Dr St. Hilaire: That's so important because I mean, what is it, maybe 10% to 20% of people actually stay and go on in academia? Nikki Purcell: And we get a lot of questions on mentors, and how do we find our mentors. And so, the other session that we're having is our Lunch and Learn really is to show new faculty with their chairs, postdocs with their mentor, and graduate students with their mentor, and really get it that the early careers can ask them questions. Especially if you're leaving the lab, how are you taking your project? How did you work that out with your mentor? You're a new faculty, how did you negotiate? All those questions that they don't teach you maybe so much along the way. Dr St. Hilaire: No. They don't. Nikki Purcell: So, we're having the panel up there so that they can throw questions at them- Dr St. Hilaire: That's great. Nikki Purcell: ... and really ask from Chair down to the graduate student. Dr St. Hilaire: And so, we're at the BCVS conference right now recording this, but you have events also at the AHA Scientific Sessions in the fall? Nikki Purcell: Yes. Sean Wu: Mm-hmm (affirmative). Dr St. Hilaire: Is there any non-conference related things? Do people ever kind of cold call the ECC saying, "I need advice," or is that a thing? Nikki Purcell: We've gotten emails, yeah. Sean Wu: Yeah. Right. Nikki Purcell: Yeah. We're really accessible. Yeah. Sean Wu: We've had inquiries, too. Dr St. Hilaire: Yeah. Sean Wu: Yeah. Besides things that we do at the meetings, we just now have this brand-new mentoring program with the BCVS where a young investigator, if they like to be able to interact with certain established investigator, can now make a request and apply to be able to make a travel visit. Dr St. Hilaire: Very nice. Sean Wu: And so, we have a full list of mentors who are willing to either sponsor the person, or both sponsor and provide some financial support for the training to come. Dr St. Hilaire: Wow, so you've already gotten buy-in from these senior mentors. Sean Wu: Yeah. Right. Nikki Purcell: Yeah. Dr St. Hilaire: That's wonderful. Nikki Purcell: We have over 30 mentors who have said yes, and we're always looking for more. So, if there's faculty out there. And what's great is also it gives a chance for let's say you want to transition to a different field, if you're a grad student postdoc it gives you that chance to meet that lab in that new field that you're interested in. And it's also for young PI, so if you're just starting out your lab, and you want that little help in that field, so it's open to that, too. So, we're really excited about that new program. Sean Wu: And I think it provides them a lot of opportunity to get exposure. Because that's one thing that the young scientists always tells us about, it's hard for them to really get to meet people or get other people to know who they are and what they do. And the Early Career Committee is one that really helped facilitate giving people opportunity, and put them in front of other people to help getting leadership training, and getting exposure. Nikki Purcell: And this year, we're actually having the poster competition, which we've never had before. So again, three established judges will definitely come to all these posters and speak to them, and that also gets them exposure. So, we're giving out five awards to both the early career trainees as well as postdoctoral. Dr St. Hilaire: That's wonderful. Nikki Purcell: Yeah. And so, we'll have some honorable mentions, too. The more people we can recognize, the more names we can get out there. Dr St. Hilaire: Absolutely. I remember one of my very first conferences as a postdoc, we just kind of made this discovery of a new disease, and I had written down the names of five big names that I was like, "I know they're going to be at that meeting. I really want to meet them." And I just had business cards at the ready, "Please come to my poster. Please come to my poster." That's the biggest fear as a poster presenter, what if nobody comes? What if I can't share this? So, I think that's an amazing avenue of interactions you've created. Nikki Purcell: And we have over 200 that have applied for our award, but there's 600 posters. And we know that a large proportion of those are Early Career. Sean Wu: Yeah, yeah. Dr St. Hilaire: That's great. If there's one thing a trainee, or a postdoc, or even junior faculty could do at a conference, of this size at BCVS we're about I think 500 to 1,000 people. Nikki Purcell:1,000 this year. Dr St. Hilaire: 1,000 this year. Amazing. Nikki Purcell: 1,000. Biggest conference ever. Dr St. Hilaire: That's wonderful. Oh, that's great. Sean Wu: Yeah. That's right. The first time. Dr St. Hilaire: So, 1,000 at BCVS versus, I don't know, the tens of… Nikki Purcell: Yeah. 13,000. Dr St. Hilaire: 13,000 at Scientific Sessions. What can someone who just feels lost in this little sea of all these big people do? What would you recommend as advice to a more junior person to interact? Nikki Purcell: I would say one, find us, because if we know your name and we know what you do, we promote the early careers, and we try to, and I would introduce who I'm with. In our social event that we have at Tuesday night brings together not only early career but the established investigators. It's everyone can come in, and we try to welcome that. My biggest thing, and when I met with a small group the other day of postdocs and students, is just grab people. You see people walk past your poster, start saying, "Are you interested in seeing what I'm doing?" Engage them. People are going to look at your poster and keep walking, but if you engage and are excited about what you do, they're going to be excited to say, "Oh, okay. I'm going to stop and listen." So, my big thing is get out of your comfort zone and just engage. Sean Wu: I do think that it is a little daunting. If you were just starting out as a new graduate student, and you have never been to an AHA meeting, and especially if you go to the annual session in November, it does feel a little bit like you're just overwhelmed by too many people, too many sessions, too much- Nikki Purcell: It's too much walking. Sean Wu: Right. Too much going on. And I do think that the Early Career Committee is what gives you a little bit more of a home for you as a trainee because by, at least, starting out meeting other people in the specific sessions that we create for them, now they can start building their network from a much more cozier, comfortable environment of the Early Career Committee activity. And before eventually moving out to get to know more people in other councils and the bigger AHA. Hopefully that also allows people to get excited about taking on more of a leadership role in the AHA down the row in the future as they become more familiar. Dr St. Hilaire: Well, thank you so much Dr Sean Wu and Dr Nikki Purcell. Everyone come to BCVS and meet them in person. Nikki Purcell: Thank you. Sean Wu: All right, thank you. Dr St. Hilaire: Yes. Thank you. Nikki Purcell: Thank you so much. Dr St. Hilaire: All right, so now we're going to talk with the three finalists of the outstanding Early Career Investigator Competition that's held annually at the BCVS Conference. With me today is Dr Luigi Adamo, Dr Swati Dey, and Dr Jihoon Nah. So, welcome all of you. Jihoon Nah: Thank you. Thank you for inviting us. Dr St. Hilaire: Yeah, thank you. Swati Dey: Yeah. Nice to meet you. Dr St. Hilaire: Congratulations again on becoming the finalists. I don't know how many submitted, but I know it's always very steep competition. Jihoon Nah: Well, thank you. It's an honor to be here. Dr St. Hilaire: Maybe we can all take a turn, and you can just give a quick introduction. Say where you're at, and what stage you're in in your career. Jihoon Nah: Yes. So, I'm Jihoon Nah in Rutgers University, and I'm now a post doctorate fellow in Dr Sadoshima’s lab. Dr St. Hilaire: How long have you been there? Jihoon Nah: I came to USA three years ago from South Korea. Dr St. Hilaire: Oh, goodness. How do you like it? Jihoon Nah: Yeah, very good. Dr St. Hilaire: Very Good? Jihoon Nah: Yeah. Dr St. Hilaire: Good. Luigi Adamo: So, hi, my name is Luigi Adamo. I'm a physician scientist. I'm a cardiologist at Washington University in St. Louis, and I just concluded this long training as a physician scientist doing residency fellowship, advanced fellowship, postdoc final, and faculty. I'm an instructor of medicine there, and I'm looking for starting my own lab. So, it's a transition phase. Dr St. Hilaire: Ah, so maybe we can use the podcast to promote you. Luigi Adamo: Oh, anybody want a motivated physician scientist in cardio immunology? Please send me an email. Dr St. Hilaire: Perfect. Okay. Wonderful. Swati Dey: So, my name is Swati Dey. I am a new PI. I started my lab at Vanderbilt University Medical Center a couple of months ago. So, it's a really new experience for me right now. I did my postdoctoral training from Johns Hopkins for about four years with Dr Brian O’Rourke, and then for two years I was a junior faculty. And like I said, I recently transitioned. Dr St. Hilaire: Yeah, yeah. Excellent. So, we got kind of three different spots in the career. I'm also relatively new faculty. I got my lab in 2015, so we just had our fourth birthday, and I have at the same time feelings of I've been here forever and I'm still brand new. Hopefully we can share some of the early career ups and downs with everybody who's listening. So, thanks again for coming. Dr St. Hilaire: I was actually wondering, how did you guys ... We're all in the cardiovascular field, and at this conference in a little bit more cardiology than the rest of it, so how did you get into this field? What was your path? Swati Dey: So for me, it was I don't know how I got there. I have been very lucky. Dr St. Hilaire: It just happened. Swati Dey: No. So, my PhD was from Ohio State. I got a PhD in microbiology. Dr St. Hilaire: Interesting. Swati Dey: And then, I was looking for postdocs. So when I was young, my mother, she passed away due to a cardiac condition. So, when I got an opportunity to start a postdoc in a cardiovascular lab studying cardiovascular diseases, I just couldn't believe that this would just fall in front of me. I just went with the flow. It was a little hard in the beginning because the learning curve is essentially longer. Dr St. Hilaire: I'm sure. Swati Dey: I had no background in cardiac physiology, electrophysiology, anything related to cardiac. But it was also fun. I was learning so many new things. Everything I did was just brand new, and it made my postdoctoral training period so exciting, and I was just feeling proud of myself, everything I accomplished. Dr St. Hilaire: Well, the title of your talk, I'm not going to read it because it's very long, but essentially, you're looking at the neurocardiac access, and how that can be manipulated to help with myocardial infarction treatments. You've gone from teeny tiny bugs to ... Swati Dey: Absolutely. Yeah. It's been great. So yeah, this work essentially focuses on nonischemic heart failure. So sudden cardiac death, like if you have been to my talk, it talks about it happens in patients with even before the signs and symptoms of heart failure appear. Like very early stages of heart failure. I could be doing late stage of heart failure, too. So, there's no signs and symptoms for sudden cardiac death. Swati Dey: And to prevent that, there are very few treatment options available. There are ICDs, the defibrillators, but they are expensive, and if you go running they might just shock you,. So there are very appropriate shocks, but there are also inappropriate shocks. So, the quality of life for these patients are very poor. And I remember when I started working on this project, we got some human samples of patients who were my age, and they had defibrillators, and they were in such poor health that they had to go through this new surgical treatment. And it was so exciting to study the underlying mechanisms because I could see it translate into the real world. Dr St. Hilaire: And in people young enough to really benefit from it. That's wonderful. That's a great story. Luigi Adamo: Great story. Dr St. Hilaire: Yeah. I started in microbiology, too, actually with a fungal genetic lab. Swati Dey: Oh, wow. Dr St. Hilaire: Yeah. Now I do valve research, so it's funny where it takes you. Swati Dey: Yeah, exactly. Dr St. Hilaire: Luigi, how'd you get in this field? Luigi Adamo: So today, I presented work about B-cells in the heart. I think God has a good sense of humor, and also kind of serendipitous stories. So, I've always wanted to do cardiology. My dad is a cardiologist. But so, I did a PhD in hemodynamics, and then when I joined the physician scientist, phew, I actually ended up doing cardiac inflammation and heart failure just because I was so strong there. And I picked a mentor, Dr Doug Mann, a giant in cardio inflammation, but he didn't want to study B-cells, I didn't want to study B-cells. So, I started doing a different experiment, and then a friend was teaching me how to do a flow cytometer and heart samples gave me as a control an anti B-cell antibody. Luigi Adamo: And then, I remember telling her, "Why do you give me this?" It was like, "Whatever. We need a control in that color." And then in my model, I saw this dramatic effect on B-cells, and then I kept doing my experiments, and all my hypotheses were wrong, and there was always a signal on B-cells- Dr St. Hilaire: Oh, that is so funny. Luigi Adamo: ... and it was you know what? I think I need to study B-cells. Dr St. Hilaire: I think there's a B-cell there. Luigi Adamo: And it was a blessing because I might be one of the very few people in the world studying B-cells in the heart, and that's what I think sometime make people interested in my work because there's very little known about it. Dr St. Hilaire: Yeah. And how about you? What's your story? Jihoon Nah: So when I was a PhD student, I was working on some molecular biology in neurons. But it was a little bit basic in the field, and I just focusing on some cells, some intracellular cells And after I got my PhD, I want to move my field from basic to more clinical field. And I have a lot of interest in autophagy and mitophagy, and I tried to find some post doctorate position in more some clinical field which focusing on autophagy. And fortunately, I can join Dr Sadoshima’s laboratory, focusing on autophagy and mitophagy in cardiovascular disease. That's what I can do in this field. And I think autophagy is a very important role, especially in non-dividing cell like a cardiomyocyte. And I can allow many news and knowledge [inaudible 00:26:54] in this cardiovascular field, and I knew there are many things that are known about the role of autophagy or mitophagy in cardiovascular disease. And I think I want to stay this field, yeah, to find- Dr St. Hilaire: Yeah? You don't think you'll switch? Maybe like the microbiology, that hard switch. Jihoon Nah: Yeah. I really like this field. Dr St. Hilaire: Well, you say that. We're going to come back in five years and we'll see. Dr St. Hilaire: So, everyone's a little bit early career. So, what's really been a hard hurdle for you to overcome? Whether it was in a particular experiment, or paper, or just in the career itself. Swati Dey: It wasn't a hurdle, but one thing which took a long time to learn and was very hard was grant writing. So as a postdoc, so Hopkins is a great institution, but also you're competing with people who are equally, or well, actually smarter than you. Dr St. Hilaire: Well and also, if it's English as a first language versus English as a foreign language, I can't imagine. Swati Dey: Exactly. So, the tools and techniques to write your science on paper is not easy to communicate such that I understand my science, but to make another person convinced that my science is good, it's not easy. So, I think grant writing has been the hardest thing I had to learn. Because as a graduate student, you don't write. So, other things I knew I could do, it was in my control, but grant writing required so much rigorous training. And I'm happy I had colleagues and my mentor who took the time out to actually make my entire grant red. It came back with all tracking and comments, and- Dr St. Hilaire: Oh, yeah. I know. It's so disheartening. Swati Dey: It's actually so helpful. Dr St. Hilaire: Yeah, yeah. Swati Dey: But yeah, they took the time out. They thought that they were invested in my success, and my colleagues, and my mentor. Dr St. Hilaire: So essentially, you kind of formed a mentoring team that really helped train you or teach you how to properly write a grant. Swati Dey: Yeah. Dr St. Hilaire: That's really good advice for people to have. Swati Dey: And it doesn't really have to be someone who is very senior. Maybe someone who is recent. You have to find people who have been successful in that particular phase of science. Let's say grant writing, or maybe networking, which is also very important, or doing certain techniques. Reach out to different people, seek help, and learn from them, and never think that you are just too good or someone is going to judge you. That's the problem more that we think that if we go to someone with our weaknesses, they're going to judge that, "Oh, you're not good enough," but we all are not good enough in some parts. Dr St. Hilaire: Yeah. We're all weak at some point. Exactly. Swati Dey: Yeah. Dr St. Hilaire: Oh, that's really great advice. Luigi Adamo: I agree with all that. It sounds like very wise and very thoughtful. I am a physician scientist, as I mentioned. For me, one thing that has been very hard has been the length of the path because when you try to do both things, and you have the passion for both, it just takes a long time. And then, there are people that ... people who did their PhD with me, and they did it well as I did, or maybe a little bit more, I don't know, but then they were already an established investigator, and I was a trainee back to the bottom. And then, I was doing medicine, and then my classmates were leaving and getting big jobs, and I was back in the lab. And it just it takes a very supportive family, a lot of dedication. I think if you have that fire and passion for science and for medicine, it just keeps you afloat. But sometimes it's hard. Dr St. Hilaire: How about you? Any big hurdles yet or not? Jihoon Nah: No. So fortunately, I think with the experiment. I think I have a very small some problems, and I can overcome every time. But in my case, it always feels a little bit difficult to grant-writing because using English is very difficult to me. And also, in my case, I came USA around the two and half years later after I got my PhD degree. And many of fellowship, or first doctor fellowship, or grant has some time limitation within four years of the PhD degree. So, it's very tough to me to get a grant. Dr St. Hilaire: No, that's a really good point. I don't think enough graduate students fully understand all the different requirements of getting the postdoc, and then knowing if you want to write a K grant you need to have a project at year two because you'd have to submit it about twice, and you need the timeframe to resubmit it. And that's the thing that's really important that I don't think we spend enough time teaching trainees on. Swati Dey: My PhD was not in cardiovascular sciences, so I did not know what a K grant was. Dr St. Hilaire: Sure. Swati Dey: So when I came in, after two years I started seeing, okay, people are talking about this Dr St. Hilaire: What is this K99? Swati Dey: What is it? And apparently, a lot of my colleagues they had this in their life plan. They planned this out when they were still in their, probably med school, or in the graduate school, and I had no clue. Dr St. Hilaire: I was similar. I'm actually the first one in my family to go to college, let alone get a PhD and become a professor. And I can remember at every step of the way always finding people who I was like, "How did you already know this? How did you know what this award was, or to apply for this grant, or to go to a conference?" And I think that's partly why we want to have these conversations and get them out there is so that people in similar situations at least hear what these are in time, and have those opportunities. Dr St. Hilaire: All right. So, we'll end with a question that hopefully can help everybody else. If you could go back and give yourself any piece of advice, or any bit of nugget of knowledge that would help you had you known it then, what would you say? What would be one little thing you'd want to tell your past self? Swati Dey: Meet with your PI very early on, and sketch out your career plan. Luigi Adamo: I actually…I was about to say the same thing. I've been blessed with great mentors, but I think it's very important to have open communication about expectation and goals because very appropriate goals could be different in the minds of people. Then, there are personal needs, there are personal feelings about things. And in the end, a good mentor, if you set a goal, will help you work toward that goal. Dr St. Hilaire: How about you? You're still early, early, but that's okay. What would you tell your grad school self? Jihoon Nah: I'd say it's very interesting question. So, when I was a PhD student, I didn't want to learn some new techniques, and I think I was a little afraid to learn new techniques. And also, I feel it's very difficult and I frustrated my PI to set up new things in the laboratory. I think if I can beg, I want to say I just want to learn new techniques, and I just want to try to push my PI to set up new things because it’s very important to support our hypotheses. Swati Dey: No, he said something very important. I noticed this. Some of my fresh PhD friends, I asked them to apply to a good lab for postdoc. They're like, "Oh no, I am molecular biology. I can only do what will ... If I switch fields, I can't learn anything new." Dr St. Hilaire: Yeah. I can't do that. Swati Dey: Yeah. That's not true. You can switch fields. Go from engineering, to science, to English, to anything if you want to. Dr St. Hilaire: Absolutely. Jihoon Nah: And one more thing then. In my case, I came USA a little bit late after I got PhD degree. I just want to recommend to somebody who want to go some overseas to study, I think it's better to decide earlier, and try to just go to overseas as soon as possible. Dr St. Hilaire: Yeah. Do you guys want to add anything else? Luigi Adamo: I would say thank you. Jihoon Nah: Yeah, I'm very happy. Swati Dey: Yeah, me too. Dr St. Hilaire: Thank you. This has been really fun. Thank you for coming, and we'll talk again soon. Jihoon Nah: Thank you. Luigi Adamo: Thank you. Dr St. Hilaire: That's it for this special early career focused edition of Discover CircRes. Thank you for listening. Dr St. Hilaire: This podcast is produced by Rebecca McTavish, and edited by Melissa Stoner, and sponsored by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your source for the most up to date and exciting discoveries in basic cardiovascular research.

Cancer-associated fibroblasts lay the tracks for directional migration Cancer-associated fibroblasts, or CAFs, regulate tumor progression by secreting chemokines and remodeling the extracellular matrix. Erdogan et al. reveal that the CAF-dependent alignment of fibronectin promotes directional cancer cell migration. This biosights episode presents the paper by Erdogan et al. from the November 6th, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Begum Erdogan and Mingfang Ao (Vanderbilt University, Nashville, TN). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

KOLs, CEOs, and analysts say Ophthotech’s disappointing Fovista trials alter the landscape for companies developing new treatments for wet AMD. And all agree, the biggest losers in all of this are patients suffering from the disease.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Thu, 29 Mar 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/14217/ https://edoc.ub.uni-muenchen.de/14217/1/Wuchrer_Alexander.pdf Wuchrer, Alexander

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that plays a key role in the pathogenesis of osteoarthritis (OA). Growth factors (GFs) capable of antagonizing the catabolic actions of cytokines may have therapeutic potential in the treatment of OA. Herein, we investigated the potential synergistic effects of insulin-like growth factor (IGF-1) and platelet-derived growth factor (PDGF-bb) on different mechanisms participating in IL-1β-induced activation of nuclear transcription factor-κB (NF-κB) and apoptosis in chondrocytes. Primary chondrocytes were treated with IL-1β to induce dedifferentiation and co-treated with either IGF-1 or/and PDGF-bb and evaluated by immunoblotting and electron microscopy. Pretreatment of chondrocytes with IGF-1 or/and PDGF-bb suppressed IL-1β-induced NF-κB activation via inhibition of IκB-α kinase. Inhibition of IκB-α kinase by GFs led to the suppression of IκB-α phosphorylation and degradation, p65 nuclear translocation and NF-κB-regulated gene products involved in inflammation and cartilage degradation (COX-2, MMPs) and apoptosis (caspase-3). GFs or BMS-345541 (specific inhibitor of the IKK) reversed the IL-1β-induced down-regulation of collagen type II, cartilage specific proteoglycans, β1-integrin, Shc, activated MAPKinase, Sox-9 and up-regulation of active caspase-3. Furthermore, the inhibitory effects of IGF-1 or/and PDGF-bb on IL-1β-induced NF-κB activation were sensitive to inhibitors of Src (PP1), PI-3K (wortmannin) and Akt (SH-5), suggesting that the pathway consisting of non-receptor tyrosine kinase (Src), phosphatidylinositol 3-kinase and protein kinase B must be involved in IL-1β signaling. The results presented suggest that IGF-1 and PDGF-bb are potent inhibitors of IL-1β-mediated activation of NF-κB and apoptosis in chondrocytes, may be mediated in part through suppression of Src/PI-3K/AKT pathway, which may contribute to their anti-inflammatory effects.

Background Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor is the main target of current antiangiogenic treatment strategies in AMD. However, other growth factors, such as platelet-derived growth factor (PDGF) and placenta growth factor (PlGF), have a substantial impact on development of AMD. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells. Methods Primary human RPE cells were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reactions, immunohistochemistry and enzyme-linked immunosorbent assays. Results Light exposure decreased cell viability and increased expression and secretion of VEGF-A, PDGF-BB and PlGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 mu g/ml. Conclusion The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD.

Das Glioblastoma multiforme ist ein maligner hirneigener Tumor mit einer bislang infausten Prognose. Humane mesenchymale Progenitorzellen des Knochenmarks (hMSC) zeigen in-vitro und in-vivo einen ausgeprägten glioblastom¬induzierten Tropismus. Sie sind einfach in der Handhabung, weil sie leicht zu gewinnen, in Kultur zu vervielfältigen und anschließend autolog zu transplantieren sind. Diese Eigenschaften machen hMSC zu vielversprechenden Kandidaten für eine zellbasierte Gentherapie des Glioblastoms. Die molekularen Mechanismen, welche zu der gerichteten Migration der hMSC hin zu den Glioblastomzellen führen und die biologischen Wechselwirkungen zwischen Stammzellen und Tumorzellen sind bisher kaum verstanden. Um erste Einblicke in diese Wechselwirkungen zu erlangen, wurden im Rahmen des vorliegenden Promotionsvorhabens in-vitro Untersuchungen zu den Grundlagen des glioblastominduzierten Tropismus von hMSC durchgeführt. Die Fragestellung befasste sich insbesondere damit, welche Chemokine an der Vermittlung der glioblastomgerichteten Migration von hMSC beteiligt sind. Hierzu wurden Migrationsversuche mit einer modifizierten Boyden Kammer durchgeführt, wobei zunächst einige bekannte glioblastomassoziierte Chemokin-kandidaten (IL-8, NT-3, TGF-ß1, EGF, CNTF, GDNF, PDGF und BDNF) getestet wurden. Eine signifikante chemotaktische Eigenschaft auf hMSC wurde hierbei für IL-8, TGF-ß1 und NT-3 beobachtet. Die promigratorische Wirkung dieser drei Chemokine erwies sich hierbei als konzentrationsabhängig. Im Weiteren wurde nachgewiesen, dass die bekannte chemotaktische Wirkung von glioblastom-konditioniertem Medium auf hMSC durch die Zugabe von IL-8, TGF-ß, beziehungs¬weise NT-3 neutralisierenden Antikörpern signifikant reduziert wird. Somit konnte funktionell nachgewiesen werden, dass diese Chemokine tatsächlich eine Rolle beim glioblastominduziertem Tropismus der hMSC spielen. Ergänzend wurde mittels Immunfluoreszenzfärbung die Expression der entsprechenden Chemokin¬rezeptoren auf den hMSC nachgewiesen und die Sekretion der Chemokine durch die Glioblastomzellen mittels ELISA quantifiziert. Aus Vorarbeiten unserer Arbeitsgruppe ist bekannt, dass auch VEGF-A eine chemotaktische Wirkung auf hMSC besitzt. Wie VEGF-A werden auch IL-8, TGF-ß1 und NT-3 von Glioblastomen überexprimiert. Zudem wird über diese Chemokine die Neoangiogenese jener Tumore vermittelt. Dies führt zu der Hypo-these, dass Glioblastome die Migration der hMSC aus dem peripheren Blut in das Tumorgebiet über angiogenetische Signalwege vermitteln. Damit könnten hMSC an dem Prozess der Angiogenese des Glioblastoms beteiligt sein. Ein genaues Verständnis des möglichen Beitrages von hMSC zum Glioblastomwachstum ist eine unabdingbare Voraussetzung für ihre mögliche klinische Anwendung als gentherapeutische Vektoren beim Menschen. Deshalb müssen zukünftig neben weiteren in-vitro vor allem in-vivo Studien mit Langzeit-beobachtungen im Tiermodell durchgeführt werden. In diesen Studien sollten die Auswirkungen einer Transplantation nativer hMSC einerseits und genetisch modifizierter therapeutischer hMSC andererseits auf das Glioblastomwachstum untersucht werden. Die vielversprechenden Ergebnisse der bisher vorliegenden Arbeiten lassen hoffen, dass in nicht allzu ferner Zukunft eine bessere Therapie für Patienten mit Glioblastom gefunden werden kann.

Background: We have previously shown that small molecule PDGF receptor tyrosine kinase inhibitors (RTKI) can drastically attenuate radiation-induced pulmonary fibrosis if the drug administration starts at the time of radiation during acute inflammation with present but limited effects against acute inflammation. To rule out interactions of the drug with acute inflammation, we investigated here in an interventive trial if a later drug administration start at a time when the acute inflammation has subsided - has also beneficial antifibrotic effects. Methods: Whole thoraces of C57BL/6 mice were irradiated with 20 Gy and treated with the RTKI imatinib starting either 3 days after radiation ( during acute inflammation) or two weeks after radiation ( after the acute inflammation has subsided as demonstrated by leucocyte count). Lungs were monitored and analyzed by clinical, histological and in vivo non-invasive computed tomography as a quantitative measure for lung density and lung fibrosis. Results: Irradiation induced severe lung fibrosis resulting in markedly reduced mouse survival vs. non-irradiated controls. Both early start of imatinib treatment during inflammation and late imatinib start markedly attenuated the development of pulmonary fibrosis as demonstrated by clinical, histological and qualitative and quantitative computed tomography results such as reduced lung density. Both administration schedules resulted in prolonged lifespans. The earlier drug treatment start resulted in slightly stronger beneficial antifibrotic effects along all measured endpoints than the later start. Conclusions: Our findings show that imatinib, even when administered after the acute inflammation has subsided, attenuates radiation-induced lung fibrosis in mice. Our data also indicate that the fibrotic fate is not only determined by the early inflammatory events but rather a complex process in which secondary events at later time points are important. Because of the clinical availability of imatinib or similar compounds, a meaningful attenuation of radiation-induced lung fibrosis in patients seems possible.

Extensive studies have shown that undifferentiated cellular components of human bone marow are involved in the formation and renewal of bone tissue (osteogenic cascade). In this study, human mesenchymal stem cells were stimulated by bFGF, IGFI, PDGF-BB or TGF-ß1, in 2 different concentrations respectively (1 and 10 µg/mL). in vitro to assess their influence on differentiation to the osteoblastic phenotype. Thus human marrow could be used as a malleable basic element in bone engineering. The study clearly showed a stimulatory or suppressive effect of each of the respective growth factors. In particular the addition of TGF-ß1 directed the differentiation of mesenchymal stem cells of human bone marrow toward the osteoblastic phenotype.

Thu, 18 Oct 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7576/ https://edoc.ub.uni-muenchen.de/7576/1/Kowarik_Markus.pdf Kowarik, Markus

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in proliferation, survival and sprouting of human microvascular- and umbilical vein endothelial cells (HMEC, HUVEC) using antisense oligonucleotides (AS-ODN) and a pharmacological SHP-2 inhibitor (PtpI IV). Knock-down of SHP-2 decreased bFGF and PDGF dependent endothelial cell proliferation (p

In der Pathogenese, Progression und den akuten Ereignissen der Atherosklerose haben die Wachstumsfaktoren VEGF und PDGF und das Chemokin MCP-1 große Bedeutung. Durch Veränderung der Ausbildung dieser Proteine könnte der Lauf der durch Atherosklerose bedingten Erkrankungen positiv beeinflusst werden. Untersuchungen von Medikamenten oder Nahrungsbestandteilen die einen Einfluss auf die Genexpression dieser Proteine haben sind somit von großer Bedeutung. In dieser Arbeit wurde der Einfluss von diätetisch zugeführten, niedrig dosierten w-3 Fettsäuren auf die Serumspiegel von VEGF, PDGF-AB und MCP-1 und die Expression und Proteinbildung von MCP-1 und PDGF unter dem Einfluss von alleiniger Adhärenzstimulation oder Zugabe von verschiedenen gängigen Stimulanzien in mononukleären Zellen untersucht. In der Atherogenese spielen mononukleäre Zellen eine zentrale Rolle. Da w-3 Fettsäuren einen positiven Effekt in den durch Atherosklerose bedingten Krankheiten haben und vorausgegangene Studien sehr hohe, in der Praxis nicht mögliche Dosierungen gewählt wurden, ist eine Studie zu deren Einfluss, in niedriger, jedoch wirksamer Dosierung, auf die Expression von VEGF, PDGF-AB und MCP-1 von großer Bedeutung. Dafür wurde ein randomisierte, doppelblinde, Placebo kontrollierte Interventionsstudie an 14 männlichen gesunden Freiwilligen durchgeführt. Die Probanden der Verumgruppe erhielten zusätzlich zu ihrer normalen Ernährung für sechs Wochen täglich 3g und dann für weitere sechs Wochen 1,5g w-3 Fettsäuren. Die anfängliche hohe Dosierung wurde gewählt um eine Aufsättigung mit w-3 Fettsäuren zu erreichen. Die Probanden der Placebogruppe erhielten entsprechend Placebokapseln die in ihrem Fettsäurenprofil der westlichen Ernährung angepasst waren. Die Expressionsänderungen der genannten Proteine wurden in den Zellstimulationen auf der Genomebene mittels der etablierten 3n-rT-PCR als auch auf der Proteinebene mittels ELISA gemessen. Aufgrund von o.g. methodischen Problemen waren diese Ergebnisse jedoch angesichts der großen Mühen leider nicht verwertbar. Die Konzentrationen von VEGF, PDGF-AB und MCP-1 im Serum der Probanden wurden mittels ELISA gemessen. Hier zeigten sich deutliche interindividuelle Schwankungen. Die Konzentration von VEGF im Serum der Probanden der Verumgruppe senkte sich nach 3 Monaten durchschnittlich um 54±18% gegenüber den Ausgangswerten. Die Konzentration von VEGF im Serum der Placebogruppe änderte sich im Durchschnitt nicht, jedoch schwankten die Werte. Die Konzentration von PDGF-AB senkte sich im Serum der Verumgruppe nach 3 Monaten durchschnittlich um 57±20%. Die Konzentration von PDGF-AB veränderte sich in der Placebogruppe über den Untersuchungszeitraum nicht relevant. In der Verumgruppe senkte sich die Konzentration von MCP-1 im Serum der Probanden nach 3 Monaten im Durchschnitt um 43±17%. In der Placebogruppe war keine nennenswerte Veränderung vorhanden. Diese Ergebnisse waren statistisch relevant. Bei gesunden Probanden beeinflussen niedrig dosierte w-3 Fettsäuren die Regulation von VEGF, PDGF-AB und MCP-1. Somit wird die antiatherosklerotische Wirkung von w-3 Fettsäuren über die Beeinflussung der Genexpression und Proteinbildung proatherogener Faktoren auch in niedrigen Dosierungen bestätigt. Ein Einfluss von w-3 Fettsäuren auf VEGF wurde hier erstmals beim Menschen beschrieben.

Im Rahmen dieser Arbeit wurde zum ersten Mal die PKC-vermittelte Inhibition der EGF-induzierten JNK-Aktivität durch GPCRn gezeigt, die durch Transmodulation des EGF Rezeptors verursacht wird. Darüber hinaus wurde anhand einer dominant negativen Mutante der Effekt von PKD auf diesen Prozess nachgewiesen und ihre Rolle in der bereits durch (Bagowski et al., 1999) beschriebenen PDGF-vermittelten JNK-Inhibition verifiziert. Weiterhin wurde gezeigt, dass die Liganden Endothelin und LPA, die ihre Signale über ver-schiedene G-Proteine vermitteln, in Rat1-Zellen über die Aktivierung von PKD unterschiedliche Signalwege verfolgen. So vermittelt Endothelin, welches PKD über Gq-Proteine aktiviert, ebenso wie PDGF die Inhibition der EGF-induzierten JNK-Aktivierung. Hingegen führt LPA, welches PKD zusätzlich über Gi-Proteine stimuliert, zu einer Verdopplung der EGF-induzierten JNK-Aktivität. Neben der EGF Rezeptortransmodulation wurden in dieser Arbeit Untersuchungen zu seiner Transaktivierung durchgeführt. Hier wurde zum ersten Mal die PKC-abhängige Transaktivierung des EGF Rezeptors durch PDGF gezeigt. Hierbei werden dazu in Rat1-Zellen Phor-bol-ester-abhängige PKCs, in 3T3 L1-Zellen dagegen Phor-bol-ester-unabhängige PCKs benötigt. Weiterhin wurde im Rahmen dieser Arbeit die konstitutive Assoziation von PKD mit dem PDGF Rezeptor nachgewiesen, die sowohl in gesunden Nagetierzellen als auch in humanen Glioblastomzellen stattfindet. Verantwortlich für diese Bindung scheint der Juxtamembranbe-reich des PDGF Rezeptors zu sein, während bei PKD mit hoher Wahrscheinlichkeit der Carbo-xyterminus involviert ist. Auch die aus B-Zellen bereits bekannten Interaktionen von PKD mit PLC und Syk (Sidorenko et al., 1996) wurden untersucht, und die PDGF-induzierte Assoziation von PKD mit PLC in denselben Systemen nachgewiesen, in denen auch die Assoziation von PKD mit dem PDGF Rezeptor gezeigt wurde. Eine Assoziation von PKD mit Syk fand sich dagegen nur in HEK 293-Zellen, die PKD und Syk überexprimierten.