Podcasts about EGF

family food tour epiphany third sunday divine service egf

Play Episode Listen Later Jan 26, 2025

Order a hymnal for your home Upcoming Events Tuesday, 1:00 pm: Quilting Wednesday, 6:00 pm: Faith, Family, Food, and Fellowship @ Christ the King Free Lutheran Church, EGF 7:45 pm: Confirmation class Thursday, 2:00 pm: Tour of Northlands Rescue Mission Sunday, 10:00 am: Divine Service with Holy Communion 11:15 am: Sunday school

Second Sunday after the Epiphany

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Play Episode Listen Later Jan 19, 2025

Order a hymnal for your home Upcoming Events Tuesday, 1:00 pm: Quilting Wednesday, 6:00 pm: Faith, Family, Food, and Fellowship @ Christ the King Free Lutheran Church, EGF 7:45 pm: Confirmation class Sunday, 10:00 am: Service of the Word Special offering for AFLC World Missions Annual meeting following worship No Sunday school

Intelligent Medicine Radio for Sept 28, Part 1: Anti-Aging Skin Products

Intelligent Medicine

Play Episode Listen Later Sep 30, 2024 41:31

Milestone Senate round table on harnessing natural therapies to address U.S. chronic disease crisis—but mainstream media ignores and skeptics rail; Rating Epidermal growth factor (EGF), the new ingredient in anti-aging skin products; former NYC Covid Czar attended sex parties and private dance events during lockdown he enforced; A Harvard med student ate over 700 eggs in a month—what was his cholesterol? Severe obesity rises in US; death rates rise in the U.S.—and it's not about Covid; numbness in toes—what are possible causes?

Combining Response and Toxicity Data to Implement Project Optimus

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later Sep 30, 2024 23:55

In this JCO Article Insights episode, Subodh Selukar interviews author Dr. Robert Maki on "Combining Response and Toxicity Data to Implement Project Optimus" by Maki, et al published in the Journal of Clinical Oncology September 11, 2024. TRANSCRIPT Subodh Selukar: Welcome to this episode of JCO Article Insights. This is Subodh Selukar, JCO's editorial fellow. Today, I am interviewing Dr. Robert Maki on his recent editorial, “Combining Response and Toxicity Data to Implement Project Optimus.” At the time of this recording, our guest has disclosures that are available in the manuscript and will be linked in the transcript. Dr. Maki, welcome to our podcast. Dr. Robert Maki: Hi, Subodh. It's a pleasure to be able to take part. Subodh Selukar: Yeah, thank you. So, to start us off, would you give an overview of your article? Dr. Robert Maki: Yes. Well, it's not my article, but it's just an editorial which is a commentary on an article by authors Cheng and Associates. It's called, “Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.” That's a very technical title and so forth, and yet it's a JCO article because we think that it makes an important point that in oncological trials, we talk a lot about primary endpoints, oftentimes of overall survival or progression free survival, sometimes even just response rates, but most of the time, we don't take into account the toxicity of an agent. So, you can imagine that if a drug is relatively nontoxic, then what you see is what you get. Progression free survival could be associated with what is called some sort of so-called clinical benefit. However, if a drug is really toxic and you're just laid up on the couch all day or bed bound, or need transfusions three days a week, where is that really beneficial for the patient? But, by the same token, there's no quality of life without life itself. You have to have some sort of evidence that someone is going to be around for a longer period of time as an indication of benefit. So, these are ideas that have been played out to some degree for the better part of a quarter of a century. There's a biostatistician at MD Anderson named Peter Thall, who's one of the first people to think about this idea of combining toxicity data and response data as some sort of a combination primary endpoint for a trial. And where this comes into play for Project Optimus, this FDA initiative to come up with not just necessarily one dose or one dose and schedule, but rather a range or multiple doses and schedules for a drug based on the toxicity that's seen, is that this new paper by Dr. Cheng and colleagues provides one mechanism for doing this, for combining not just traditional clinical outcomes data, but also toxicity data. Subodh Selukar: So, you mentioned Project Optimus is an important component of all of this. So, can you tell a little bit about what Project Optimus is and maybe a little bit potentially about how Project Optimus has affected you so far? Dr. Robert Maki: I'd say it's having an effect mostly in the earlier phases of drug development. I'm not certain, but I think it was an outgrowth of some of the toxicity that was seen in some of the studies that were done over the course of the last 10 to 15 years with kinase-targeted drugs. The overall goal from the FDA Project Optimus was to work with companies, with academia, groups like ASCO and regulatory authorities, as well as patients to try and come up with dosing for everyone basically based on patient characteristics that they're focusing not just on those outcomes, such as progression, pre survival, overall survival, but also looking for quality of life and adding that into the mix in terms of how you choose a dose. So that's an effort that's been going on for the last several years now. There's been some nice articles on that from FDA on that and perhaps we could provide some links to those as well for people who are interested in some of the more introductory core information about Project Optimus. Subodh Selukar: Yeah, for sure. And so, I mean you're on the editorial board at JCO and you've written this editorial, but has Project Optimus affected your clinical research yet? Dr. Robert Maki: It's just beginning to. So, in phase 1 and 2 clinical trials, especially in phase 1, the goal is not necessarily to look for activity, but just to come up with a recommended phase 2 dose and schedule of a drug. Well, Project Optimus says, “Okay. Well, maybe there's more than one dose and schedule that should arise.” And as I was alluding to earlier, this may have arisen out of what was seen previously where a number of the multi targeted tyrosine kinase inhibitors were developed. But when you got to the phase 3 trial, it was necessary to have dose reductions in 30%, 40%, 50%, 60%, even 70% of patients in some situations. So that to me represents a drug or a development pathway for that drug that was in essence incorrect. Yes, we talk about in traditional chemotherapy of trying to get the maximum dose we can, but is that always the best thing for the patient? And we recognize that there really is a plateau usually for systemic therapies we give, that there is a limit to dose escalation even within an individual patient to try and achieve that same benefit. At some point you're just going to add toxicity. The idea is to bring some element of toxicity into the decision making for a recommended phase 2 dose and schedule or schedules in that case. Subodh Selukar: And so, building on that, so I think one advantage of these different approaches is that they might identify a single optimal dose, or maybe they'll recommend this range of doses that maximize some maybe clinical utility score combining these different aspects. In the current paradigm, it seems like probably response and toxicity are just these separate concepts that aren't typically linked together. But we typically do have a single recommended dose. But like you said, they might in subsequent trials have a lot of dose reductions and stuff like that. So how do you think about the process now where this is a single recommended dose of, but there are deviations from that recommended dose in the research process. Like you said, in subsequent trials or within a trial, maybe patients are needing their own dose reductions as well. And then separately once a product is approved, what do you think about deviating from the recommended dose for your standard clinical practice? Dr. Robert Maki: Oftentimes a work in progress. So even after phase 1, maybe having only treated 30 to 50 patients, they may be relatively homogeneous and that they have to be healthier to qualify for phase 1 trial. Once the drug is released to the whole wide world, then it becomes a different scenario, and you may have patients with poor performance status to start with. Can they still get the same benefit as the patients who got the medication in the context of a clinical trial? And it may not be the case. And I think this is where Project Optimus and the idea of giving more than one dose or schedule may be useful and say, “Okay. Well, you can give 20% less,” and what's the trade off? Maybe the drug doesn't work as well, but it is less toxic. On average, do you really lose a whole lot as a matter of a few weeks of median progression free survival? Or does the response rate really drop off as you decrease the dose intensity of your drug? One concern about having more than one dose and schedule is could you potentially be underdosing patients by the same token? Since we usually have some amount of time, at least a few weeks, to work out what's tolerable for our patient, at least the parameters of having more than one dose and schedule to choose from can be useful. Subodh Selukar: So then thinking about potentially maybe we would have a range of doses to recommend, what do you think are going to be challenges once that starts to be incorporated into clinical practice? What kind of complications do you think might happen explaining this to a patient? Dr. Robert Maki: That's a really, really good question and something that we- I think, just have a difficult time with just the regular consent form. It used to be that maybe you had a couple of information sheets on a standard drug, or if it's a clinical trial, then you'll have a relatively modest consent form that's supposed to be at, whatever, 7th, 8th, 9th grade reading level. But now you start adding this form with complex text to a consent form for a clinical trial. What are people really signing up for? They get a 40-page document, and I don't think they really understand that. So, the idea that you're trying to relate to them, pushing as hard as you can, but by the same token watching out for that toxicity, I think really does speak to those endpoints of the program, that it really can be a patient-friendly idea. Are we going to necessarily get it right every time? No. As I was mentioning previously there, if you're only treating 30 to 50 patients, you may only have partial information and you come up with some sense of dose and schedule to give. And then you move that into phase 2 and phase 3, and you may have to, you see that maybe one dose and schedule is a lot more effective as you get into a randomized portion of a phase 2 trial before you move to phase 3, for example, or you see that the toxicity is much greater with no better evidence of progression free survival. So those two scenarios could certainly rise. You can't predict them in the early phases of development of a drug, but you have to be able to react or be able to react with a solid clinical trial design that allows you to have that flexibility to make those decisions later. This is where discussion with the regulators, obviously is very important to make sure that what you're doing really still fits these guardrails, as it were, of traditional clinical trial design, or these ideas of adding in the toxicity-based information from Project Optimus. Subodh Selukar: One of the challenges in early phase trials is, like you said, we might have 30 to 50 patients at the end of the study. I think in the editorial, you mentioned that some of these newer metrics might require more and more patients. Maybe we need 30 to 50 patients on a single dose in order to have reliable understanding of these clinical utility scores. Whereas right now a sample size at a single dose might be six patients, it might even be fewer. What are your thoughts on that aspect of it? Dr. Robert Maki: That's an important point, too. When you're doing, let's say, a quick and dirty, as you might say, 3+3 design, which has very large error bars in terms of the confidence intervals around a dose and schedule compared to some of the newer Bayesian-based designs, yes, you can get a phase 1 trial quote done, especially if it's a ‘me too' sort of drug, so say, another checkpoint inhibitor, you kind of know the characteristics of those over another inhibitor of a specific kinase, you know the toxicities to expect when you block, let's say, EGF receptor. So, if you have some idea, and therefore you're able to more rapidly get to that recommended phase 2 dose from a phase 1 trial, if it ends up being a new drug, then maybe 30 to 50 patients isn't enough. And you really do need to continue that assessment of both response and toxicity as the trials move forward into phase 2 and phase 3. So, it's kind of one of those ideas of continuous process improvement that if we are going to do this, we really do need to include it, not just in early phase trials, but especially for agents that are acting through a new mechanism of action, that we look at that holistically across the drug development spectrum. And now that trials are kind of being smashed together, phase 1 and 2, now phase 2 and 3, that really increases our need to also add in the assessment of toxicity, and maybe not just on the basis of our own evaluations or lab evaluations of toxicity, but patient reported outcomes, which is something that wasn't addressed in the Cheng article and really hasn't been well addressed in clinical trials in general, I would offer. There are precious few trials that incorporate patient reported outcome data as a means to determine what's too toxic for a patient, for example. So how do we do that? As you know, we do have patient reported CTCAE clinical toxicity criteria that are based on patient reported outcomes. And wouldn't it be interesting, at the very least, as an academic project, but even more importantly, later on, to use those as the key means to determine whether a dose is too toxic or not in the development of the drug. That, to me, would be really, really interesting and kind of turns the idea of some of the data that we collect on its head. I guess, yes, we do need to collect things like liver function tests and so forth. It is one metric of toxicity of a drug. But patients have a lot of fatigue, we really do a poor job of documenting that as clinicians, and not to mention the elements that go into what that fatigue is. To be able to capture that through PROs would be another noble effort that I think has been underutilized and underappreciated in oncology clinical trials overall. Subodh Selukar: And so, what do you think are barriers to doing it now? Dr. Robert Maki: We tend to, for lack of a better term, cut and paste from what we've done before, to develop new, let's say, by patient reported outcome score or metric or worksheet for a given diagnosis. That can be hard, that takes a lot in and of itself, and perhaps has been one of the barriers that we don't have enough disease specific PROs, at least for some diagnoses. For others we do. And the fact that we do have PRO-scored CTCAE sorts of score tables, now, certainly makes it easier to validate and use these tools in clinical trials. So, I would love to see more of that, even if it ends up being secondary tertiary endpoints on phase 1, 2, and 3 trials. It's a pretty easy thing to add, even if you're doing that for the first time. Get some experience with it, and it can only help patients get through a trial or even just assessing it as part of a standard of care that will help our patients in the longer run. Subodh Selukar: Yeah. And so, thinking about other metrics of success, you mentioned a couple in your article. These aren't necessarily patient reported outcome ones, but like RECIST and RANO. I was curious. I think the Cheng article, maybe I would think about it as a general framework for combining response and toxicity together, whereas some of these other metrics are a lot more disease specific, potentially, or agent and disease specific, maybe even. Do you think that clinical research will end up settling on these metrics that are kind of increasingly specific, or do you think that there's a possibility for general frameworks? Dr. Robert Maki: Yeah, that's a tough question. I'm just trying to think of some of those patients reported outcomes. They've got kind of the general assessment ones, and then you do have ones that are more disease specific, just like we do have response criteria that are different for, let's say, lymphoma versus brain tumors versus colorectal cancer. We do have different ways of measuring those outcomes, and we all complain that those are imperfect measures. You can always find circumstances where that patient was responding, but it was called progression or vice versa. So even from these more objective tools like RECIST and the like, it's a challenging field, that's for sure. We keep going around and trying to find ways of improving those sorts of systems. But let's say, for example, you used - this is part of the reason we moved from two dimensional measurements in WHO criteria versus one dimensional RECIST - if you have two dimensions, well, you have that much more variability in the measurements of the lesion. So, it turned out that we just didn't gain anything by having those bidimensional measurements. Now, since we have the ability to measure tumors better in three dimensions, should we be using volumetric assessments? Part of it depends on the size of the tumor. If you're dealing with a tumor that's 1 cm versus 8 cm, well, then the volumetric changes, you have a lot more variability, the small ones, than the big ones. Not to mention the fact that you have shapes that are not just an ovoid mass in a lot of cancers. There's just so many pitfalls in these sorts of data. What really matters at the end of the day, one thing that's underappreciated, and again is underscored by Project Optimus, is getting back to the patient. Subodh Selukar: Your editorial made me have this one thought, and so bear with me, it's like a multi-part question. One of the reasons that we're becoming more and more interested in these alternative approaches, these clinical utility scores and everything, is that these new agents are being proposed, where there's a hypothesis that there's more complicated relationships between dose, response and toxicity. And so, 50 years ago, researchers probably didn't hypothesize that these complicated relationships were happening. They probably thought that they were more straightforward. What do you think would have happened if we had had these conversations that we're having today if we'd had them 50 years ago, what do you think would be different? Do you think that maybe we would have different therapies that kind of ended up becoming standard today? Maybe would we interpret or run studies differently today? Dr. Robert Maki: I like that question as well. Now, if we go back to the Charles Moertel studies back from the 1970s, the whole reason that we have tumor measurements as a criterion are really based on his work, where he got a series of clinicians together and he put these masses underneath a piece of rubber sheeting, and they tried to determine how well they could determine the difference between a mass that they could palpate. And this is when we came up with the idea that a partial response was a 50% decrease in the cross-sectional area of a mass. That came from that very crude but important work from about 50 years ago. And of course, that was also a time when there really wasn't any imaging. Maybe the best you would have would be x-ray tomography to look at a lung nodule or something like that. It was a little bit of a different era. We didn't know how our drugs worked very well. We had at least some biochemical reason to use chemotherapy, and we tried to leverage that. But it was always the idea of more is better, finally disproved later on, in let's say the era of breast cancer, looking at the AC combination or doxorubicin as part of a treatment for breast cancer, that there was a ceiling to the benefit of doxorubicin in the adjuvant setting. Even then, it was clear that we needed to think about dose and schedule. We also didn't have the variety of drugs that we have now, or the different metrics that we have, circulating tumor DNA or something along those lines. Those sorts of things just never existed then either. So, we need metrics that are appropriate for their time, and we have more tools to work with. I suspect that we'll have more specialization in oncology along disease lines, or even molecularly characterized subsets of diagnoses as well. All the detailed classification that we now need for a lymphoma, for example, or different flavors of triple negative breast cancer, all of those things are impacting how we even put a person on a trial. Similarly, since these patients are also going to get different classes of drugs that are relatively unique to them, there are a lot of drugs now that are available that really are only approved for one diagnosis. Then you really have to drill down pretty deeply in order to be able to focus on that clinical scenario. But I think we have the means to do so. Nonetheless, the general idea of these frameworks, again, the idea of combining response and toxicity data that can apply across essentially any cancer or neoplasm that we want to study. Subodh Selukar: Okay. So, I want to move a little bit to aspirational, like where we want to move forward now. And so I think you've talked a little bit about this so far already, but would you tell me a little bit about when you're seeing a patient, interpreting results that have been given in clinical trials, are there results, metrics, summaries of trials that you wish you could communicate to them, metrics that actually already exist but don't really get implemented? You already mentioned quality of life is something that doesn't seem to be there but are there other things that maybe quality of life might not just be collected enough yet. But are there metrics on data that we have and we just don't really report them at all? Dr. Robert Maki: That may be the case, or maybe the data end up in a secondary and tertiary publication, so they don't really become part of the lingua franca of the oncologist. I think it really speaks to just having the experience as an oncologist that you try the FDA-approved dose for medication for somebody and you run into trouble if they're, let's say, in their 80s, whereas the study population was in their 40s and their 50s with better bone marrows or better renal function on average, and things like that. So, another untested waters are geriatric oncology. What are the maximum tolerated doses when they're 80 versus when they're 40 or 50? It's a real challenge. Probably they had the most experience of that with things like prostate cancer, where we do treat largely an older population of men compared to other diagnoses, potentially. I suspect we're going to see just more specialization, just like we do with the medications. We do need more specialized assessments for those adverse events and or quality of life that will be diagnosis specific. If you have GI cancer, abdominal pain is going to be a bigger issue or obstruction sorts of questions. And the symptoms that you may have from having a tumor within the abdomen versus, let's say, another diagnosis, which may tend to give you more, let's say, lung metastases. So those little subtleties can't come out. And the toxicities of the drugs that we use in those diagnoses are also going to differ as well. So those should be kept in mind as we come up with, let's say, disease specific toxicity metrics that we want to combine with those outcome data. So, I think we're going to see more and more specialization of that over time. You have to create the tool and you've got to validate it. So, all these things will take some time. But again, people have been interested in this for a long, long time. There are any number of careers that are built around quality of life and cancer, or for example, long term survivorship in pediatric cancer patients. And all of these things can be very useful and just require our attention, both as clinical investigators as well as clinicians, when we face our patient's day to day. Subodh Selukar: And so just one last question before we close. Is there anything that we haven't had a chance to talk about that you like to share with our listeners? Dr. Robert Maki: If it's anything it's that I'm really heartened as I get older with this very large influx of new clinicians and new investigators. Oncology continues to get more interesting and more sophisticated. We need more people- we still don't have enough oncologists, even for our population here in the United States. We'll have plenty to do for a very, very long time. So, I'm excited to see a new generation of young oncologists such as yourself and the trainees that I see here, the new fellows, junior faculty who are all beginning to answer these questions, thinking about them. And as me and some of my more senior friends can help promote this kind of idea and help together to answer some of these questions. We're still trying to figure it out and there are just so many variables and clinical scenarios that we need to chase down in terms of clinical research. It is going to be an ongoing discussion and hopefully this article is just one example towards the goal again of finding the right dose for our given patient. Subodh Selukar: Thank you so much for sharing and yeah, I'm very excited to be a part of this as well. This has been Subodh Selukar interviewing Dr. Robert Maki on his recent editorial, “Combining Response and Toxicity Data to Implement Project Optimus.” Thank you for listening and stay tuned for the next episode of JCO Article Insights. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Dr. Robert Maki Disclosures: Consulting or Advisory Role: Deciphera, PEEL Therapeutics, Eisai, GlaxoSmithKline, Medtronic, Boehringer Ingelheim Speakers' Bureau: MJH Life Sciences Research Funding: Amgen, Astex Pharmaceuticals, Boehringer Ingelheim, BioAtla, C4 Therapeutics, InhibRx, Regeneron, SARC: Sarcoma Alliance for Research though Collaboration, TRACON Pharma Patents, Royalties, Other Intellectual Property, Uptodate Travel, Accommodations, Expenses Company name: Stand up to Cancer, Fondazione Enrico Pallazzo

Ep. 14 - East Grand Forks Youth Hockey with Judd Stauss

Individual Skills Hockey Podcast

Play Episode Listen Later Feb 8, 2024 61:00

The podcast brings in Judd Stauss this week to discuss youth hockey development. Judd is the Development Coordinator at East Grand Forks Youth Hockey and brings a ton of experience to the table. Judd is from EGF and played college hockey at Denver University. EGF does some really unique things in their youth hockey organization when compared to the rest of the state of Minnesota. This is an awesome episode for new ideas to youth hockey development!

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The Ethical Gambling Forum - is it an oxymoron or can the EGF bring ESG principles to bear on the gambling industry?

The ESG Podcast

Play Episode Listen Later Jan 1, 2024 22:41

Adrian Sladdin, Founder and Director of EnviroEducation, and convener of the EGF, explains that whilst the gambling industry will be regarded by some as beyond redemption that shouldn't stop efforts to engage in dialogue with the sector, exploring ways in which it can be more ethical, without just tick boxing ESG criteria in an attempt to greenwash its image. What are the odds of a breakthrough in 2024? 10 - 1 or nearer 50/50? Have a listen.

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86. Topical Cosmetic Peptides & Growth Factors (Part 2) - Uses and Function of Individual, Specific Peptides Designed to Stimulate Collagen, Mimic Botox, Reduce Skin Irritation, & More

The Synthesis of Wellness

Play Episode Listen Later Dec 29, 2023 24:53

Building upon our previous discussion on growth factors like EGF and FGF (featured in episode 84: part 1), we'll explore a range of intriguing peptides that have gained popularity for their skin-enhancing properties. From stimulating collagen production to calming irritated skin and even targeting dynamic wrinkles (acting like "botox in a bottle"), we'll cover a variety of topical peptides that are revolutionizing skincare. Stay tuned for this topical cosmetic peptide guide! Topics: 1. Introduction - Recap of last week's episode on growth factors (EGF and FGF) - Shift in focus to topical peptides - Skin anatomy for context 2. Skin Anatomy Overview - Epidermis - Layers and sublayers - Cornification process - Function of each sublayer - Dermis - Papillary and reticular dermis - Role of fibroblasts - Components and functions of the dermis 3. Topical Peptides - Palmitoyl Tripeptide-1 - Mimicking collagen - Stimulating collagen production - Benefits for skin structure and sagging prevention - Palmitoyl Tetrapeptide-7 - Relation to IgG protein - Reduction of IL-6 secretion and inflammation - Use in calming irritated skin - Palmitoyl Tripeptide-8 - Soothing irritated skin or for sensitive skin - Reduction of inflammatory cytokines like IL-8, edema, and capillaries - Palmitoyl Tetrapeptide-38 (Matrixyl 6000) - Comprehensive stimulation of skin matrix components - Greater collagen production and epidermal support - Benefits for skin structure, firmness - Neurotransmitter-Inhibiting Topical Peptides - Targeting dynamic wrinkles caused by muscle contraction - Reduction of muscle contractions and expression lines - Introduction of Acetyl Hexapeptide-8 and Acetyl Octapeptide-3 4. Other Topical Peptides (Future Episode & Featured on My Instagram) - Eyelash growth and nail growth peptides - Solutions for under-eye bags and dark circles Thanks for tuning in! ⁠⁠⁠Book An Intro Coaching Call with Chloe Porter⁠⁠⁠ Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok ⁠⁠⁠@chloe_c_porter⁠⁠⁠ Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Or visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠linktr.ee/synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

84. Topical Cosmetic Peptides & Growth Factors (Part 1) - Uses and Function of Both EGF & FGF for Skin Renewal & Anti-Aging

The Synthesis of Wellness

Play Episode Listen Later Dec 22, 2023 26:42

In this episode, we are getting into all things cosmetic peptides and growth factors (and their impact on skin). We will also quickly review the essential structure of our skin, from the surface epidermis to the underlying dermis and sublayers/cellular components of each. This knowledge will set the stage for our discussion on the pivotal roles of EGF and FGF in anti-aging. Also, stay tuned for Part 2, where we'll delve deeper into these topics. Topics: 1. Introduction - Brief review of the anatomy of the skin - Overview of the topics to be discussed (cosmetic peptides and growth factors) 2. Epidermis - Overview of the epidermis - Sublayers of the epidermis - Stratum Corneum - Stratum Lucidum - Stratum Granulosum - Stratum Spinosum - Stratum Basale - Functions and characteristics of each sublayer - Keratinocyte differentiation and lipids production - Role of melanocytes and Merkel cells 3. Dermis - Overview of the dermis - Sublayers of the dermis - Papillary Dermis - Reticular Dermis - Composition and functions of each sublayer - Role of collagen, elastin, fibroblasts, sebaceous glands, sweat glands, hair follicles, and mast cells 4. Cosmetic Peptides and Growth Factors - Introduction to EGF (Epidermal Growth Factor) - Mechanism of action - Effects on keratinocytes and epidermis - Indirect effects on collagen and elastin production - Application in skincare - Introduction to FGF (Fibroblast Growth Factor) - Mechanism of action - Effects on fibroblasts and dermis - Enhancement of skin firmness and elasticity - Upcoming topics in Part 2 - Other growth factors - Additional cosmetic topical peptides - Tips and tricks for skincare formulations Thanks for tuning in! ⁠⁠Book An Intro Coaching Call with Chloe Porter⁠⁠ Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok ⁠⁠@chloe_c_porter⁠⁠ Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! Or visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠linktr.ee/synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

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Worldviews: Data-Backed Discoveries on Americans' Opinions

america israel americans joe biden data gaza backed discoveries worldviews egf none of the above

Play Episode Listen Later Oct 17, 2023 29:24

With the 2024 presidential election on the horizon, the Biden administration's foreign policy decisions will face increasing scrutiny. Some think foreign policy decisions should be exempt from regular public debate. To gain a better understanding of the concerns and priorities of voting age Americans, we at the Eurasia Group Foundation compiled our sixth annual survey of Americans' foreign policy views. In this episode of None Of The Above, Mark is joined by his EGF colleagues, Zuri Linetsky and Lucas Robinson, as well as media consultant Deepika Choudhary to dive into our annual report of Americans' foreign policy views. Across partisan, age, and racial differences, our survey reveals a public attentive to global realities, and supportive of recalibrating America's international activities. Though this survey data was collected before the outbreak of violence in Israel and Gaza, we think the discussion provides useful context for how Americans' view their country's role in this turbulent time.

What is bovine colostrum and why is everyone taking it?

Period Chats

Play Episode Listen Later Oct 17, 2023 12:16

Certainly, here are the show notes with the addition of research studies: Review of Bovine Colostrum: Let's begin by delving into what bovine colostrum (BC) is all about: Bovine colostrum is the initial milk produced immediately after birth, brimming with essential macro- and micro-nutrients, immunoglobulins, and peptides boasting antimicrobial properties and growth factors. Now, let's explore the potential advantages: Immune Support: Colostrum is abundant in immunoglobulins, particularly IgG, IgM, and IgA, which can fortify the immune system. Additionally, it contains lactoferrin, lysozyme, and other immune components that might aid in enhancing immunity. Gut Health: Colostrum is said to assist in maintaining a healthy gut lining. Its growth factors could contribute to the repair of damaged intestinal tissue and play a role in preserving gut permeability. Nutritional Content: Bovine colostrum is replete with proteins, vitamins, and minerals that can contribute to overall nutrition. Growth Factors: It encompasses various growth factors such as insulin-like growth factors (IGF-1 and IGF-2), transforming growth factors (TGF-alpha and TGF-beta), and epithelial growth factor (EGF), potentially promoting tissue growth and healing. Antimicrobial Properties: The presence of lactoferrin, lysozyme, and immunoglobulins in colostrum imparts antimicrobial properties, which may combat harmful bacteria and viruses. Athletic Performance and Recovery: Some athletes turn to colostrum supplements with the belief that it aids in recovery and enhances performance, although scientific evidence in this area is still evolving. Anti-inflammatory: Colostrum has been suggested to possess anti-inflammatory properties, potentially benefiting conditions involving inflammation. May reduce the risk of upper respiratory infections: Studies have indicated that athletes who consumed colostrum had fewer instances of upper respiratory infections compared to those who received a placebo. So, what does the research reveal? Processing and Heat Treatment: Processing and heat treatment, necessary for safety, can diminish the bioactive composition and the inhibitory and immunomodulatory capabilities of colostrum. Rich in Bioactive Components: Bovine colostrum is notably rich in biologically active peptides, antioxidants, anti-inflammatory agents, and growth-promoting factors, distinguishing it from mature milk. Intestinal Permeability Study: One study involving 12 athletes vulnerable to intestinal permeability due to intense exercise found that daily consumption of 20 grams of bovine colostrum prevented 80% of the increase in intestinal permeability experienced by those who received a placebo. (Reference: Trusted Source) Saliva IgA Antibodies Study: In a 12-week study with 35 adult distance runners, taking a daily bovine colostrum supplement increased saliva IgA antibodies by 79% compared to baseline levels. (Reference: Trusted Source) It's important to keep in mind that bovine colostrum supplements and powders can be relatively costly, ranging from $50 to $100 per 16 ounces (450 grams), with a typical daily dosage of half a teaspoon (1.5 grams). Additionally, the composition of bovine colostrum may vary depending on how the cows are raised, potentially containing antibiotics, pesticides, or synthetic hormones.

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RNAi-based screen for cuticle pigmentation in Drosophila melanogaster reveals novel regulators of brain dopamine

Play Episode Listen Later Jul 24, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.20.549932v1?rss=1 Authors: Deal, S. L., Bei, D., Gibson, S. B., Delgado-Seo, H., Fujita, Y., Wilwayco, K., Seto, E. S., Yamamoto, S. Abstract: The dopaminergic system has been extensively studied for its role in behavior in various animals as well as human neuropsychiatric and neurological diseases. However, we still know little about how dopamine levels are tightly regulated in vivo. In order to identify novel regulators of dopamine levels, we utilized Drosophila melanogaster cuticle pigmentation as a readout, where dopamine is used as a precursor to melanin. First, we measured dopamine from classical mutants of genes that are known to be important for cuticle pigmentation to understand the relationship between dopamine levels and cuticle color. We then performed an RNAi-based screen to identify novel regulators of cuticle pigmentation. We identified 153 genes that were not only enriched for conserved homologs and disease-associated genes, but were unexpectedly enriched for multiple developmental signaling pathways and mitochondria-associated proteins. Upon measuring dopamine from 35 prioritized candidates from this cohort, we found 10 that caused significant reduction in dopamine in the head while one caused an increase. While most of these 11 genes are expressed in the fly brain, only two of them, clu and mask, altered dopamine levels specifically in the brain upon knockdown in dopaminergic cells. Interestingly, mask may act as a hub of dopamine regulation since it is associated with three nodes found in our screen (Receptor tyrosine kinase/EGF signaling, Hippo signaling, and mitochondrial dynamics). Further examination suggests that Mask likely acts on dopamine synthesis by regulating transcription of the rate-limiting dopamine synthesis enzyme, tyrosine hydroxylase. In conclusion, this screen identified 11 new regulators of dopamine levels and provides molecular handles to investigate how dopamine levels are controlled in vivo, as well as revealed an unexpected relationship between fly pigmentation genes, developmental signaling and human neurological and neurodevelopmental disease genes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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BUB1 Regulates EGFR Signaling by Reducing EGFR Internalization

Aging-US

Play Episode Listen Later Jul 17, 2023 4:21

A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 13, entitled, “Budding uninhibited by benzimidazoles-1 (BUB1) regulates EGFR signaling by reducing EGFR internalization.” EGFR signaling initiates upon ligand binding which leads to activation and internalization of the receptor-ligand complex. In this new study, researchers Shyam Nyati, Grant Young, Corey Speers, Mukesh K. Nyati, and Alnawaz Rehemtulla from the University of Michigan, Henry Ford Health System and Case Western Reserve University evaluated if BUB1 impacted EGFR signaling by regulating EGFR receptor internalization and activation. “We postulate that BUB1 helps in the formation and stabilization of EGFR dimers at the membrane and may regulate endocytosis of activated EGFR into either clathrin dependent (EEA1 coated) or independent (caveolin coated) vesicles thus impacting receptor recycling or degradation and subsequently signaling amplitude and duration [38, 39].” BUB1 was ablated genomically (siRNA) or biochemically (2OH-BNPP1) in cells. EGF ligand was used to initiate EGFR signaling while disuccinimidyl suberate (DSS) was used for cross linking cellular proteins. EGFR signaling was measured by western immunoblotting and receptor internalization was evaluated by fluorescent microscopy (pEGFR (pY1068) colocalization with early endosome marker EEA1). siRNA mediated BUB1 depletion led to an overall increase in total EGFR levels and more phospho-EGFR (Y845, Y1092, and Y1173) dimers while the amount of total EGFR (non-phospho) dimers remained unchanged. BUB1 inhibitor (BUB1i) decreased EGF mediated EGFR signaling including pEGFR Y845, pAKT S473 and pERK1/2 in a time dependent manner. Additionally, BUB1i also reduced EGF mediated pEGFR (Y845) dimers (asymmetric dimers) without affecting total EGFR dimers (symmetric dimers) indicating that dimerization of inactive EGFR is not affected by BUB1. Furthermore, BUB1i blocked EGF mediated EGFR degradation (increase in EGFR half-life) without impacting half-lives of HER2 or c-MET. BUB1i also reduced co-localization of pEGFR with EEA1 positive endosomes suggesting that BUB1 might modulate EGFR endocytosis. “Our data provide evidence that BUB1 protein and its kinase activity may regulate EGFR activation, endocytosis, degradation, and downstream signaling without affecting other members of the receptor tyrosine kinase family.” DOI - https://doi.org/10.18632/aging.204820 Corresponding authors - Shyam Nyati - snyati1@hfhs.org, and Alnawaz Rehemtulla - alnawaz@umich.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204820 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, BUB1, EGFR, cancer, signaling, endocytosis About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

149. Muzeum bez filcu

2historyków1mikrofon

Play Episode Listen Later Jul 10, 2023 80:40

Rozpoczęliśmy od wydarzenia formującego, choć lekko ogłuszającego jednego z nas. W ramach nowinek pierwszy z nas opowiadał o zaginionym na kilkanaście lat mieście, które odnalazło się, gdy zabrakło pewnych rud. Drugi z nas opowiadał o pięknie ogrodów, które wyrosły z rywalizacji między dwiema tyleż pięknymi, co zamożnymi Polkami. W sekcji lektur pierwszy z nas opowiadał o bardzo ważnym i ciekawym reportażu poświęconym historii kobiet wiejskich w dwudziestoleciu międzywojennym. Dorzucił także biografię znanego, angielskiego pisarza jako źródło do poznania prowincjonalnej Anglii. Drugi z nas szerzej opowiadał o trzecim tomie serii opisującej stosunki polsko-niemieckie, przedstawił intrygujące zestawienie dwóch migracji – XVIII-wiecznej i XX-wiecznej, obu związanych z Niemcami, zaprezentował album poświęcony widokówkom, ale tak naprawdę tramwajom wrocławskim. Na zakończenie omówił najnowszy numer czasopisma „Dialog”, który poświęcony jest relacjom niemiecko-polskim w czasie wojny. Tematem głównym odcinka było zwiedzanie muzeów. Nie był to nasz osobisty ranking jednostek muzealnych, lecz dyskusja o tym, jak zwiedzamy muzea? W jaki sposób historyk podchodzi do odwiedzin w muzeum, co dodaje od siebie zwiedzając je, a czego oczekuje? Trochę był to też apel do muzealników, by wychodząc od przykładów dobrych praktyk niewielkim kosztem otwierali swoje instytucje na potrzeby odwiedzających. Bo przecież każdy z nas obcuje z muzealnymi artefaktami w różny sposób, ale najważniejsze, byśmy dostrzegli w nich zmieniającą się w czasie człowieka. Ramówka: - Rozgrzewka:)) - Nowinki / starowinki - 6:17 - Lektury - 24:32 - Temat przewodni -57:25 Pełny tekst opisu zamieściliśmy na stronie internetowej naszego projektu: https://shrtm.nu/eGg Wymienione w czasie audycji publikacje i materiały: - Jörg Hackmann, Marta Kopij-Weiß, Narody w kontakcie i w konflikcie. Stosunki polsko-niemieckie 1806-1918, Wrocław 2023, https://esbn.pl (ostatni dostęp: 10.07.2023) - Ogrodowa mapa Polski, https://omp.oop.org.pl/mapa/ (ostatni dostęp: 10.07.2023) - Muzeum im. Anny i Jarosława Iwaszkiewiczów w Stawisku, http://stawisko.pl (ostatni dostęp: 10.07.2023) - Muzeum Narodowe w Warszawie. Oddział Muzeum w Nieborowie, https://shrtm.nu/eG6 (ostatni dostęp: 10.07.2023) - Joanna Kuciel-Frydryszak, Chłopki. Opowieść o naszych babkach, Marginesy, 2023, https://shrtm.nu/eGf (ostatni dostęp: 10.07.2023) - Rob Wilkins, Terry Pratchett: Życie z przypisami. Oficjalna biografia, tłum. Piotr Cholewa, Insignis, 2023, https://shrtm.nu/eGe (ostatni dostęp: 10.07.2023) - Tomasz Sielicki, Tramwajem przez Wrocław, Wrocław: Wydawnictwo Wrocławski Neptun, 2023, https://wroclawskineptun.pl/produkt/tramwajem-przez-wroclaw/ (ostatni dostęp: 10.07.2023) - Plötzlich da. Deutsche Bittsteller 1709. Türkische Nachbarn 1961, hrsg. von Simone Blaschka-Eick und Christoph Bankert, Bremerhaven 2016, https://www.dah-bremerhaven.de/exhibitions/ploetzlich-da-deutsche-bittsteller-1709-tuerkische-nachbarn-1961 (ostatni dostęp: 10.07.2023) - Stosunki polsko-niemieckie / Deutsch-polnische Beziehungen in Zeiten des Krieges, "Deutsch-Polnisches Magazin Dialog / Magazyn Polsko-Niemiecki Dialog", 2023/1, http://przegladpolityczny.pl/magazyn-polsko-niemiecki-dialog/ (ostatni dostęp: 10.07.2023) Krzysztof Ruchniewicz Blog: www.krzysztofruchniewicz.eu Facebook: https://www.facebook.com/krzysztof.ruchniewicz.3 Instagram: www.instagram.com/ruchpho/ Twitter: twitter.com/krzyruch YouTube: www.youtube.com/channel/UCT23Rwyk…iew_as=subscriber Przemysław Wiszewski Blog: www.przemysławwiszewski.pl Facebook: www.facebook.com/przemyslaw.wiszewski Instagram: www.instagram.com/przewisz/ Twitter: twitter.com/wiszewski YuoTube: www.youtube.com/channel/UCuq6q08E…iew_as=subscriber Do nagrania intro i outro wykorzystaliśmy utwór RogerThat'a pt. „Retro 70s Metal” (licencja nr JAM-WEB-2020-0010041).

pl metal zeiten ram retro xx beziehungen deutsch nie dialog xviii nachbarn polski krieges terry pratchett jaros temat warszawie drugi wroc troch opowie bremerhaven anglii tematem muzeum rozpocz neptun ege niemcami egf oficjalna lektury insignis marginesy

Modi's Trip to Washington: Shivshankar Menon on How India Sees the World

Play Episode Listen Later Jun 21, 2023 28:40

This week, Indian prime minister Narendra Modi traveled to the United States in his first official state visit as prime minister. Once denied entry into the United States for inciting communal violence in the Indian state of Gujarat, Modi is now being given one of the highest honors for foreign dignitaries by addressing a joint session of Congress. Modi's trip to Washington intends to celebrate, as well as strengthen, the already strong partnership between the United States and the world's largest democracy. And this is all despite Modi's controversial human rights track record as well as India's reluctance to condemn Russia's invasion of Ukraine with targeted sanctions. What makes the US-India partnership so important to America's interests that the Biden administration is willing to overlook such contradictions? EGF's senior researcher and producer, Caroline Gray, sits down with someone who knows India's strategic thinking best: former national security advisor to India's prime minister and foreign secretary Shivshankar Menon. Shivshankar argues there is far too much to be gained for both India and the United States for differences – domestic or international – to stand in the way. Shivshankar Menon is a visiting professor of international relations at Ashoka University. He has served in many roles in India's government, including as national security advisor to the prime minister, foreign secretary, and ambassador to Israel, Sri Lanka, Pakistan, and China. His latest book is India and Asian Geopolitics; The Past, Present. To listen to more episodes or learn more about None Of The Above, go to www.noneoftheabovepodcast.org. To learn more about the Eurasia Group Foundation, please visit www.egfound.org and subscribe to our newsletter.

Sudan and the Limits of Western Peacebuilding

united states israel west washington dc western revolution united nations saudi arabia limits betrayal lt sudan uae peacebuilding burhan abdel fattah egf hemedti

Play Episode Listen Later May 2, 2023 25:20

On April 15, violence erupted across Sudan between the Sudanese Army, led by Gen. Abdel Fattah al-Burhan, and a paramilitary group called the Rapid Support Forces, led by Lt. Gen. Mohamed Hamdan–known also as Hemedti. As the warring factions compete for control of resource-rich Sudan, regional leaders like Egypt, Saudi Arabia, the UAE, Israel, as well as the United States and the United Nations are figuring out how to respond to help mitigate the catastrophic violence. But as this week's guest reminds us, peacebuilding efforts from external actors like the U.S. and the UN, however well-intentioned, have unintended consequences. This week, guest host and EGF research fellow Zuri Linetsky speaks with Sudan expert Justin Lynch to help us make sense of the conflict playing out today and how attempts at peacebuilding and diplomacy by the West helped embolden the military leaders bringing the country to the brink of collapse. Justin Lynch is a researcher and analyst living in Washington DC. He formerly worked as a reporter and United Nations official in Sudan. He is a co-author of Sudan's Unfinished Democracy: The Promise and Betrayal of a People's Revolution.

Downregulation of Angulin-1/LSR Induces Malignancy in Lung Adenocarcinoma

Oncotarget

Play Episode Listen Later Mar 30, 2023 4:23

A new research paper was published in Oncotarget's Volume 14 on March 24, 2023, entitled, “Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells.” Abnormal expression of bicellular tight junction claudins, including claudin-2 are observed during carcinogenesis in human lung adenocarcinoma. However, little is known about the role of tricellular tight junction molecule angulin-1/lipolysis-stimulated lipoprotein receptor (LSR). In the present study, researchers Wataru Arai, Takumi Konno, Takayuki Kohno, Yuki Kodera, Mitsuhiro Tsujiwaki, Yuma Shindo, Hirofumi Chiba, Masahiro Miyajima, Yuji Sakuma, Atsushi Watanabe, and Takashi Kojima from Sapporo Medical University School of Medicine examined expression of claudin-2 in the lung adenocarcinoma tissues and found it was higher than in normal lung tissues, while angulin-1/LSR was poorly or faintly expressed. “We investigated how loss of angulin-1/LSR affects the malignancy of lung adenocarcinoma cell line A549 and normal human lung epithelial (HLE) cells.” The researchers found that the EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. Knockdown of LSR induced expression of claudin-2 at the protein and mRNA levels and AG1478 prevented the upregulation of claudin-2 in A549 cells. Knockdown of LSR induced cell proliferation, cell migration and cell metabolism in A549 cells. Knockdown of claudin-2 inhibited the cell proliferation but did not affect the cell migration or cell metabolism of A549 cells. The TGF-β type I receptor inhibitor EW-7197 prevented the decrease of LSR and claudin-2 induced by TGF-β1 in A549 cells and 2D culture of normal HLE cells. EW-7197 prevented the increase of cell migration and cell metabolism induced by TGF-β1 in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma. “In conclusion, AG1478 and EW-7197 demonstrated potent in vitro anti-lung adenocarcinoma therapeutic activities via LSR/CLDN-2 and the cell metabolism. The use of both AG1478 and EW-7197 may provide a clinical therapeutic approach for lung adenocarcinoma caused by loss of angulin-1/LSR.” Full research paper: DOI: https://doi.org/10.18632/oncotarget.27728 Correspondence to: Takashi Kojima - ktakashi@sapmed.ac.jp Keywords: angulin-1/LSR, claudin-2, cell metabolism, malignancy, lung adenocarcinoma About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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Senescence and Extracellular Vesicles: Novel Partners in Vascular Amyloidosis

Aging-US

Play Episode Listen Later Mar 30, 2023 3:32

A new editorial paper was published in Aging (Aging-US) Volume 15, Issue 5, entitled, “Senescence and extracellular vesicles: novel partners in vascular amyloidosis.” In their editorial, researchers Meredith Whitehead, Marco Antonazzi and Catherine M. Shanahan from King's College London discussed amyloidosis—a prevalent age-associated pathology caused by the accumulation of fibrous, insoluble protein fibrils in tissues. The most common human amyloid is aortic medial amyloid (AMA), caused by aggregation of a 50-amino acid peptide called medin, which is cleaved by an unknown mechanism from its parent protein, milk fat globulin EGF-factor 8 (MFGE8). Medin is present in the vessel wall of 97% of Caucasians aged over 50- years ,yet despite its prevalence in the ageing population there is a very limited understanding of the mechanisms driving AMA. “Despite several forms of amyloidosis, including AMA and Alzheimer's disease (AD), being frequently associated with ageing, there has been limited research to date on the effect of cellular ‘ageing', termed senescence, on amyloidosis.” The novel data presented in the paper by Whitehead et al. provides evidence that vascular smooth muscle cell (VSMC)-derived small extracellular vesicles (sEVs) are key mediators of medin accumulation in the vessel wall. In addition, the authors identify, for the first time, a role for cellular senescence in triggering amyloidosis via changes in sEVs and extracellular matrix (ECM) composition. Thus, this study not only advances our understanding of how AMA is formed but uncovers potential therapeutic targets for mitigating the detrimental effects of amyloidosis on tissue function. “Further work is now required to understand the relationships between cellular ageing pathways, different forms of amyloidosis and potentially other ageing pathologies with shared mechanisms, such as vascular calcification, that often occur concomitantly within the aged ECM.” Full Editorial: DOI: https://doi.org/10.18632/aging.204571 Corresponding Author: Catherine M. Shanahan -cathy.shanahan@kcl.ac.uk Keywords: amyloid, smooth muscle cells, senescence, extracellular vesicles, medin Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204571 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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rtPA Directly Protects Neurons After Intracerebral Hemorrhage through PI3K/AKT/mTOR Pathway

Play Episode Listen Later Feb 13, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.13.528249v1?rss=1 Authors: Jing, J., Chen, S., Wu, X., Yang, J., Liu, X., Wang, J., Wang, J., Li, Y., Zhang, P., Tang, Z. Abstract: Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high disability and mortality rates. Recombinant tissue plasminogen activator (rtPA) is commonly applied for hematoma evacuation in minimally invasive surgery (MIS) after ICH. However, rtPA may contact directly with brain tissue during MIS procedure, which makes it necessary to discuss the safety of rtPA. We found that, in the in vivo ICH model induced by VII-type collagenase, rtPA treatment improved the neurological function of ICH mice, alleviated the pathological damage and decreased the apoptosis and autophagy level of the peri-hematoma tissue. In the in-vitro model of ICH induced by hemin, the administration of rtPA down-regulated neuronal apoptosis, autophagy, and endoplasmic reticulum stress of neurons. Transcriptome sequencing analysis showed that rtPA treatment upregulated the PI3K/AKT/mTOR pathway in neurons, and PI3K inhibitor (LY294002) can reverse the protective effects of rtPA in inhibiting excessive apoptosis, autophagy and ER-stress. Epidermal growth factor receptor inhibitor (AG-1487) reversed the effect of rtPA on PI3K/AKT/mTOR pathway, which might indicate that the EGF domain played an important role in the activation of PI3K/AKT/mTOR pathway. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

er llc copy li pathway chen yang wang mis tang zhang protects wu vii liu neurons mtor hemorrhage biorxiv recombinant egf pi3k epidermal intracerebral transcriptome pi3k akt

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain

PaperPlayer biorxiv cell biology

Play Episode Listen Later Feb 6, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.06.527377v1?rss=1 Authors: Yin, Z., Wu, L., Zhang, Y., Sun, Y., Chen, J. W., Subudhi, S., Ho, W., Lee, G. Y., Wang, A., Gao, X., Ren, J., Zhu, C., Zhang, N., Ferraro, G. B., Muzikansky, A., Zhang, L., Stemmer-Rachamimov, A., Mao, J., Plotkin, S. R., Xu, L. Abstract: Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The LCLAT1/LYCAT acyltransferase supports EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Play Episode Listen Later Jan 27, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.26.524308v1?rss=1 Authors: Chan, V., Bone, L., Anderson, K. E., Zhang, K., Orofiamma, L., Awadeh, Y., Lee, D. K. C., Fu, N. J., Chow, J. T. S., Salmena, L., Stephens, L. R., Hawkins, P. T., Antonescu, C. N., Botelho, R. J. Abstract: Receptor tyrosine kinases such as epidermal growth factor (EGF) receptor (EGFR) stimulate phosphatidylinositol 3-kinases (PI3Ks) to convert phosphaitydlinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then promotes various pathways leading to actin remodelling, changes in gene expression, and enhanced anabolic activity, cell survival and proliferation. In part, PtdIns(3,4,5)P3 achieves these functions by stimulating the kinase Akt, which phosphorylates numerous targets like Tsc2 and GSK3{beta}. Overall, unchecked upregulation of PtdIns(3,4,5)P3-Akt signalling can promote tumourgenesis and cancer progression. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate at sn-1 and sn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. It is thought that LCLAT1/LYCAT and MBOAT7/LPIAT1 acyltransferases are respectively responsible for enriching PtdIns with this acyl composition. We previously showed that disruption of LCLAT1 altered the acyl profile of bis-phosphorylated PtdInsPs, lowered PtdIns(4,5)P2, and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3 signaling was not explored. Here, we show that LCLAT1 silencing in MDA-MB-231 and ARPE-19 cells abated the levels of PtdIns(3,4,5)P3 in response to EGF signalling. Importantly, LCLAT1-silenced cells were also impaired for EGF-mediated Akt activation and downstream signalling, and consequently, were depressed for cell proliferation and survival. Thus, our work provides first evidence that the LCLAT1 acyltransferase supports receptor tyrosine kinase signalling through the PtdIns(3,4,5)P3-Akt axis and may represent a novel target for therapeutic development against cancers. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc bone copy hawkins stephens zhang chow p3 akt botelho mediated egfr signalling biorxiv egf mda mb gsk3

Is a Chinese Invasion of Taiwan Inevitable? The Future of Cross-Strait Relations and Washington's Commitments to Taipei

Play Episode Listen Later Jan 18, 2023 27:11

After Russia's invasion of Ukraine, observers anxiously watched China's reactions as many feared a similar conflict would break out in the Taiwan Strait. In recent years, it appears China has been increasingly determined to enforce its One-China policy, first against Hong Kong and now against Taiwan. From afar, the United States is caught between deterring China from an all-out military conflict and supporting a democratic Taiwan. A few months ago, President Joe Biden broke away from America's traditionally ambiguous stance and said the US would defend Taiwan if China attacks. However, Eurasia Group Foundation's annual survey found that the number of Americans who support US intervention to help Taiwan is waning. So, how likely is it that a conflict between China and Taiwan breaks out? Is it possible for the US to navigate conflicting interests without resorting to involving itself in another war? In this episode, EGF senior fellow Mark Hannah sits down with Bonnie Glaser of the German Marshall Fund to discuss the state of US-China relations and the future of Taiwan. Bonnie Glaser is the managing director of the Indo-Pacific program at the German Marshall Fund. Glaser has worked at the intersection of Asia-Pacific geopolitics and US policy for more than three decades. To listen to more episodes or learn more about None Of The Above, go to www.noneoftheabovepodcast.org. To learn more about the Eurasia Group Foundation, please visit www.egfound.org and subscribe to our newsletter.

Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis

Play Episode Listen Later Jan 10, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.10.523252v1?rss=1 Authors: del Puerto, A., Marti-Prado, B., Barrios-Munoz, A. L., Lopez-Fonseca, C., Pose-Utrilla, J., Alcover-Sanchez, B., Cesca, F., Schiavo, G., Campanero, M. R., Farinas, I., Iglesias, T., Porlan, E. Abstract: In the adult mammalian brain, neural stem cells (NSCs) located in highly restricted niches sustain the generation of new neurons that integrate into existing circuits. A reduction in adult neurogenesis is linked to ageing and neurodegeneration, whereas dysregulation of proliferation and survival of NSCs have been hypothesized to be at the origin of glioma. Thus, unravelling the molecular underpinnings of the regulated activation that NSCs must undergo to proliferate and generate new progeny is of considerable relevance. current research has identified cues promoting or restraining NSCs activation. Yet, whether NSCs depend on external signals to survive or if intrinsic factors establish a threshold for sustaining their viability remains elusive, even if this knowledge could involve potential for devising novel therapeutic strategies. Kidins220 (Kinase D-interacting substrate of 220 kDa) is an essential effector of crucial pathways for neuronal survival and differentiation. It is dramatically altered in cancer and in neurological and neurodegenerative disorders, emerging as a regulatory molecule with important functions in human disease. Herein, we discover severe neurogenic deficits and hippocampal-based spatial memory defects in Kidins220 deficient mice. Mechanistically, we demonstrate that Kidins220-dependent activation of AKT in response to EGF restraints GSK3 activity preventing NSCs apoptosis. Hence, Kidins220 levels set a molecular threshold for survival in response to mitogens, allowing adult NSCs to proliferate. Our study identifies Kidins220 as a key player for sensing the availability of growth factors to sustain adult neurogenesis, uncovering a molecular link that may help paving the way towards neurorepair. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc survival adult copy threshold sustain stem cells iglesias puerto neural akt kda neurogenesis schiavo biorxiv egf progenitors cesca nscs gsk3

Bibi's Back: What the New Hardline Government Means for Israel, Palestine, and the United States

Play Episode Listen Later Dec 20, 2022 35:31

In early December, just weeks after Benjamin Netanyahu and his Likud party won Israel's parliamentary election (again), US Secretary of State Antony Blinken remarked that America's commitment to Israel has “never been stronger.” The incoming governing coalition that Netenyahu is forming is expected to be the most right-wing in Israeli history. What does this mean for Israel and the Israeli-Palestinian conflict? Does this change US policy vis-à-vis one of its closest partners in the Middle East? This week, guest host and EGF research fellow Zuri Linetksy speaks with journalists Neri Zilber and Muhammad Shehada who help us break down what affect Bibi's new government might have on Israeli-Palestinian relations, and offer thoughts on what the United States can do to mitigate potential violence coming from both sides of the Green Line. Neri Zilber is an Israeli journalist and analyst living in Tel Aviv, and host of the Israel Policy Pod. Muhammad Shehada is a Palestinian journalist and analyst from the Gaza Strip. To listen to more episodes or learn more about None Of The Above, go to www.noneoftheabovepodcast.org. To learn more about the Eurasia Group Foundation, please visit www.egfound.org and subscribe to our newsletter.

Growth/differentiation factor 15 controls number of ependymal and neural stem cells in the ventricular/subventricular zone

Play Episode Listen Later Dec 2, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.02.518869v1?rss=1 Authors: Baur, K., Carrillo Garcia, C., San, S., von Hahn, M., Strelau, J., Hölzl-Wenig, G., Mandl, C., Ciccolini, F. Abstract: Late in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE). However, the function of GDF15 in this region is unknown. We here show that ablation of GDF15 leads to an increase in proliferation of apically and subapically dividing progenitors in the GE. This is associated with faster cell cycle progression in both progenitor groups, and an increase in the total number of cycling progenitors. Enhanced proliferation of apically dividing progenitors leads to a permanent significant increase in the number of ependymal and apical neural stem cells (NSCs). Our data also indicate that the extra proliferation of subapically dividing progenitors causes a transient increase in the number of neuronal progenitors, which is compensated by increased apoptosis. Independent of the genotype, activity of endogenous epidermal growth factor (EGFR) signalling is essential for the proliferation of apically and subapically dividing progenitors. However, lack of GDF15 leads to a reduced cell surface expression of EGFR and altered dynamics of MAPK activation in response to EGF stimulation. Application of exogenous GDF15 rescued the effect of the genotype on the expression of EGFR and decreased proliferation in the mutant GE. Taken together, our results indicate that GDF15 modulates proliferation and growth factor responsiveness of apical progenitors in the developing GE, thereby regulating the number of total ependymal and NSCs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

growth llc independent factor application copy ge controls enhanced stem cells hahn wenig differentiation neural egfr ventricular biorxiv gdf egf mapk ciccolini nscs

Of Mushrooms and Midterms: How Pennsylvania Voted on Foreign Policy

america house americans joe biden ukraine pennsylvania congress republicans senate election day mushrooms midterms foreign policy voted westchester pennsylvanians egf

Play Episode Listen Later Nov 8, 2022 15:30

It's Election Day in the U.S. Americans across the country head to the polls to cast their vote in this year's midterm elections. Much is at stake for the Biden administration: Republicans are poised to take control of the House of Representatives, if not both houses of Congress. What are the issues motivating Americans to vote (or not)? A month after we at the Eurasia Group Foundation released its annual survey of Americans' foreign policy views, EGF's Caroline Gray and Lucas Robinson traveled to Pennsylvania, the site of one of this year's fiercest Senate races. Caroline and Lucas spoke with Pennsylvanians in Kennett Square, the self-proclaimed mushroom capital of the world, and West Chester to hear about the issues they care about most. Though foreign policy is not at the top of most Americans' minds when they cast their ballot, they have a lot to say about the war in Ukraine and how much of America's tax dollars should be spent on defense.

Novel Therapies Targeting KRAS in Lung Cancer & RAS-altered Tumors

ASCO Daily News

Play Episode Listen Later Nov 3, 2022 28:33

Dr. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors. TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these noble new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan's really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury's still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid's lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you'd still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great having us. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer. Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Benjamin Neel: None disclosed Dr. John Heymach: None disclosed

medicine rev scientists fda targeting map advances sos pd emt atp tumors merck checkpoint altered ras checkmate ret new england journal novartis lung cancer cancer care gsk precision medicine neel asco genentech bristol myers squibb aegean mtor md anderson cancer center kevan pfs egfr kras nyu langone health alk nci mek gtp nyu grossman school braf eisai novel therapies egf emd serono foundation medicine hras g13 nras pi3 tead t790m transcript dr thoracic oncology program genoptix astrazeneca medimmune

When Does an Uprising Become a Revolution? Reza Aslan and Assal Rad on the Protests in Iran

Play Episode Listen Later Oct 25, 2022 36:06

Iran is in upheaval. The death of a young woman, Mahsa Amini, in the custody of Iran's “morality police” has sparked an uprising throughout the country. Protesters have turned the current regime's revolutionary iconography against it. Faced with what might be the biggest test to its legitimacy since 1979, the Iranian government has imposed a brutal crackdown on dissent. Countries and human rights organizations around the world condemn the government's violence. In the United States, President Biden has paused nuclear negotiations and expressed his administration's support for the protesters. But there is little consensus on how and whether this support should transform into official U.S. policy. This week on None Of The Above, EGF's Mark Hannah speaks with Assal Rad and Reza Aslan, two experts on Iranian politics and culture. They discuss Iran's history of uprisings and revolutions, the importance of international solidarity, and why Iran's future is ultimately in Iranian hands. To listen to more episodes or learn more about None Of The Above, go to www.noneoftheabovepodcast.org. To learn more about the Eurasia Group Foundation, please visit www.egfound.org and subscribe to our newsletter. Assal Rad is the research director at the National Iranian American Council and the author of The State of Resistance: Politics, Culture, and Identity in Modern Iran (2022). Reza Aslan is a scholar, writer, and television producer. He is the author of numerous books including his most recent, An American Martyr in Persia: The Epic Life and Tragic Death of Howard Baskerville (2022). Reza is a Professor of Creative Writing at the University of California, Riverside.

Twentieth Sunday after Pentecost

family bible service food forgiveness confessions harvest sermons twentieth sunday after pentecost egf

Play Episode Listen Later Oct 23, 2022

Order a hymnal for your home Upcoming Events Wednesday, 6:00-7:45 pm: "Faith, Family, Food, and Fellowship" @ Christ the King, EGF. There is a free meal for all, followed by kids group, youth group, and adult Bible study. 7:45 pm: Confirmation class Sunday: 7:30 am: “Sermons from Trinity” on KNOX 1310/107.9 10:00 am: Service of the Word 11:15 am: Sunday school for all ages Sunday, November 23: Harvest festival potluck after Sunday school

Press Release: PDGF Cross-Signaling Indicates Bypassed Signaling in Colorectal Cancer

Oncotarget

Play Episode Listen Later Oct 20, 2022 4:02

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)

university cross pinterest harvard medical school souza paran doi press releases correspondence signaling colorectal cancer crc egfr platelet vegf caco egf vegfr wuerzburg pdgf oncotarget uicc vegfr2 pdgfr

Nineteenth Sunday after Pentecost

family bible prayer service food sermons nineteenth sunday after pentecost egf

Play Episode Listen Later Oct 16, 2022

Order a hymnal for your home Upcoming Events Monday, 7:00 pm: Council meeting Wednesday, 6:00-7:45 pm: "Faith, Family, Food, and Fellowship" @ Christ the King, EGF. There is a free meal for all, followed by kids group, youth group, and adult Bible study. 7:45 pm: Confirmation class Sunday: 7:30 am: “Sermons from Trinity” on KNOX 1310/107.9 10:00 am: Service of the Word 11:15 am: Sunday school for all ages

ERK3/MAPK6 dictates Cdc42/Rac1 activity and ARP2/3-dependent actin polymerization

PaperPlayer biorxiv cell biology

Play Episode Listen Later Oct 13, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511969v1?rss=1 Authors: Bogucka-Janczi, K., Harms, G., May-Coissieux, M., Bentires-Alj, M., Thiede, B., Rajalingam, K. Abstract: The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding proteins and nucleation-promoting factors to perform fundamental cellular functions. Here, we show that ERK3, an atypical MAPK, directly acts as a guanine nucleotide exchange factor for Cdc42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent Rac1 and Cdc42 activation, maintenance of F-actin content, filopodia formation and epithelial cell migration. Further, ERK3 protein binds directly to the purified ARP2/3 complex and augments polymerization of actin in vitro. ERK3 kinase activity is required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc activity copy dependent harms dictates actin rac1 biorxiv egf mapk polymerization cdc42 arp2

Eighteenth Sunday after Pentecost

family bible service food home faithfulness sermons eighteenth sunday after pentecost egf

Play Episode Listen Later Oct 9, 2022

Order a hymnal for your home Upcoming Events Wednesday, 6:00-7:45 pm: "Faith, Family, Food, and Fellowship" @ Christ the King, EGF. There is a free meal for all, followed by kids group, youth group, and adult Bible study. 7:45 pm: Confirmation class Thursday, 2:00 pm: WMF Bible study & meeting Sunday: 7:30 am: “Sermons from Trinity” on KNOX 1310/107.9 10:00 am: Service of the Word (noisy offering for the Miriam Children's Home" 11:15 am: Sunday school for all ages

Seventeenth Sunday after Pentecost