Podcasts about tregs

founders nature regulatory therapies derived parmar cord blood treg tregs simrit

Play Episode Listen Later Feb 18, 2025

Dr. Simrit Parmar, Founder of Cellenkos, is developing T regulatory cell therapies from cord blood to treat aplastic anemia, myelofibrosis, and acute lymphoblastic leukemia. Their three-prong strategy focuses on resolving inflammation and alleviating the burden of transfusions. Treg cells from cord blood are naturally tolerant and do not risk rejection, meaning they can be administered to patients without the need for matching. The cells can be consistently manufactured in a scalable way and distributed globally. Simrit explains, "Tregs, the T regulatory cells, are actually regulators of our immune system. So if you think about it every day as a human being, we face many challenges. We face many insults and injuries to our body, both externally and internally, but our body has a way to maintain that balance. The T regulatory cells are the cells that are the mastermind of making sure that any response by our body, for example, to get rid of an antigen or to get rid of an irritant does not overstay the welcome because our body utilizes the mechanism of inflammation to get rid of these injuries or these insults." "So umbilical cord blood is, or the umbilical cord is, the connection between the baby, the fetus, and the mother. And if you think about it, the baby is 50% mismatched to the mother, and nature allows it. Nature allows a permissive environment where the baby can grow and eventually give birth, and the whole species is advanced. What happens is that nature has allowed the tolerance, and one of the mechanisms by which this tolerance, the maternal-fetal tolerance, is induced by the very T regulatory cells that populate the conduit between the mother and the baby, is the cord blood. So what we did is harness the power that nature has bestowed upon these cells to just do one job and one job only, which is to resolve inflammation. This is the fundamental reason we went after cord blood as a starting material because as a physician and drug developer, we wanted to make sure that the product, the cells we're giving into the patient, are doing its job." #Biotechnology #DrugDevelopment #LifeSciences #AplasticAnemia #Myelofibrosis #GVHD #ALS #Tregs #CellTherapies #TargetedTherapies #AutoimmuneDiseases cellenkosinc.com Listen to the podcast here

Cord Blood-Derived T Regulatory Cell Therapies with Dr. Simrit Parmar Cellenkos

founders nature regulatory therapies derived parmar cord blood treg tregs simrit

Play Episode Listen Later Feb 18, 2025 23:57

Transcriptome and ctDNA Associates with Pembrolizumab Benefit

JCO Precision Oncology Conversations

Play Episode Listen Later Dec 18, 2024 23:19

JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.” Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us. Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off. Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance. Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes? Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations. Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study? Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort? Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil? Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in. Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial. Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees. Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology. And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own 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.

155. The Gut-Immune Axis & The Role That Gut-Microbiome Metabolites / Postbiotics Play | SCFAs, Polyphenol Metabolites, & Supporting Butyrate Production

The Synthesis of Wellness

Play Episode Listen Later Dec 13, 2024 16:08

In this episode, we dive into the interplay between the gut microbiota (their postbiotics) and the immune system. We will examine how gut microbiome-derived metabolites, such as short-chain fatty acids (SCFAs) and polyphenol metabolites, influence immune function by modulating key cellular and molecular pathways within the intestinal mucosa. Additionally, we discuss strategies for supporting butyrate production and optimizing microbiome health to foster a balanced and resilient gut-immune axis. Topics: 1. Introduction Overview of the gut-immune axis. Importance of gut microbiome-derived metabolites in supporting immune function. 2. The Intestinal Barrier Layers of the intestinal wall Focus on mucosa, specifically the epithelium and lamina propria. 3. Structure of the Intestinal Layers The intestinal lumen, mucus layer, epithelium (with tight junctions), and lamina propria. Importance of the lamina propria as a hub for immune responses and structural integrity. 4. Cellular and Structural Components of the Lamina Propria Extracellular matrix (ECM): structural support. Fibroblasts and myofibroblasts. Lymphatic vessels: immune cell transport, linking mucosal and systemic immune systems. 5. Immune Cells in the Lamina Propria T cells: immune tolerance, regulatory T cells (Tregs). B cells: Secretory immunoglobulin A (sIgA). Dendritic cells: antigen sampling and presentation. Macrophages: pathogen clearance. Mast cells 6. Role of Secretory Immunoglobulin A (sIgA) Functions as a first-line defense in the intestinal mucus layer. Neutralizes pathogens, prevents epithelial adhesion. 7. Postbiotics Overview Bioactive compounds produced by gut microbiota. Examples: short-chain fatty acids (SCFAs) 8. Short-Chain Fatty Acids (SCFAs) and Their Functions Influence on Treg cells in the lamina propria, promoting immune tolerance. Butyrate also as an energy source for epithelial cells. 9. Supporting Butyrate Production Microbiome optimization to enhance beneficial butyrate-producing microbes. Use of prebiotics: resistant starch, soluble fibers, and polyphenols. Supplementation with sodium butyrate as an additional tool. 10. Other Postbiotics Antimicrobial peptides produced by beneficial microbes. Complex carbohydrates produced by beneficial microbes and can act as prebiotics. Polyphenol metabolites: Gut microbiota biotransforms polyphenols into bioactive metabolites with increased bioavailability. 11. Specific Polyphenols Examples: resveratrol, quercetin, and ellagitannins. Effects on intestinal barrier function, inflammation, and immune cell populations. "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

141. The Role that Gut-Microbiome Metabolites, Including Tryptophan Metabolites & Butyrate, Play in Supporting the Gut-Immune Axis | Tools for Supporting Butyrate Levels

The Synthesis of Wellness

Play Episode Listen Later Sep 20, 2024 23:50

In this episode, we dive into how short-chain fatty acids (SCFAs), particularly butyrate, and tryptophan metabolites support the gut-immune axis by promoting regulatory T cell differentiation, strengthening the intestinal barrier, and enhancing antimicrobial defenses through IL-22 signaling. We break down how butyrate can improve immune tolerance as well as epithelial integrity, aiding in the prevention of chronic inflammatory responses. We also detail practical ways to support butyrate levels and aid in strengthening both the epithelial barrier and gut-immune axis. Topics: 1. Introduction - Overview of the role of SCFAs and tryptophan metabolites in supporting the gut-immune axis. - Quick review of the location of immune cells in relation to the gut microbiota. 2. The Intestinal Barrier - Structure of the intestinal wall and layers - Focus on the mucosal layer, specifically epithelium and lamina propria. 3. The Lamina Propria - Structural elements: fibroblasts, extracellular matrix (ECM), and myofibroblasts. - Vascular components: endothelial cells, capillaries, and lymphatic vessels. - Importance of the lamina propria as a hub for immune responses. 4. Immune Cells in the Lamina Propria - T cells: Role of regulatory T cells (Tregs) in immune modulation. - B cells: Production of IgA, class switching, and plasma cells. - Dendritic cells: Sampling luminal antigens and initiating immune responses. - Macrophages: Phagocytic activity, pro-inflammatory (M1) vs. anti-inflammatory (M2) states. - Mast cells: Role in allergic responses, chronic inflammatory conditions, and MCAS. 5. Short-Chain Fatty Acids (SCFAs) - Production of SCFAs (acetate, propionate, butyrate) by gut microbiota. - Butyrate's role in supporting regulatory T cell (Treg) differentiation and immune tolerance. -Butyrate as fuel for epithelial cells and the production of tight junction proteins. 6. Mechanisms of Butyrate in Immune Modulation - Impact on Tregs through FoxP3 expression. - SCFA's role in maintaining immune balance. 7. Butyrate and Epithelial Integrity - Support for tight junction protein expression. - Prevention of translocation of harmful microbes and antigens. - Reduced systemic inflammation through a strengthened barrier. 8. Supporting Butyrate Production - Sodium butyrate supplementation and microbiome optimization. - Role of fiber, polyphenols, and probiotics. 9. Tryptophan Metabolites - Overview of tryptophan metabolism by gut bacteria into indoles. - Indoles' role in promoting IL-22 production, contributing to antimicrobial defense and immune tolerance. 10. IL-22 - IL-22's enhancement of antimicrobial peptides (AMPs) and mucin production. - Case Study: Role of Lactobacillus strains in restoring IL-22 and helping to mitigate colitis. 11. Conclusion - Recap of how SCFAs and tryptophan metabolites interact with the gut-immune axis. - Importance of gut microbiome support for maintaining immune balance. Thank you to our episode sponsor: 1. Check out ⁠⁠⁠⁠Daily Nouri⁠⁠⁠⁠ and use code ⁠⁠⁠⁠CHLOE20⁠⁠⁠⁠ for 20% off your order. Thanks for tuning in! Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" 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! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

Key Takeaways From 2024 ASCO Breakthrough

ASCO Daily News

Play Episode Listen Later Aug 22, 2024 14:26

Dr. Lillian Siu and Dr. Melvin Chua discuss the new technologies and novel therapeutics that were featured at the 2024 ASCO Breakthrough meeting. TRANSCRIPT Dr. Lillian Siu: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Lillian Siu, a medical oncologist and director of the Phase 1 Trials Program at the Princess Margaret Cancer Center in Toronto, Canada, and a professor of medicine at the University of Toronto. On today's episode, we'll be discussing key takeaways from the 2024 ASCO Breakthrough meeting in Yokohama, Japan. Joining me for this discussion is Dr. Melvin Chua, who served as the chair of Breakthrough's Program Committee. Dr. Chua is the head of the Department for Head, Neck and Thoracic Cancers in the Division of Radiation Oncology at the National Cancer Center in Singapore. Our full disclosures are available in the transcript of this episode. Dr. Chua, it's great to be speaking with you today and congratulations on a very successful Breakthrough meeting. Dr. Melvin Chua: Thanks Dr. Siu. It was really inspiring to come together again to showcase the innovative work of world-renowned experts, clinicians, researchers, med-tech pioneers, and drug developers from around the globe. Our theme this year was inclusivity and thus it was important to bring people together again in the Asia Pacific region and to foster international collaborations that are so important in advancing cancer care. This year, we invited 65 international faculty, of which 55% were from Asia. Also, importantly, we achieved approximately a 50-50 split for male to female representation. These are remarkable statistics for the meeting, and we really hope to retain this for future Breakthrough [meetings]. Dr. Lillian Siu: The meeting featured renowned keynote speakers who shared great insights on new technologies and therapies that are shaping the future of drug development and care delivery. Let's first talk about artificial intelligence and the keynote address by Dr. Andrew Trister. He gave a very interesting talk titled, “Plaiting the Golden Braid: How Artificial Intelligence Informs the Learning Health System.” What are the key messages from his talk? Dr. Melvin Chua: Couldn't agree with you more, Dr. Siu. Dr. Trister is the chief medical and scientific officer of Verily, a precision health company. He previously worked in digital health and AI at The Bill and Melinda Gates Foundation, and worked at Apple where he led clinical research and machine learning with Apple partners. But perhaps it was really his background and training as a radiation oncologist that was most pertinent as he was able to weave both the components of new AI models and the applications and pitfalls in the clinic to the audience. Dr. Trister provided a very high-level view through the history of AI and showcased the progression of the different AI models and he basically explained between deep and shallow methods as well as deductive logic versus inductive probabilistic methods. He then provided several clinical examples where these models have shown their utility in the clinic, for example, pathology and so forth. At the same time, he illustrated several pitfalls with these models. So overall, I think Dr. Trister's talk was very well received by the audience with several key messages, including the importance of [using] high-quality data as the basis of a good AI model. AI was also addressed in an Education Session that looked at Artificial Intelligence in the Cancer Clinic. And we had a panel of experts that highlighted current progress and successes with AI in the clinic, advances with AI assisted pathology for clinical research and precision medicine, large language models (LLMs) for applications in the clinic, and how we could leverage AI in precision oncology. And from this session, I had several key takeaways. Dr. Alexander Pearson [of the University of Chicago] gave a very illustrative talk on how multimodal information across clinical omics, radiological information and multi omics could be used to improve diagnostic tasks and clinical prediction across different cancers. And Dr. Joe Yeong [of Singapore General Hospital] gave a very good talk on how AI can be applied in digital pathology to accelerate research in immunology and help in the development of immunotherapies. Dr. Danielle Bitterman [of Brigham and Women's Hospital] shared very good examples of how LLMs could be used in a clinic. And I think the example that really stood out for me was how LLMs could be deployed to create responses to patient queries. And of course, the big question in the room was: How could AI eventually encapsulate compassion in their response? I think this again showcased how LLMs could really help to accelerate our clinical work going forward. And ultimately circling back to data, Dr. Caroline Chung [of MD Anderson] gave a very poignant description on the importance of data quality and how poor-quality data could eventually lead to underperforming AI models. So all in all, I think this was a great session. And what do you think, Dr. Siu? Dr. Lillian Siu: Melvin, I totally agree with you. I like all your comments and I really enjoyed the keynote as well as the session on AI in the cancer clinic chaired by Dr. Pearson. I think all these sessions were really informative. Discussions on the latest AI and machine learning, algorithms and technologies on digital pathology, LLMs and big data, as you said, really enables the attendees, especially clinicians like me, to gain a deep understanding of how AI can be translated to practical applications. Dr. Melvin Chua: Great. So, Dr. Siu, let's talk about some of the novel therapeutics that were featured at the meeting. Again, this was an important session for Breakthrough, and it's always been there. So could you share some highlights from the sessions on novel drug development from your perspective? Dr. Lillian Siu: Yes, indeed. Drug development is such an exciting aspect of this meeting. On Day 3 of the meeting, we had a keynote by Dr. Shimon Sakaguchi of Osaka University, who discussed “Targeting Regulatory T cells (Tregs) in Cancer: The Science, Trials, and Future.” And he talked about T cells, especially Treg biology, the role of Tregs in immune regulation, new developments in Treg immuno-oncology drugs, and how we can actually target Tregs to treat early cancers, etc. This talk is particularly exciting because there are now anti CCR8 antibodies in the clinic that specifically target Tregs, and some early signals of anti-tumor activities are already being observed. Dr. Sakaguchi also emphasized the importance of combination sequence and timing of drugs for the successful use of cancer immunotherapeutic agents. I also want to emphasize the Education Session that followed, titled, “The Future of Immunotherapy, New Drugs and New Ideas.” In that particular session, we heard about engineering T-cell immunity to eradicate tumors. We heard about CAR T-cell therapy in GI cancers, novel immunotherapeutic combinations, and T-cell engagers, which are bispecifics in cancer. While success with some of these immunotherapeutic modalities, such as cell therapies and T-cell engagers have been largely seen in hematological malignancies, we are beginning to observe efficacy signals in solid tumors. For example, the CAR T targeting Claudin18.2 in gastrointestinal cancers and the recently approved FDA-approved DLL3/CD3 bispecific T-cell engager, tarlatamab, in small cell lung cancer are really exciting examples. We also heard from investigators who are exploring neoadjuvant therapies in the neoadjuvant therapy session, and the key takeaway from that session is that we have growing interest in using neoadjuvant therapy or perioperative therapy. In other words, neoadjuvant plus adjuvant therapy in different cancers. In the neoadjuvant session, there were updates provided by different experts on the roles of neoadjuvant therapy in melanoma, liver cancer, bladder cancer, and nasopharyngeal cancer. Increasingly, there is randomized trial evidence to support the use of neoadjuvant therapy or perioperative immunotherapy in several cancer types with survival-based endpoints. Very exciting indeed. Dr. Melvin Chua: Indeed, I couldn't agree with you more. I think one of the things that went into designing the case-based discussions this year was that we wanted to talk about cancers that were relevant to this part of the world and hence we again showcased lung cancers, gastric cancers and melanomas, and whereby we have again perspectives from an expert from the West coupled to an expert from the East, thereby showcasing the diversity of practice around the world. The other thing that we did this year was we decided to pair the case-based discussions with the keynotes and the Education Sessions as well. For example, on Day 3, we had Dr. Sakaguchi speak on Tregs, as you mentioned. And this was followed by an in-depth session on new immunotherapies, and then followed by a case-based discussion on different melanoma cases on the role of neoadjuvant immunotherapy in this disease, and the strikingly relevance of response to prognostication. This is an important trait that we're seeing now that seems to pan out across different cancers, where we find that neoadjuvant response to combination systemic therapies and/or radiotherapy is a strong prognosticator. Dr. Lillian Siu: So, Dr. Chua, we've discussed some breakthrough treatments and promising advances in cancer care, and we've touched upon some barriers to success in cancer treatment. I would like to ask you about the keynote address by Dr. Raffaella Casolino of the World Health Organization, who spoke passionately about efforts by the WHO and its partners to build equity in cancer care. Can you share some highlights with us? Dr. Melvin Chua: Absolutely, Dr. Siu. In spite of the tremendous advances we've seen in recent years in oncology, there are still major disparities in cancer care, such as cost and access, which affect patients worldwide. I think Dr. Casolino's talk was a very nice overview whereby she showed, first of all, the WHO's impact in terms of the WHO Cancer Resolution initiative that was implemented in 2017, where through this initiative, WHO has impacted 100 countries, invested $1 billion in funds, and that has led to millions of lives saved. But she then really drilled down to some of the key examples of the focus of the WHO in terms of equalizing care in cancer. I think one which struck me was the appreciation of the disparities in the clinical trials landscape. I think it is clear that there's still a huge barrier to clinical trials between the high- and middle-income countries and the low- and middle-income countries, and the majority of clinical trials these days are industry sponsored and we really need to look at leveling the playing field in this regard. Then she highlighted the WHO's work on trying to lower the barriers to precision oncology. And I think there are several issues in that sense, but I think what the WHO has really worked hard on is promoting education for genomic medicine, where they've done several reviews with experts around the world to educate the field across the world on how we interpret and apply genomics in the clinic. So all in all, it was very interesting to hear Dr. Casolino's insights from a policy perspective, and again, this emphasizes that there's so much work to be done at the end of the day and the dialogue needs to continue. We also heard about policy, academic and industry perspectives in the context of clinical trials, and that led to a discussion on real-world evidence generation for regulatory approvals. It was very nice that we had a session on that at the end of Breakthrough 2024 (Real-World Evidence and Clinical Trials: Beyond the Ivory Tower). And in that session, we heard from Dr. Shaalan Beg [of the NIH], and Dr. Janet Dancey [of Queen's University] who represented views from academia and Dr. Hidetoshi Hayashi [of Kindai University Hospital] shared perspectives on decentralized trials. I'd like to encourage our listeners to watch these sessions if they were unable to attend. The content is very rich, and I'm sure they'll learn from it. Dr. Lillian Siu: Thank you so much, Dr. Chua. Is there anything else you would like to cover before we wrap up the podcast today? Dr. Melvin Chua: Thank you, Dr. Siu. The thing I really want to emphasize is, apart from all these Educational Sessions and having very eminent keynote speakers, one of the key points that we really want to bring out for Breakthrough is to showcase the high-quality research. This year we had 300 abstracts submitted and they were all high quality, cutting across trials, omics research, AI and technology, and eventually we selected 235 of them and we were able to showcase some of them across three oral sessions over three days. I think this is an important component of Breakthrough that we really wish to continue building upon where people are now excited to use this forum to present their work. Dr. Lillian Siu: Thank you so much, Dr. Chua. I really enjoyed our discussions today. I look forward to seeing how the Breakthrough meeting will continue to grow in future years. Dr. Melvin Chua: Thank you again, Dr. Siu. Thank you for all your leadership and efforts in making Breakthrough a successful meeting series the past few years. Dr. Lillian Siu: Thank you to our listeners for your time today. You'll find links to the session discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Lilian Siu @lillian_siu Dr. Melvin Chua @DrMLChua Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Lillian Siu: Leadership (Immediate family member): Treadwell Therapeutics Stock and Other Ownership Interests (Immediate family member): Agios Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen Dr. Melvin Chua: Leadership, Stock and Other Ownership Interests: Digital Life Line Honoraria: Janssen Oncology, Varian Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene Speakers' Bureau: AstraZeneca, Bayer, Pfizer, Janssen Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)

women university head canada chicago ai apple japan future west toronto hospitals east artificial intelligence trials phase singapore breakthrough stock drug fda pfizer world health organization gi neck key takeaways cart astrazeneca pearson asia pacific nih bayer roche detection merck new ideas brigham janssen avid novartis melinda gates foundation royalties immunotherapy yokohama gsk new drugs asco verily amgen glaxosmithkline on day ivory tower chua siu radiation oncology boehringer ingelheim md anderson navire iqvia real world evidence treg osaka university sakaguchi program committee tregs seattle genetics cancer clinic mirati therapeutics merck sharp dohme arvinas transcript dr telix pharmaceuticals astrazeneca medimmune educational sessions

Immunotherapy at ASCO24: NADINA and Other Key Studies

ASCO Daily News

Play Episode Listen Later Jun 19, 2024 34:51

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in the neoadjuvant immunotherapy space that were presented at the 2024 ASCO Annual Meeting, including promising outcomes in high-risk melanoma from the NADINA trial, as well as other new treatment options for patients with advanced cancers. TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I am an associate professor of medicine and the clinical director of the Melanoma Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I am delighted to have my colleague and friend Dr. Jason Luke on the podcast today to discuss key late-breaking abstracts and advances in immunotherapy that were presented at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the associate director of clinical research, and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. You will find our full disclosures in the transcript of this episode. Jason, it's always a pleasure to hear your insights on the key trials in these spaces and to have you back as a guest on this podcast that highlights some of the work, especially advances, that were just presented. Dr. Jason Luke: Well, thanks very much for the invitation. I always love joining the podcast. Dr. Diwakar Davar: We'll start very quickly by talking about some advances and really interesting things that happened both in the context of melanoma but also in immunotherapy in general. And we'll start with what I think was certainly one highlight for me, which was LBA2, the late-breaking abstract on the NADINA trial. It was featured in the Plenary Session, and in this abstract, Dr. Christian Blank and colleagues reported on the results of this phase 3 trial of neoadjuvant ipi-nivo. This is the flipped dose of ipi1/nivo3 versus adjuvant nivolumab in PD-1 naive, macroscopic, resectable, high-risk stage 3 melanoma. By way of background, neoadjuvant immunotherapy for those listening is an area of increasing interest for drug developers and development for both approved and novel agents. Neoadjuvant immunotherapy has been studied with multiple approved agents, including PD-1 monotherapy, PD-1 LAG-3, PD-1 CTLA-4, T-VEC, as well as investigational agents and multiple randomized and non-randomized studies. The benchmark pathologic response rates with these agents range from 17% PCR with PD-1 monotherapy, 45% to 55% PCR with PD-1 CTLA-4 combination therapy, and slightly higher 57% PCR with PD-1 LAG-3 has recently reported by Dr. Rodabe Amaria from MD Anderson. However, as we embark on phase 3 comparisons for various neoadjuvant compared to adjuvant immunotherapy trials and combinations, we're increasingly moving towards event-free survival as the primary endpoint for neoadjuvant versus adjuvant studies. And this was most recently studied in the context of SWOG S1801, a study that was led by Dr. Sapna Patel. So, Jason, before we start on NADINA, can you briefly summarize the SWOG S1801 trial and the event-free survival statistic reported by Dr. Patel and her colleagues? Dr. Jason Luke: Well, absolutely. And these data were reported at ESMO about two years ago and then in the New England Journal last year. The S1801 study answered a very simple question: What would happen if you took three of the doses of standard adjuvant therapy with pembrolizumab and moved them prior to surgery? And on a high level, the study is as simple as that. And many of us were somewhat skeptical of this trial design because we thought that just moving the doses earlier may not actually have a major impact. In the study, you alluded to the event-free survival statistic, and that alludes to what was considered an event. And so, without reading all of it, there were several different aspects that were included in terms of time, based on the date of randomization until the first of a series of events, such as disease progression, toxicity from treatment, if the patient was unable to go to surgery or had surgical complications, or if they had delay in starting the adjuvant therapy due to toxicity, and obviously, recurrence of melanoma or death from any cause. In that context, merely moving the 3 doses of pembrolizumab to the neoadjuvant setting saw an improvement in this two-year event free survival to 72% for the neoadjuvant therapy compared to 49% for the adjuvant therapy. That was quite an outstanding change. And again, noting the power of neoadjuvant treatment, really dictating the impact of anti PD-1, again, just with 3 doses moving from adjuvant into the neoadjuvant setting, and I think all of us were somewhat surprised to see that magnitude of a benefit. But it set up the current study very well, where we now look at combination therapy. Dr. Diwakar Davar: So let's move on to the phase 3 NADINA trial. Do you want to perhaps discuss the study design, particularly focusing on the EFS primary endpoint and maybe also touching on the different schedules? So, SWOG S1801 was a neoadjuvant study of 3 cycles of pembrolizumab and how did that compare and contrast to the neoadjuvant combination that was studied in NADINA? Dr. Jason Luke: Well, as you alluded to, NADINA investigated the regimen of nivolumab plus ipilimumab and compared that against adjuvant therapy with nivolumab alone. So, in the study, as you alluded, the dose and schedule of the two drugs used was nivolumab at 3 milligrams per kilogram, and ipilimumab with 1 milligram per kilogram. That was based on a series of signal finding and safety studies that had been previously done by the same group of authors identifying that as the optimal treatment regimen. And it's worth noting that's slightly different than the labeled indication that's generally used for those same drugs for metastatic melanoma, albeit that the NCCN also endorses this schedule. So, in the trial, 423 patients were randomized, 1:1 to receive either neoadjuvant therapy with those 2 doses of nivolumab plus ipilimumab as compared with standard adjuvant therapy with nivolumab following surgery. Now, one interesting tweak was that there was an adaptive nature to the study, meaning that patients had a fiducial placed at the index lymph node, and after the neoadjuvant therapy in that arm, that lymph node was removed. And if the patient had a major pathological response, they did not go on to receive the adjuvant portion of the treatment. So it was adaptive because those patients who did very well to the neoadjuvant did not require the adjuvant portion. And in those patients who did not achieve a major pathological response, they could go on to have the adjuvant therapy. And that also included the BRAF therapy for those whose tumors were BRAF mutants. It's also worth pointing out that the definition of event free survival was slightly different than in the S1801 study that was alluded to just a second ago. And here, EFS was defined from the date of randomization until progression due to melanoma or due to treatment. So that's slightly different than the definition in the S1801 trial. So, a somewhat complicated study, but I really applaud the authors because I think this study does mirror what we would likely be doing in actual clinical practice. Dr. Diwakar Davar: So, just to briefly summarize the efficacy, and then to get your comments on this, the path response, the PCR rate was 47%. The major pathologic response rate, which is the proportion of patients with between 0% to 1/10% of residual viable tumors, was about 12%. And for a major pathologic response rate of 0% to 10% of 59%. And then the rest of the patients had either pathologic partial response, which was 10% to 50%, or pathologic non response or 50% or greater residual viable tumor, all assessed using central pathology grades. The one year RFS was 95% in the FDR patient population versus 76% in the pathologic partial response patient population, 57% in the pathologic non response patient population. So how do you view these results? Can you context the FDR rates and the EFS rates from NADINA relative to nivo-rela and also potentially SWOG 1801? Dr. Jason Luke: Well, I think these are very exciting results. I think that for those of us that have been following the field closely, they're actually not especially surprising because they mirror several studies that have come before them. When we put them in context with other studies, we see that these rates of major pathological response are consistent with what we've seen in phase 2 studies. They're relatively similar. Or I should say that the results from nivolumab and relatlimab, which was also pursued in a phase 2 study of somewhat similar design, are somewhat similar to this. So, combination immunotherapy does look to deliver a higher major pathological response than pembrolizumab alone, as was known in S1801. Which of course, the caveat being is these are cross control comparisons that we need to be careful about. So I think all of these are active regimens, and I think adding a second agent does appear to enhance the major pathologic response rates. When we look at the event free survival, we see something similar, which is that numerically it looks to be that combination immunotherapy delivers a higher event free survival rate. And that looks to be rather meaningful given the difference in the hazard ratios that were observed between these various studies. And here in the NADINA study, we see that 0.3 hazard ratio for EFS is just extremely impressive. So the abstract then, from ourselves, out of these specific studies, what does this mean more broadly in the real world, where patients exist and the rest of the landscape for clinical trials? I think we can't take enough time to stop for a second and just think about what a revolution we've come forward in with immune checkpoint blockade and melanoma. When I started my career, now, more than 15 years ago, melanoma was the cancer that made cancer bad. And now here we say, in the highest risk of perioperative patients, we can deliver 2 doses of nivolumab and ipilimumab, and essentially half of the patients then don't need to go on, and more than half the patients don't need to go on to have a full surgery and don't need adjuvant therapy. And from what we could tell of a very, very low risk of every heavy recurrence of melanoma. Of course, there's the other half of patients where we still need to do better, but these are just fantastic results and I think highly meaningful for patients. In the context of ongoing clinical trials, another abstract that was presented during the meeting was the update to the individualized neoantigen therapy, or V940 with pembrolizumab or against pembrolizumab alone. That's the KEYNOTE-942 study. In that study, they presented updated data at two and a half years for relapse free survival, noting a 75% rate without relapse. So those results are also highly intriguing. And these are in a similar population of very high risk patients. And so I think most of us believe that neoadjuvant therapy with this study in NADINA is now confirmed as the priority approach for patients who present with high-risk stage 3 disease. So that would be bulky disease picked up on a scan or palpable in a clinic. I think essentially all of us now believe patients should get preoperative immunotherapy. We can debate which approach to take, and it may vary by an individual patient's ability to tolerate toxicity, because, of course, multi agent immunotherapy does have increased toxicity relative to anti PD-1 alone. But we'll have to wait now for the full phase 3 results from the V940 individualized neoantigen therapy. And if those come forward, that will be an extremely attractive approach to think about for patients who did not achieve a major pathological response to neoadjuvant therapy, as well as of course to the other populations of patients with melanoma where we otherwise currently give adjuvant therapy stage 2B all the way through stage 4 resected. It's an amazing time to think about perioperative therapy in melanoma. Dr. Diwakar Davar: So this is clearly outstanding data, outstanding news. Congratulations to the investigators for really doing what is an investigative initiated trial conducted across multiple continents with a huge sample size. So this clearly appears to be, at this point in time at least, a de facto standard. But is this going to be FDA-approved, guideline-approved, or is it possible in your mind? Dr. Jason Luke: Well, that's an interesting question. This study was not designed with the intent to necessarily try to register this treatment regimen with the FDA. One would have to take a step back and say, with how powerful these data appear, it sort of seemed like it would be too bad if that doesn't happen. But all the same, I think the community and those of us who participate in guideline recommendations are fully supportive of this. So, I think we will see this move into compendium listings that support insurance approval, I think, very, very quickly. So, whether or not this actually becomes formally FDA approved or is in the guidelines, I think this should become the standard approach that is considered for patients, again presenting with high-risk stage 3 disease. Dr. Diwakar Davar: Fantastic. So now we're going to go in and talk about a slightly different drug, but also from the melanoma context, and that is the safety and efficacy of RP1 with nivolumab in the context of patients with melanoma who are PD-1 failures. So, this is Abstract 9517. And in this abstract, our academic colleagues essentially talked about these data, and we'll start by describing what RP1 is. RP1 essentially is a HSV-1 based oncolytic immunotherapy. And RP1 expresses GM-CSF as well as a fusogenic protein, GALV-GP-R-. And in this abstract, Dr. Michael Wong from MD Anderson and colleagues are reporting the results of IGNYTE, which is a phase I trial of intratumoral RP1 co-administered with systemic nivolumab in patients with advanced metastatic treatment refractory cutaneous melanoma. And the data presented in this abstract represents data from a registration directed, abbreviated as RD, registration directed cohort of RP1 plus nivolumab in PD-1 refractory melanoma. So, let's start with the description of the cohort. Dr. Jason Luke: Right. So, in this study, there were a total of 156 patients who were presented, and that included an initial safety and dose finding group of 16, as well as the RD cohort, as you noted, of 140 patients. And it's important to point out that this was a cohort that was selected for a very strict definition of progression on anti PD-1, or a combination immunotherapy as their immediately prior treatment. So, all of the patients in the cohort had exposure to anti PD-1, and 46% of them had anti PD-1 plus anti CTLA4, nivolumab and ipilimumab as their immediately prior therapy. This was also a group of relatively high-risk patients when one considers stage. So, within the stage 4 population, the entry here included 51% who had stage M1B, C, and D melanoma. And that is worth pointing out because this is an injectable therapy. So, trials like this in the past have tended to be biased towards earlier stage, unresectable or metastatic melanoma, meaning stage 3B, 3C, 3D and then stage 4m1a. Again, to emphasize the point here, these were pretreated patients who had a strict definition of anti PD-1 resistance, and over half of them, in fact, had high-risk visceral metastatic disease. In that context, it's very interesting to observe that the overall response rate was described in the total population, as 31%, and that included 12% who achieved complete response. And so, again, to make sure it's clear, we're talking about a treatment where the oncolytic virus is injected into one or multiple sites of recurrent disease, and then the patients administer nivolumab as per standard. And so, I think these data are quite intriguing. Again, such a high- risk population and their maturity now, with a follow-up of over a year, I think, makes this look to be a very interesting treatment option. Dr. Diwakar Davar: I guess on that topic of mature follow-up, it probably would be important for us to inform our audience that the top line data for the primary analysis was actually just released, I think, earlier today, and wherein the central confirmed objective response rate was 34% by modified RECIST and 33% by RECIST, clearly indicating that these responses, as you noted, very treatment refractory patient population, these responses were clearly very durable. So, you mentioned that there were responses seen in uninjected visceral lesions, responses seen in both PD-1 and PD-1 CTLA-4 refractory patients. Can you talk a little bit about the response rate in these high-risk subgroups, the uninjected visceral lesions, the patients who had both combination checkpoint and epidural refractory response rate by primary PD-1 resistance. Dr. Jason Luke: Sure. You know, I think, again, to emphasize this point in the study, we saw that there were responses in the non-injected lesions, and I think it's really important to emphasize that. Some have referred to this as a putative abscopal like effect, similar to what is described in radiation. But it implies that local treatment with the oncolytic virus is triggering a systemic immune response. In the higher risk patient population, we'll note that whereas the overall response rate in PD-1 refractory patients was 34%, in the combination of PD-1 and CTLA-4 refractory patients, the response rate was 26%. So, [this is] still very good. And when we looked at that split by stage, as I alluded to before, in the population of patients that had, what you might call earlier unresectable diseases, so 3B through 4A, the response rate was 38%, and in the stage 4 M1b through M1d, it was 25%. So slightly lower, but still very good. And that would be as expected, because, of course, the patients with visceral metastatic disease have more advanced disease, but those response rates look quite good. Again, looking at the combination refractory population as well as the more high-risk disease. Dr. Diwakar Davar: So, clearly, these are very promising data and exciting times for multiple investigators in the field and the company, Replimune, as well. So, what are the next steps? I believe that a registration trial is planned, essentially, looking at this with the goal of trying to get this combination registered. Can you tell us a little bit about IGNYTE-3, the trial design, the control arm, and what you foresee this trial doing over the next couple of years? Dr. Jason Luke: So, as this agent has been maturing, it's worth pointing out that the company that makes this molecule, called RP1, but I guess now we'll have to get used to this name vusolimogene oderparepvec as the actual scientific term, they have been having ongoing discussions with the FDA, and there is the potential that this agent could come forward on an accelerated path prior to the results being released from a phase 3 trial. That being said, the phase 3 confirmatory study, which is called the IGNYTE-3 study, is in the process of being launched now. And that's a study investigating this molecule in combination with nivolumab, as was alluded to earlier, and a randomized phase 3 design, where that combination is compared with a physician's choice, essentially a chemotherapy-based option. In that study, it will be 400 patients with stage 3B through stage 4; patients will have progressed on anti PD-1, either as a combination or in sequence, and then come on the study to be randomized to either vusolimogene oderparepvec plus nivolumab versus that physician's choice. And the physician's choice includes chemotherapy agents, but also nivolumab plus relatlimab as another option, or an anti PD-1 monotherapy, if that's deemed to be a reasonable option by the treating investigator. And the primary endpoint of that study is overall survival. And unfortunately, in this highly refractory patient population, that's something that may not take long to identify with key secondary endpoints of progression free survival, as well as overall response rate. I'm quite enthusiastic about this study, given these data, which have now been centrally confirmed as you alluded to before. I think this is a very exciting area of investigation and really crossing my fingers that this may be perhaps the first locally administered therapy which does appear to have a systemic impact that can hold up in phase 3. Dr. Diwakar Davar: Very, very, very exciting results. And I guess it's worthwhile pointing out that this company also has got, I think, multiple studies planned with both RP1 and cutaneous squamous cell carcinoma in a solid organ transplant patient population where single agent activity has already been reported by Dr. Migden at prior meetings, as well as a novel trial of potentially RP2 metastatic uveal melanoma. So we'll now pivot to Abstract 6014. So, 6014 is a drug by a company known as Merus. Essentially, it's a very novel agent. Merus essentially is a company that is specialized in making bicyclics and tricyclics. And these are not bicycles or tricycles, but rather drugs that essentially are bispecific antibodies. And Merus essentially has come up with petosemtamab. I think we're going to have to figure out better names for all of these drugs at some point. But petosemtamab, or MCLA-158, essentially is a bicyclic, targeting both EGFR as well as LGR-5. So EGR-5, of course, is a known oncogenic driver in multiple tumor types, squamous, including non small cell lung cancer, cutaneous squamous cell carcinoma, but also head and neck squamous cell carcinoma. And LGR-5 essentially is leucine-rich repeat-containing G-protein coupled receptor 5, but it's a receptor in cancer stem cells and certainly highly expressed in head neck squam. And MCLA-158, or petosemtamab is a IgG one bispecific with ADCC-activity because of IgG1 backbone co-targeting EGFR and LGR5. Merus had earlier results that evaluated petosemtamab monotherapy. They defined the RP2D and second- and third-line head and neck blastoma patients with a respectable response rate of 37% investigator-assessed ORR with six months median DoR, and this was published by Ezra Cohen about a year or so ago. In this abstract, Dr. Fayette and colleagues report on the results of the MCLA-158-CL01 trial, which is a trial of pembrolizumab plus petosemtamab in one front line head and neck squamous cell population. So maybe let's start with the description of the cohort. And it is a small trial, but we'll be able, I think, to dig into a little bit about why this might be exciting. Dr. Jason Luke: Yes. So, as alluded to, it's not the biggest trial as yet, but there were 26 patients with anti PD-1 treatment naive head and neck squamous cell carcinoma. And all the patients in the study did receive, as you alluded to, pembrolizumab plus petosemtamab. Based on the label for pembrolizumab, all the patients in this study were PDL-1 positive. So that's one point that it's worth pointing out to make sure that that's understood. This is the population of patients who would be expected to benefit from pembrolizumab in the first place. Now, in the abstract, they reported out only 10 response evaluable patients, but they updated that in the actual slides of presentation at the meeting. So among 24 patients that were alluded to, 67% were described as having had a response, although some of those were yet to be confirmed responses. And when it was evaluated by PDL-1 status, there didn't seem to be a clear enrichment of response in the PD-1 positive more than 20% group, as compared to the 1-19% group. That isn't especially surprising because that was a trend that one would see, presumably with pembrolizumab alone. But overall, I think these data are pretty exciting in terms of a preliminary study. Dr. Diwakar Davar: You know, you mentioned that the objective response rate was high, almost 60-something%. The prognosis of these patients is generally poor. The OS is typically thought of as between 6-15 months. And based on KEYNOTE-048, which was led by Dr. Burtness and colleagues, the standard of care in the setting is pembrolizumab +/- platinum based chemotherapy regimens. Allowing for the fact that we only have 10 patients here, how do you think these results stack up against KEYNOTE-048? And you made a very important point earlier, which was, by definition, pembro is on label only for the CPS. So PDL-1 score, at least in head and neck squamous cell carcinoma CPS and not TPS. But in the CPS 1% or greater patient population, where pembro is on label, how do these results stack up against the KEYNOTE-048 results. Dr. Jason Luke: Right. KEYNOTE-048 is considered the seminal study that dictates frontline treatment in head and neck cancer. And before we dive into this too far, we do want to acknowledge that here we're comparing 26 patients versus a phase 3 trial. So, we're not trying to get too far ahead of ourselves, but this is just a preliminary comparison. But in KEYNOTE-048, as you alluded to, two regimens were superior to chemotherapy. One was the pembrolizumab monotherapy, as well as pembrolizumab plus chemotherapy. So again, the study overall survival, of course, was much higher, the PDL-1 positive subgroup, which is what dictated the unlabeled use of this. But response to pembro monotherapy in that population of patients is still modest. We're talking about upwards of 20-30%. So, if you compare that to, again, preliminary evidence here from this trial of only 24 patients, that response rate of 60% seems extremely high. And so even if that were to come down somewhat in a larger data series of patients, that still looks to be quite promising as a treatment regimen, that might eventually even be chemotherapy sparing for this population of patients. I think this raises a lot of eyebrows that perhaps this dual targeting approach, EGFR and LDR-5, may bring something really important to the field that evolves it. Dr. Diwakar Davar: So, what are the next steps for petosemtamab? You mentioned that the activity was interesting. Are we going to see a larger trial? Any thoughts on where things are going to go? Dr. Jason Luke: Well, based on the phase 2 data of petosemtamab alone, even without pembrolizumab, the molecule had already been given fast track designation by FDA, which means allowing for greater communication between the drug sponsor in the FDA and designing a seminal study design. One would assume that this trial will be rapidly expanded quite greatly, perhaps to 100 or 200 patients, to try to flush out what the real response rate is in a more meaningful number of patients. But I think these data will probably also trigger the design and probably near-term evaluation or expedited acceleration of a phase III clinical trial design that would potentially validate this against the current standard of care. So, I'm pretty excited. I think we'll see a lot more about this agent in the relatively near future. Dr. Diwakar Davar: So, finally, we'll pivot to the last abstract that we're going to talk about, which is Abstract 2504. It's a relatively interesting target, CCR8 monoclonal antibody. But this is the efficacy and safety of LM-108, and LM-108 is an anti CCR8 monoclonal antibody that is being developed by LaNova Medicine. And the results that are described, actually a pool set of results of combinations of LM-108 with anti PD-1, two separate anti PD-1, in patients with gastric cancer, mostly done ex-U.S., which is interesting because of this patient population, and it's a pool result of several, 3 phase 1 and 2 studies. LM-108 is an Fc-optimized anti CCR8 monoclonal antibody that selectively depletes tumor infiltrating Tregs. The abstract reported a pooled analysis of three phase 1, 2 trials with 3 different NCT numbers that all evaluated the efficacy of LM-108 and anti PD-1 in patients with gastric cancer. So, let's start with the description of the cohort. Maybe, Jason, you can tell us a little bit about before you start, as you describe the cohort, sort of what we know, editorially speaking, about the difficulty with which Tregs depletion has been tried and obviously failed up until now in the tumor microenvironment. Dr. Jason Luke: Right. I think that's a really interesting comment. And so, for decades, in fact, targeting regulatory T-cell to alleviate immune exclusion in the tumor microenvironment has been of interest in immuno-oncology. And in preclinical mouse models, it seems quite clear that such an approach can deliver therapeutic efficacy. However, by contrast, in human clinical trials, various different Treg depleting strategies have been attempted, and there's really little to no evidence that depleting Tregs from human tumors actually can deliver therapeutic responses. And by that we're referring to CD-25 antibodies. The drug ipilimumab, the CTLA-4 antibody, was punitively described as a Tregs depleter preclinically, but that doesn't seem to be the case in patients. And so, in that background, this is quite an eye raiser that an anti CCR8 antibody could be driving this effect. Now, before we talk about the results of this trial, I will point out, however, that given the Fc-optimization, it's entirely possible that the Tregs are being depleted by this mechanism, but that more could also be going on. Because Fc gamma RII binding by this antibody that could be nonspecific also has the potential to trigger immune responses in the tumor microenvironment, probably mediated by myeloid cells. So I think more to come on this. If this turns out to be the first meaningful Tregs depletor that leads to therapeutic efficacy, that would be very interesting. But it's also possible this drug could have multiple mechanisms. So, having said all of that, in the clinical trial, which was a pooled analysis, like you mentioned, of LM-108 in combination with anti PD-1 of a couple different flavors, there were 48 patients treated either with LM-108, with pembrolizumab, or with toripalimab, which is another anti PD-1 antibody. On the drug combination was, generally speaking, pretty well tolerated, noting grade 3 treatment related adverse events in the range of 38%, which is somewhat expected given combination immunotherapy. We talked about nivolumab and ipilimumab before, which, of course, gives even higher rates of immune-related adverse events, with the most common toxicities being anemia, lipase elevations, rash, ALC decrease; albeit, quite manageable. Dr. Diwakar Davar: So, what about the objective response rate? Can you contextualize the efficacy? And as you do that, maybe we'll think about what you'd expect in the context of, say, gastric cancer, especially in patients who've never really had a prior checkpoint inhibitor before. What do you think about the ORR? What do you think about the relative efficacy of this combination? Dr. Jason Luke: Well, so, in the study, they described overall response rate in the 36 patients as 36% and described immediate progression for survival of about 6.5 months. And so that was among patients who were treatment naive. And in second-line patients, they actually described an even higher response rate, although it was only 11 patients, but they're at 64%. And so, I think those data look to be somewhat interesting. When I was actually scrutinizing the actual data presented, it was of some interest to note that the quality of responses seemed to be about as good on the lower dose of LM-108, so 3 milligrams per kilogram as compared to 10 milligrams per kilogram. I think there's definitely more to learn here to try to optimize the dose and to fully understand what the overall efficacy of this treatment combination would be. I would emphasize that in this disease, I think novel treatment strategies are certainly warranted. While anti PD-1 with chemotherapy has moved the needle in terms of standard of care treatment, it's really only a minor subset of patients who derive durable long-term benefit like we normally associate with immune checkpoint blockade. I think these are preliminary data. They're very intriguing. You alluded to earlier that this population of patients was an Asian data set, and it is well known that the efficacy of chemotherapy and immunotherapy does appear to be somewhat enhanced in Asian populations, and that goes to distributions of metastasis and tumor microenvironment effects, etc. Very difficult to try to tease any of that out in this abstract, other than to look at these data and suggest that this is pretty interesting, both from a novel therapeutic approach, we talked about the Tregs consideration, but also straight up on the efficacy because I think if these data could hold up in a larger number of patients, and particularly in a western population of patients, I think it would be very intriguing. Dr. Diwakar Davar: Certainly, ASCO 2024 had a lot of interesting data, including data from targeted agents, the LAURA trial, ADCs. But just focusing on the immune therapy subset, we certainly saw a lot of great advances in patients who were treated with neoadjuvant as well as relapse refractory disease in the context of RP1 and then a couple of newer agents such as this petosemtamab as well as LM-108. And of course, we cannot forget to highlight the extended DMFS data from the pembro vaccine study from KEYNOTE-942. Jason, as always, thank you for taking a little bit of time out of your extremely busy schedule to come and give us insights as to how these agents are impacting the landscape. We really value your input and so thank you very much. Dr. Jason Luke: Thank you for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for your time today. You will find the links to all the abstracts that we discussed in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. So, thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use 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. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Diwakar Davar: Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

university ai spring 3d asian pittsburgh os cd studies fda congratulations pfizer keynote patel werewolf relation franklin delano roosevelt pd bayer immune pcr abstract oncology merck 2b endeavor cps 3b janssen new england journal novartis dor melanoma alc royalties lag accommodations hsv cancer care immunotherapy gsk tps asco 4a lm genentech 3c ldr orr abbvie bristol myers squibb stipe takeda nct igg regeneron adcc egfr gilead sciences adverse events md anderson rfs nektar pdl onc adcs efs prognostic cancer immunotherapy braf esmo neoadjuvant plenary session eisai immuno oncology asco annual meeting treg pyxis nccn nadina rubius servier michael wong ctla rp1 incyte emd serono ezra cohen lgr alnylam genmab tregs mcla moderna therapeutics gm csf swog ignyte ctla4 rp2 tesaro jason luke recist transcript dr igg1 array biopharma synlogic

118. (Lyme & Mold Part 3) Thymosin Alpha 1 Peptide, Immune System Modulation, Th1 & Th2 Responses, How Borrelia Evades the Immune System (+ Ways to Overcome This), & More

The Synthesis of Wellness

Play Episode Listen Later May 10, 2024 24:59

In today's episode, we explore the role of Thymosin Alpha 1 Peptide in modulating the immune system, specifically its effects on Th1 and Th2 responses. The episode further delves into the mechanisms by which Borrelia burgdorferi evades immune detection and offers strategies to enhance immune effectiveness against this stealthy pathogen. Additionally, we discuss the broader implications of immune modulation in chronic Lyme disease and mold exposures. Topics: Introduction Recap of the series on Lyme and mold Highlighting the key steps in the biotoxin illness resolution process Importance of working with a medical professional Key Steps in Biotoxin Illness Resolution Lowering inflammation Lipid replacement therapy (phospholipids) Use of antimicrobial and antiparasitic herbs for Lyme and coinfections Employing binders to eliminate toxins and reduce inflammation Checking for MARCoNS and utilizing treatments like silver spray or biofilm busters (e.g., xylitol) Detoxification post-MARCoNS clearance using agents like chlorella and glutathione Assessing and normalizing various health markers (e.g., ADH, osmolality, MMP9, C4a, C3a, TGF-beta, sex hormones) Additional Resources and Episodes Early stages of Lyme infection and Herxheimer reaction: Episode 116 Chronic inflammation and biotoxin management: Episode 117 Role of binders in interrupting enterohepatic circulation and toxin elimination Discussion on Biofilm Importance of addressing biofilm in antimicrobial therapies Potential supplements and strategies (e.g., garlic, oil of oregano, stevia) Overview of Lyme Disease Impact & Immune Function Chronic inflammation due to miscommunication between the innate and adaptive immune systems + dysregulated adaptive responses How borrelia evades the immune responses Immunomodulation in Lyme Disease Background on immune modulation Role of T cells in adaptive immune response Th1 and Th2 cell imbalance in chronic Lyme Strategies to support Th1 cells and decrease Th2 response Focus on Thymosin Alpha 1 Benefits of Thymosin Alpha 1 in modulating immune function Promoting Th1 response and managing Th2 dominance Effects on regulatory T cells (Tregs) and immune tolerance Conclusion Reminder to work with a Lyme literate or biotoxin illness literate medical professional Thanks for tuning in! 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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Akiko Iwasaki: The Immunology of Covid and the Future

Ground Truths

Play Episode Listen Later May 4, 2024 41:48

If there's one person you'd want to talk to about immunology, the immune system and Covid, holes in our knowledge base about the complex immune system, and where the field is headed, it would be Professor Iwasaki. And add to that the topic of Women in Science. Here's our wide-ranging conversation.A snippet of the video, Full length Ground Truths videos are posted here and you can subscribe. Ground Truths is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Transcript with many external link and links to the audio, recorded 30 April 2024 Eric Topol (00:06):Hello, it's Eric Topol and I'm really thrilled to have my friend Akiko Iwasaki from Yale, and before I start talking with Akiko, I just want to mention there aren't too many silver linings of the pandemic, but one for me was getting to know Professor Iwasaki. She is my go-to immunologist. I've learned so much from her over the last four years and she's amazing. She just, as you may know, she was just recently named one of the most influential people in the world by TIME100. [and also recognized this week in TIME 100 Health]. And besides that, she's been elected to the National Academy of Medicine, National Academy of Sciences. She's the president of the American Association of Immunologists and she's a Howard Hughes principal investigator. So Akiko, it's wonderful to have you to join into an extended discussion of things that we have of mutual interest.Akiko Iwasaki (01:04):Thank you so much, Eric, for having me. I equally appreciate all of what you do, and I follow your blog and tweets and everything. So thank you Eric.Eric Topol (01:14):Well, you are a phenom. I mean just, that's all I can say because I think it was so appropriate that TIME recognize your contributions, not just over the pandemic, but of course throughout your career, a brilliant career in immunology. I thought we'd start out with our topic of great interest on Long Covid. You've done seminal work here and this is an evolving topic obviously. I wonder what your latest thoughts are on the pathogenesis and where things are headed.Long CovidAkiko Iwasaki (01:55):Yeah, so as I have been saying throughout the pandemic, I think that Long Covid is not one disease. It's a collection of multiple diseases and that are sort of ending up in similar sets of symptoms. Obviously, there are over 200 symptoms and not everyone has the same set of symptoms, but what we are going for is trying to understand the disease drivers, so persistent viral infection is one of them. There are overwhelming evidence for that theory now, all the way from autopsy and biopsy studies to looking at peripheral blood RNA signatures as well as circulating spike protein and nucleocapsid proteins that are detected in people with Long Covid. Now whether that persistent virus or remnants of virus is driving the disease itself is unclear still. And that's why trials like the one that we are engaging with Harlan Krumholz on Paxlovid should tell us what percentage of the people are suffering from that type of driver and whether antivirals like Paxlovid might be able to mitigate those. If I may, I'd like to talk about three other hypotheses.Eric Topol (03:15):Yeah, I'd love for you to do that.Akiko Iwasaki (03:18):Okay, great. So the second hypothesis that we've been working on is autoimmune disease. And so, this is clearly happening in a subset of people, again, it's a heterogeneous disease, but we can actually not only look at reactogenicity of antibodies from people with Long Covid where we can transfer IgG from patients with Long Covid into an animal, a healthy animal, and really measure outcomes of a pathogenesis. So that's a functional evidence that antibodies in some people with Long Covid is really actually causing some of the damages that are occurring in vivo. And the third hypothesis is the reactivation of herpes viruses. So many of us adults have multiple latent herpes virus family members that are just dormant and are not really causing any pathologies. But in people with Long Covid, we're seeing elevated reactivation of viruses like Epstein-Barr virus (EBV) or Varicella-zoster virus (VZV) and that may again be just a signature of Long Covid, but it may also be driving some of the symptoms that people are suffering from.(04:32):So that's again, we see the signature over and over, not just our group, but multiple other groups, Michael Peluso's group, Jim Heath, and many others. So that's also an emerging evidence from multiple groups showing that. And finally, we think that inflammation that occurs during the acute phase can sort of chronically change some tissue tone. For instance, in the brain with Michelle Monje's team, we developed a sort of localized mild Covid model of infection and showed that changes in microglia can be seen seven weeks post infection even though the virus is completely gone. So that means that inflammation that's established as a result of this initial infection can have prolonged sequence and sequela within the person and that may also be driving disease. And Eric, the reason we need to understand these diseases separately is because not only for diagnostic purposes, but for therapeutic purposes because to target a persistent virus is very different approach from targeting autoantibodies, for example.Eric Topol (05:49):Well, that's great. There's a lot to unpack there as you laid out four distinct paths that could result in the clinical syndrome and sequelae. I think you know I had the chance to have a really fun conversation with Michelle about their joint work that you've done, and she reminded me how she made a cold call to you to start as a collaboration, which I thought was fantastic. Look what that yielded. But yeah, this is fascinating because as I think you're getting at is that it may not be the same pathogenesis in any given individual so that all these, and even others might be operative. I guess maybe I first delve into the antibody story as you're well aware, we see after people get Covid a higher rate of autoimmune diseases crop up, which is really interesting because it seems to rev up self-directed immune response. And this I think many people haven't really noted yet, although obviously you're well aware of this, it's across all the different autoimmune diseases, connective tissue disease, not just one in particular. And it's, as you say, the idea that you could take the blood from a person suffering from Long Covid and give it to an experimental animal model and be able to recapitulate some of the abnormalities, it's really pretty striking. So the question I guess is if you were to do plasmapheresis and try to basically expunge these autoantibodies, wouldn't you expect people to have some symptomatic benefit pretty rapidly or is it just that the process is already far from the initiating step?Akiko Iwasaki (07:54):That's a great question. Plasmapheresis may be able to transiently improve the person if they're suffering from these autoantibody mediated diseases. People have reported, for example, IVIG treatment has dramatically improved their symptoms, but not in everybody. So it's really critical to understand who's suffering from this particular driver and appropriately treat those people. And there are many other very effective therapies in autoimmune disease field that can be repurposed for treating these patients as well.Eric Topol (08:34):The only clinical trial that has clicked so far, interestingly, came out of Hong Kong with different types of ways to manipulate the gut microbiome, which again, you know better than me is a major modulator of our immune system response. What are your thoughts about taking advantage of that way to somehow modulate this untoward immune response in people with this condition?Akiko Iwasaki (09:07):Yeah, so that is an exciting sort of development, and I don't mean to discount the importance of microbiome at all. It's just the drivers that are mentioning are something that can be directly linked to disease, but certainly dysbiosis and translocation of metabolites and microbiome itself could trigger Long Covid as well. So it's something that we're definitely keeping our eyes on. And as you say, Eric, the immune system is in intimate contact with the gut microbiome and also the gut is intimate contact with the brain. So there's a lot of connections that we really need to be paying attention to. So yeah, absolutely. This is a very exciting development.Eric Topol (09:57):And it is intriguing of course, the reactivation of viruses. I mean, we've learned in recent years how important EBV is in multiple sclerosis (MS). The question I have for you on that pathway, is this just an epiphenomena or do you actually think that could be a driving force in some people?Akiko Iwasaki (10:19):Yeah, so that's really hard to untangle in people. I mean, David Putrino and my team we're planning a clinical trial using Truvada. Truvada obviously is an HIV drug, but it has reported antiviral activity to Epstein-Barr virus (EBV) and others. So potentially we can try to interrogate that in people, but we're also developing mouse models that can sort of recapitulate EBV like viral reactivation and to see whether there's any sort of causal link between the reactivation and disease process.Eric Topol (10:57):Right now, recently there's been a bunch of anecdotes of people who get the glucagon-like peptide one (GLP-1) drugs which have a potent anti-inflammatory, both systemic and in the brain. I'd love to test these drugs, but of course these companies that make them or have other interests outside of Long Covid, do you think there's potential for a drug like that?Akiko Iwasaki (11:23):Yeah, so those drugs seem to have a lot of miraculous effects on every disease. So obviously it has to be used carefully because many people with Long Covid have issues with liver functions and other existing conditions that may or may not be conducive to taking those types of GLP-1 agonists. But in subset of people, maybe this can be tried, especially due to the anti-inflammatory properties, it may benefit again, a subset of people. I don't expect a single drug to cure everyone. That would be pretty amazing, but unlikely.Eric Topol (12:09):Absolutely. And it's unfortunate we are not further along in this whole story of clinical trials, testing treatments and applauding your efforts with my friend Harlan there to get into the testing which we had hoped RECOVER was going to do with their more than billion dollars or allocation, which didn't get us too far in that. Now before we leave Long Covid, which we could speak about for hours, I mean it's so darn important because so many people are really out there disabled or suffering on a daily basis or periodically they get better and then get worse again. There's been this whole idea that, oh, it's going away and that reinfections don't pose a threat. Maybe you could straighten that story out because I think there seems to be some miscues about the risk of Long Covid even as we go along with the continued circulating virus.Akiko Iwasaki (13:11):Right, so when you look at the epidemiological evidence of Long Covid, clearly in the beginning when we had no vaccines, no antivirals, no real good measure against Covid, the incident of developing Long Covid per infection was higher than a current date where we do have vaccines and Omicron may have changed its property significantly. So if you compare, let's say the Delta period versus Omicron period, there seems to be a reduced risk per infection of Long Covid. However, Omicron is super infectious. It's infected millions of people, and if you look at the total number of people suffering from Long Covid, we're not seeing a huge decline there at all because of the transmissibility of Omicron. So I think it's too early for us to say, okay, the rates are declining, we don't need to worry about it. Not at all, I think we still have to be vigilant.(14:14):We need to be up to date on vaccines and boosters because those seem to reduce the risk for Long Covid and whether Paxlovid can reduce the rate of Long Covid at the acute phase for the high risk individual, it seems to be yes, but for people who are not at high risk may or may not be very effective. So again, we just need to be very cautious. It's difficult obviously, to be completely avoiding virus at this time point, but I think masking and anything you can do, vaccination boosters is going to be helpful. And a reinfection does carry risk for developing Long Covid. So that prior infection is not going to prevent Long Covid altogether, even though the risk may be slightly reduced in the first infection. So when you think about these risks, again we need to be cognizant that reinfection and some people have multiple infections and then eventually get Long Covid, so we're just not safe from Long Covid yet.Nasal Vaccines and Mucosal ImmunityEric Topol (15:24):Right. No, I think that's the problem is that people have not acknowledged that there's an ongoing risk and that we should continue to keep our guard up. I want to applaud you and your colleagues. You recently put out [Yale School of Public Health] this multi-panel about Covid, which we'll post with this podcast that gave a lot of the facts straight and simple diagrams, and I think this is what you need is this is kind of like all your threads on Twitter. . They're always such great educational ways to get across important information. So now let's go onto a second topic of great mutual interest where you've also been a leader and that's in the mucosal nasal vaccine story. I had the privilege of writing with you a nice article in Science Immunology back in 2022 about Operation Nasal Vaccine, and unfortunately we don't have a nasal vaccine. We need a nasal vaccine against Covid. Where do we stand with this now?Akiko Iwasaki (16:31):Yeah, so you're right. I mean nasal vaccines, I don't really know what the barrier is because I think the preclinical models all support the effectiveness against transmission and infection and obviously disease. And there is a White House initiative to support rapid development of next generation vaccine, which includes mucosal vaccine, so perhaps that's sort of pushing some of these vaccine candidates forward. You're probably more familiar than me about those kinds of events that are happening. But yeah, it's unfortunate that we don't have an approved mucosal booster vaccine yet, and our research has shown that as simple as a spray of recombinant spike protein without any adjuvants are able to restimulate immune response and then establish mucosal immunity in the nasal cavity, which goes a long way in preventing infection as well as transmission. So yeah, I mean I'm equally frustrated that things like that don't exist yet.The Neomycin and Neosporin SurpriseEric Topol (17:52):Well, I mean the work that you and many other groups around the world have published on this is so compelling and this is the main thing that we don't have now, which is a way to prevent infection. And I think most of us would be very happy to have a spray that every three or four months and gave us much higher levels of protection than we're ever going to get from shots. And your whole concept of prime and spike, I mean this is something that we could have had years ago if there was a priority, and unfortunately there never has been. Now, the other day you came with a surprise in a paper on Neomycin as an alternate or Neosporin ointment. Can you tell us about that? Because that one wasn't expected. This was to use an antibiotic in a way to reduce Covid and other respiratory virus.Akiko Iwasaki (18:50):Right. So yeah, that's a little known fact. I mean, of course widespread use of antibiotics has caused some significant issues with resistance and so on. However, when you look at the literature of different types of antibiotics, we have reported in 2018 that certain types of antibiotics known as aminoglycoside, which includes Neosporin or neomycin, has this sort of unintended antiviral property by triggering Toll-like receptor 3 in specialized cell types known as conventional dendritic cell type 1. And we published that for a genital herpes model that we were working on at the time. But because it's acting on the host, the Toll-like receptor 3 on the host cell to induce interferon and interferon stimulated genes to prevent the replication of the virus, we knew that it could be pan-viral. It doesn't really matter what the virus is. So we basically leverage that discovery that was made by a postdoc Smita Gopinath when she was in the lab to see if we can use that in the nasal cavity.(20:07):And that's what Tianyang Mao, a former graduate student did, in fact. And yeah, little spray of neomycin in the nose of the mice reduce this infection as well as disease and can even be used to treat shortly after the infection disease progress and using hamster models we also showed that hamsters that are pretreated with neomycin when they were caged with infected hamsters, the transmission rate was much reduced. And we also did with Dr. Charles Dela Cruz, a small clinical trial, randomized though into placebo and Neosporin arms of healthy volunteers. We asked them to put in a pea size amount of Neosporin on a cotton swab into the nose, and they were doing that twice a day for seven days. We measured the RNA from the nose of these people and indeed see that more than half the participants in the Neosporin group had elevated interferon stimulated genes, whereas the control group, which were given Vaseline had no response. So this sort of shows the promise of using something as generic and cheap as Neosporin to trigger antiviral state in the nose. Now it does require a much larger trial making sure that the safety profiles there and effectiveness against viral infection, but it's just a beginning of a story that could develop into something useful.New Frontiers in Immunology and Tx CellsEric Topol (21:51):Yeah, I thought it was fascinating, and it does bring up, which I think has also been underdeveloped, is our approaches for interferon a frontline defense where augmenting that, just getting that exploiting the nasal mucosa, the entry site, whether it be through that means or of course through even more potent a nasal vaccine, it's like a missing, it's a hole in our whole defense of against this virus that's led to millions of people not just dying, but of course also sick and also with Long Covid around the world. So I hope that we'll see some progress, but I thought that was a really fascinating hint of something to come that could be very helpful in the meantime while we're waiting for specific nasal vaccines. Now added to all these things recently, like last week you published a paper in Cell with your husband who's in the same department, I think at Yale. Is that right? Can you tell us about that and this paper about the whole new perspectives in immunology?Akiko Iwasaki (23:05):Yeah, so my husband Ruslan Medzhitov is a very famous immunologist who's in the same department, and we've written four or five review and opinion pieces together over the years. This new one is in Cell and it's really exploring new perspectives in immunology. We were asked by the editors to celebrate the 50th anniversary of the Cell journal with a perspective on the immune system. And the immune response is just a beautiful system that is triggered in response to specific pathogens and can really provide long-term or even sometimes lifelong immunity and resistance against pathogens and it really saves our lives. Much has been learned throughout the last 20, 30 years about the innate and adaptive immune system and how they're linked. In this new perspective, we are trying to raise some issues that the current paradigm cannot explain properly, some of the mysteries that are still remaining in the immune system.(24:22):And we try to come up with new concepts about even the role of the immune system in general. For instance, is the immune system only good for fighting pathogens or can it be repurposed for conducting normal physiology in the host? And we came up with a new subset of T-cells known as, or we call it Tx cells, which basically is an interoceptive type of T-cells that monitor homeostasis in different tissues and are helping with the normal process of biology as opposed to fighting viruses or bacteria or fungi. But these cells, when they are not appropriately regulated, they are also the source of autoimmune diseases because they are by design reactive against auto antigens. And so, this is a whole new framework to think about, a different arm of the immune function, which is really looking inside of our body and not really fighting against pathogens, but we believe these cells exist, and we know that the counterpart of Tx cells, which is the T regulatory cells, are indeed well known for its physiological functions. So we're hoping that this new perspective will trigger a new set of approaches in the field to try to understand this interceptive property of T-cells.Eric Topol (25:59):Yeah, well, I thought it was fascinating, of course, and I wanted to get into that more because I think what we're learning is this immune system not only obviously is for cancer whole. We're only starting to get warmed up with immunotherapy where checkpoint inhibitors were just the beginning and now obviously with vaccines and all these different ways that we can take the CAR-T cells, engineered T-cells, take the immune system to fight cancer and potentially to even use it as a way to prevent cancer. If you have these, whether it's Tx or Tregs or whatever T-cells can do this. But even bigger than that is the idea that it's tied in with the aging process. So as you know, again, much more than I do, our senescent immune cells are not good for us. And the whole idea is that we could build immune resilience if we could somehow figure out these mysteries that you're getting at, whereby we get vulnerable just as we were with Covid. And as we get older, we get vulnerable to not just infections, but everything going wrong, whether it's the walls of our arteries or whether it's the cancer or the immunity that's going on in our brain for Alzheimer's and neurodegenerative diseases. How can we fix the immune system so that we age more healthilyThe Immune System and Healthy Aging Akiko Iwasaki (27:37):Oh yeah. A lot of billionaires are also interested in that question and are pouring money into this question. It's interesting, but when you think about the sort of evolutionary perspective, we humans are only living so long. In the very recent decades, our life expectancy used to be much shorter and all we had to survive was to reproduce and generate the next progeny. But nowadays, because of this amazing wealth and health interventions and food and everything else, we're just living so much longer than even our grandparents. The immune system didn't evolve to deal with such one to begin with. So we were doing fine living up to 30 years of age or whatever. But now that we're living up to a hundred years, the immune system isn't really designed to keep up with this kind of stressors. But I think you're getting at a very important kind of more engineering questions of how do we manipulate the immune system or rejuvenate it so that we can remain healthy into the later decades? And it is well known that the immune system itself ages and that our ability to produce new lymphocytes, for example, decline over time and thymus that is important for T-cell development shrinks over time. And so anatomically it's impossible to help stop that process. However, is there a way of, for example, transferring some factors or engineering the immune cells to remain healthy and even like hematopoiesis itself can be manipulated to perhaps rejuvenate the whole immune system in their recent papers showing that. So this is a new frontier.Eric Topol (29:50):Do you think that some point in the future, we'll ex vivo inject Yamanaka factors into these cell lines and instead of this idea that you know get young plasma to old folks, and I mean since we don't know what's in there and it doesn't specifically have an effect on immune cells, who knows how it's working, but do you foresee that that might be a potential avenue going forward or even an in vivo delivery of this?Akiko Iwasaki (30:22):Yeah, it's not impossible, right? There are really rapidly evolving technologies and gene therapies that are becoming online. So it's not impossible to think about engineering in situ as you're suggesting, but we also have to be certain that we are living longer, but also healthy. So we do have to not only just deal with the aging immune system, but preventing neurodegenerative diseases and so on. And the immune system may have a role to play there as well. So there's a lot of, I mean, I can't think of a non-genetically mediated disease that doesn't involve the immune system.Eric Topol (31:03):Sure. No, I mean, it's just, when I think about this, people keep talking about the digital era of digital biology, but I actually think of it more as digital immunobiology, which is driving this because it's center stage and in more and more over time. And the idea that I'm concerned about is that we could rejuvenate the relevant immune cells or the whole immune response, but then it's such a delicate balance that we could actually wind up with untoward, whether it's autoimmune or overly stimulated immune system. It's not such a simple matter, as I'm sure you would agree. Now, this gets me to a broader thing which you've done, which is a profound contribution in life science and medicine, which is being an advocate for women in science. And I wonder if you could speak to that because you have been such a phenomenal force propelling the importance of women in science and not just doing that passively, but also standing up for women, which is being an activist is how you get things to change. So can you tell us about your thoughts there?An Activist for Women in ScienceAkiko Iwasaki (32:22):Yeah, so I grew up in Japan, and part of the reason I left Japan at the age of 16 was that I felt very stifled because of the societal norm and expectation of what a woman should be. And I felt like I didn't have the opportunity to develop my skills as a scientist remaining in Japan. And maybe things have changed over the years, but at the time when I was growing up, that's how I felt. And so, I was very cognizant of biases in society. And so, in the US and in Canada where I also trained, there's a lot less barrier to success, and we are able to do pretty much anything we want, which is wonderful, and that's why I think I'm here. But at the same time, the inequity still exists, even in pay gaps and things like that that are easy to fix but are still kind of insidious and it's there.(33:32):And Yale School of Medicine has done a great job partly because of the efforts of women who spoke up and who actually started to collect evidence for pay gap. And now there's very little pay gap because there's active sort of involvement of the dean and everyone else to ensure equity in the medical school. But it's just a small segment of the society. We really need to expand this to other schools and making sure that women are getting paid equally as men in the same ranks. And also, I see still some sexual harassment or more just toxic environment for people in general in academia. Some PIs get away with a lot of behavior that's not conducive to a healthy environment, so I have written about that as well and how we can have antidotes for such toxic environments. And it really does require the whole village to act on it. It's not just one person speaking up. And there should be measures placed to make sure that those people who does have this tendency of abusive behavior that they can get training and just being aware of these situations and corrective behavior. So I think there's still a lot of work left in academia, but things have obviously improved dramatically over the last few decades, and we are in a very, very good place, but we just have to keep working to achieve true equity.Why Don't We Have Immunome Check-Ups?Eric Topol (35:25):Well applauding your efforts for that, and I'm still in touch with that. We got a ways to go, and I hope that we'll see steady and even more accelerated and improvement to get to parity, which is what it should be. And I really think you've been a model for doing this. It isn't like you aren't busy with everything else, so to fit that in is wonderful. In closing up, one of the things that I wonder about is our ability to assess back to the immune system for a moment isn't what it should be. That is we do a CBC and we have how many lymphocytes, how many this, why don't we have an immunome, why doesn't everybody serially have an immune system checkup? Because that would tell us if we're starting to go haywire and then maybe hunt for reactivated viruses or what's going on. Do you foresee that we could ever get to a practical immunome as we go forward? Because it seems like it's a big missing link right now.Akiko Iwasaki (36:33):Yeah, I think that's a great idea. I mean, I'll be the first one to sign up for the immunome.Eric Topol (36:40):But I'm depending on you to make it happen.Akiko Iwasaki (36:44):Well, interestingly, Eric, there are lots of amazing technologies that are developed even during the pandemic, which is monitoring everything from antibody reactivity to reactivated viruses to the cytokines to every cell marker you can imagine. So the technologies out there, it's just I think a matter of having the right set of panels that are relatively affordable because some of these things are thousands of dollars per sample to analyze, and then of course clinical validation, something that's CLIA approved, and then we can start to, I guess the insurance company needs to also cover this, right? So we need to demonstrate the benefit to health in the long run to be able to afford this kind of immunome analysis. But I think that very wealthy people can already get this done.Eric Topol (37:43):Yeah, well, we want to make it so it's a health equity story, not of course, only for the crazy ones that are out there that are taking 112 supplements a day and whatnot. But it's intriguing because I think we might be able to get ahead of things if we had such an easy means. And as you said during the pandemic, for example, my friends here in La Jolla at La Jolla Immunology did all kinds of T-cell studies that were really insightful and of course done with you and others around the country and elsewhere to give us insights that you didn't get just from neutralizing antibodies. But it isn't something that you can get done easily. Now, I think this immunome hopefully will get us to another level in the future. One of the most striking things I've seen in our space clinically before wrapping up is to take the CD19 CAR T therapies to deplete the B cells of people with lupus, systemic sclerosis and other conditions, and completely stop their autoimmune condition. And when the B cells come back, they're not fighting themselves. They're not self-directed anymore. Would you have predicted this? This seems really striking and it may be a clue to the kind of mastering approaches to autoimmune diseases in the future.Akiko Iwasaki (39:19):Yeah, absolutely. So for multiple sclerosis, for example, where B cells weren't thought to be a key player by doing anti-CD20 depletion, there's this remarkable clinical effects. So I think we can only find the answer experimentally in people when they do these clinical trials and show this remarkable effects. That's when we say, aha, we don't really understand immunology. You know what I mean? That's when we have to be humble about what we think we understand. We really don't know until we try it. So that's a really good lesson learned. And these may be also applicable to people with autoimmune phenotype in Long Covid, right? We may be able to benefit from similar kinds of depletion therapy. So I think we have a lot to learn still.Eric Topol (40:14):Yeah, that's why, again, going back to the paper you just had in Cell about the mysteries and about some new ideas and challenging the dogma is so important. I still consider the immune system most complex one in the body by far, and I'm depending on you Akiko to unravel it, not to put any weight on your shoulders. Anyway, this has been so much fun. You are such a gem and always learning from you, and I can't thank you enough for all the work. And the fact is that you've got decades ahead of you to keep building on this. You've already done enough for many people, many scientists in your career, and I know you'll keep going. So we're all going to be following you with great interest in learning from you on a frequent basis. And I hope we'll build on some of the things we've talked about like a Long Covid treatment, treatments that are effective nasal vaccines, maybe even some dab of Neosporin, and keep on the momentum we've had with the understanding of the immune system, and finally, someday achieving the true parity of gender and science. And so, thank you for all that you do.Akiko Iwasaki (41:35):Thank you so much, Eric.************************CreditsHeadshot photo credits by Robert Lisak, Yale School of MedicineMy producer for Ground Truths is Jessica Nguyen, Scripps Research and our technical support for audio/video is by SInjun Balabanoff at Scripps Research.I hope you found the spot informative. Please share itThe Ground Truths newsletters and podcasts are all free, open-access, without ads.Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in.Comments are welcome from all subscribers. Get full access to Ground Truths at erictopol.substack.com/subscribe

Developing Conditionally Active Antibodies: Interview with John K. Celebi, President & CEO, Sensei Bio.

Xtalks Life Science Podcast

Play Episode Listen Later Apr 24, 2024 28:16

In this episode, Ayesha spoke with John K. Celebi, MBA, President & Chief Executive Officer, Sensei Bio, a clinical-stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients.Sensei Biotherapeutics specializes in creating conditionally active antibodies. These are engineered to operate specifically within the tumor microenvironment, enhancing the immune system's ability to combat cancer.John Celebi, MBA, has over 25 years of experience building innovative entrepreneurial biotechnology companies. Mr. Celebi currently serves on the Board of Directors of Egle Therapeutics SAS, a biotechnology company developing first-in-class immunotherapies targeting immune suppressor regulatory T cells (Tregs) for oncology and autoimmune diseases. Mr. Celebi received an MBA from Carnegie Mellon University and a BS in biophysics from the University of California, San Diego.Tune into the episode to learn more about Sensei Bio's mission and therapeutic approach. For more life science and medical device content, visit the Xtalks Vitals homepage. https://xtalks.com/vitals/ Follow Us on Social MediaTwitter: https://twitter.com/XtalksInstagram: https://www.instagram.com/xtalks/Facebook: https://www.facebook.com/Xtalks.Webinars/LinkedIn: https://www.linkedin.com/company/xtalks-webconferencesYouTube: https://www.youtube.com/c/XtalksWebinars/featured

Episode 343: Progressive MS Day with Kevin Reid

RealTalk MS

Play Episode Listen Later Mar 25, 2024 29:41

March 28th is Progressive MS Day, a day that offers an opportunity for people affected by MS, patient advocates, healthcare providers, governments, and industry to share stories online and show their support for people living with progressive forms of MS. My wife, Jeanne, lived with progressive MS for 23 years, so this day holds a special significance for me. Joining me to talk about what Progressive MS Day is all about is my friend, Kevin Reid. Kevin was diagnosed with MS in 2002 and, for the past 10 years, he's been on a mission to crush MS. As MS Awareness Month draws to a close, we're sharing a series of short videos featuring conversations I had with MS experts at the ECTRIMS congress. What makes this video series unique is that iConquer MS invited people living with MS to watch these videos. Then, I interviewed them to get their perspective on the topics the experts were discussing. It's the first time you'll not only hear from the experts, but you'll also get the thoughts and reactions of people who are living with MS. We'll tell you about the neurostimulator that was just designated as a Breakthrough Device for promoting myelin repair. We'll share the details of a newly announced Phase 2 clinical trial for a T-cell therapy for MS. You'll hear about the study that identified a biomarker that reliably predicted the likelihood of future disease activity in people with MS. And we'll tell you where you can catch the video replay of the 2024 ACTRIMS Forum Patient-Centered Webinars. We have a lot to talk about! Are you ready for RealTalk MS??! This Week: March 28th is Progressive MS Day :22 Have you seen the series of short videos featuring my conversations with MS experts at ECTRIMS along with the thoughts and reactions from people living with MS? 1:00 Catch the video replay of the 2024 ACTRIMS Forum Patient-Centered Webinars 1:57 FDA designates neurostimulator as a breakthrough device for promoting myelin repair in people living with relapsing-remitting MS 2:46 Biotech company PolTREG announces Phase 2 clinical trials to test their Tregs treatment for MS 5:28 Study shows neurofilament light chain levels can reliably predict future disease activity 7:10 Kevin Reid discusses the importance of Progressive MS Day and gives us a preview of CRUSH MS 10:35 Share this episode 28:09 Have you downloaded the free RealTalk MS app? 28:29 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/343 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com VIDEO: Dr. Jiwon Oh shares encouraging results from an extension study of Tolebrutinib, an investigational disease-modifying therapy. Then, two people living with MS share their thoughts about clinical trials and a precision medicine approach to treating MS https://youtu.be/eWoZLF4bZmo VIDEO: Dr. Anthony Feinstein discusses the outcome of the CogEx study, Then, two people living with MS share their thoughts about the impact of this study https://www.youtube.com/watch?v=UtGtCnNkYOY VIDEO: Dr. Annette Langer-Gould discusses the impact of other health conditions on people living with MS. Then, two people living with MS share their thoughts and experiences of managing their MS along with additional health conditions https://www.youtube.com/watch?v=J83jlqMbsZo VIDEO: Dr. Daniel Ontaneda discusses how artificial intelligence will impact MS treatment. Then, two people living with MS share their thoughts on the potential impact of AI on MS treatment and the future patient experience https://www.youtube.com/watch?v=_fRLW69Xc1A VIDEO: Dr. Robert Motl discusses the benefits of exercise for people living with MS. Then, two people living with MS share their thoughts on how exercise has impacted their MS journey https://www.youtube.com/watch?v=oZDdp8JumFg VIDEO: ACTRIMS Forum 2024 Webcast Replays https://actrims.memberclicks.net/forum-patient-centered-webinars STUDY: Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients with Relapsing Remitting Multiple Sclerosis: Results from the Phase 3 ASCLEPIOS I and II Trials https://pubmed.ncbi.nlm.nih.gov/35432382 Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 343 Guest: Kevin Reid Privacy Policy

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Deel gezondheidsvoordelen sport komen vanuit ons immuunsysteem

Wetenschap Vandaag | BNR

Play Episode Listen Later Nov 6, 2023 1:49

Een onderzoek uit 1902 liet het al zien: na intense sportactiviteit - denk aan een marathon - is er in het lichaam een piek aan witte bloedcellen (onderdeel van ons immuunsysteem) in het bloed te zien. Nu denken Harvard-onderzoekers eindelijk te weten waarom dit gebeurt en wat voor effect het heeft. Ze deden een onderzoek in muizen, waarin ze lieten zien dat de beschadigingen van spierweefsel als gevolg van intens sporten zorgen voor de activatie van anti-ontstekingsimmuuncellen. Deze speciale T-cellen, die Tregs worden genoemd, helpen de spieren bij herhaaldelijk sporten ook nog eens om energie beter om te zetten in brandstof en het langer vol te houden. Tregs spelen ook een rol bij het tegenaan van ontsteking in een aantal auto-immuunziektes. Maar hun rol in het sportdomein was niet eerder op deze manier uitgezocht. Het immuunsysteem is dus niet alleen een beschermer en vechter tegen ziektes, zeggen deze onderzoekers, het speelt ook een grote rol bij andere processen, zoals bij de gezondheidseffecten van sport. Natuurlijk was dit een onderzoek in muizen en zal het nog wel herhaald moeten worden onder mensen. Toch geeft het wel al een indicatie dat als we willen begrijpen hoe sport ons gezonder maakt, iets wat we nog niet volledig begrijpen, we ook het immuunsysteem niet moeten vergeten. Lees hier meer over het onderzoek: Some benefits of exercise stem from the immune systemSee omnystudio.com/listener for privacy information.

harvard maar ze deel deze toch lees vanuit komen natuurlijk tregs

Dr. Fred Grossman, Coya Therapeutics on ALS research

The Patients Speak

Play Episode Listen Later Oct 25, 2023 27:17 Transcription Available

In this podcast interview with Dr. Fred Grossman, President and Chief Medical Officer of Coya, the following key points were discussed:- The podcast, "The Patients Speak," aims to bridge the gap between healthcare science and the patient perspective.- Dr. Grossman highlighted the significant unmet needs in conditions like ALS and Alzheimer's disease, emphasizing the personal impact on patients and their families.- ALS (Lou Gehrig's disease) is a rapidly progressive neurodegenerative disease that affects muscle function, speech, and respiration, with a high fatality rate.- Alzheimer's disease is also a devastating condition, and patients and their families are eagerly seeking treatments.- The discussion touched on the importance of considering patients' perspectives on daily activities, which are greatly affected by these conditions.- Dr. Grossman emphasized the need for objective measures in clinical trials while acknowledging the importance of subjective input from patients and their families.- Patients' altruism and desire to contribute to research were highlighted as essential drivers in clinical trials.- Dr. Grossman discussed Coya's focus on regulatory T cells (Tregs) as a key cellular target in treating ALS due to their role in regulating inflammation.- Coya's treatment, Coya 302, aims to increase the number and function of Tregs to stabilize the immune system and halt ALS progression.- The potential impact of Coya 302 was discussed, with the aim of prolonging survival and improving patients' quality of life.- Dr. Grossman mentioned that Coya is planning a large-scale study for Koya 302 with a potential start in six months.- Collaboration with patient advocacy groups and the Healy Platform Trial was highlighted as a way to involve patients in research and speed up progress.- The importance of clear and honest communication between patients and healthcare providers was emphasized, with patients having the right to know what to expect in their condition.Fred's Website BSB Media

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The Growing Epidemic of Neurodegenerative Diseases - No Longer a Losing Battle

Healthcare Americana

Play Episode Listen Later Aug 17, 2023 26:49

On this episode of Healthcare Americana, host Christopher Habig, CEO of Freedom Healthworks, is joined by Howard Berman, CEO of Coya Therapeutics. Together, they discuss the complexities of neurodegenerative diseases and the groundbreaking work being done to combat them. Explore the profound impact of conditions like ALS, Alzheimer's, and Parkinson's, and discover Coya's pioneering approach that utilizes Regulatory T-cells (Tregs) to revolutionize therapy for neurodegeneration. Howard offers insights into Coya's imminent breakthroughs, explains the critical role the immune system plays in all neurodegenerative diseases, and touches upon the process of working with the government to bring new treatments to the public. He also shares the tragic circumstance that occurred, which ultimately lead him to the overnight decision of leaving his career in big pharma and propelling him on this mission-based path. Finally, Howard concludes with the high expectations he has for Coya in the next 12 months. Don't miss this enlightening discussion that sheds light on the pressing need to address the growing epidemic of neurodegenerative diseases.Follow Healthcare Americana:TwitterInstagramLinkedInMore on Freedom Healthworks & FreedomDocMore on Howard Berman & Coya TherapeuticsSubscribe at https://healthcareamericana.com/episodes/

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Targeting Neuroinflammation to Treat ALS

RARECast

Play Episode Listen Later Aug 17, 2023 25:34

Regulatory T cells target systemic inflammation and neuroinflammation, but when they fail to function properly, they can drive serious health conditions including neurodegenerative, metabolic, and autoimmune diseases. Coya Therapeutics is developing a pipeline of therapies designed to restore the ability of Tregs to modulate the immune system and reduce inflammation. The company's lead experimental therapy is a combination of two biologics designed to treat ALS by boosting anti-inflammatory Tregs while suppressing other immune cells that drive inflammation. We spoke to Howard Berman, chairman and CEO of Coya, about the role of inflammation in neurodegenerative conditions, Tregs, and the company's experimental therapy to treat ALS.

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#53 The power of Tregs with Arun Swaminathan: Harnessing Regulatory T cells to Address Neurodegenerative, Autoimmune and Metabolic Diseases & Mysteries of the human body

The MedTech Podcast

Play Episode Listen Later Aug 1, 2023 31:28

Arun began his career in clinical development and commercial roles of increasing responsibility at BristolMyers Squibb and Covance has over 20 years of hands-on healthcare business executive experience with an emphasis on corporate and business development, strategy and finance. In this episode, we delve into the paramount importance of prioritising patients amid physician shortages in the US healthcare system, the cutting-edge approach of targeting regulatory T cells to combat neurodegenerative diseases effectively, the pivotal role of biomarkers in diagnosing these conditions together with the potential of combining them with physician tests, cognitive assessments and advanced scans for a truly ideal approach alongside how the intricacies of the human body remain a profound challenge and that there is still an abundance of knowledge to unravel and discover. Timestamps: [00:00:00] Excellent healthcare: Patient-centered excellence. [00:06:09] Treating neurodegenerative diseases with Tregs. [00:11:45] Bringing therapies to patients faster. [00:18:00] Forming a company to fight neurodegenerative diseases. [00:24:39] Evolution of Coya: Follow Your Calluses. Get in touch with Arun Swaminathan - https://www.linkedin.com/in/arun-swaminathan-a8571b3/ https://coyatherapeutics.com/ Get in touch with Karandeep Badwal - https://www.linkedin.com/in/karandeepbadwal/ Follow Karandeep on YouTube - https://www.youtube.com/@KarandeepBadwal Subscribe to the Podcast --- Support this podcast: https://podcasters.spotify.com/pod/show/themedtechpodcast/support

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ImmunoEpigenetics 99. Tregs can foster a massive tumor microenvironment inhibition of T-eff cell populations via neo-antigen activation from dying tumor cells leading to cancer progression. DJGPhD

cancer massive dying foster progression activation cells tumors populations antigens inhibition tregs tumor microenvironment

Play Episode Listen Later Jul 27, 2023 29:30

Reference Cancers (Basel). 2021. Apr; 13(8): 1850. --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

A Serum- and Feeder-Free System to Generate CD4 and Regulatory T Cells from Human iPSCs

PaperPlayer biorxiv cell biology

Play Episode Listen Later Jul 2, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.01.547333v1?rss=1 Authors: Fong, H., Mendel, M., Jascur, J., Najmi, L., Kim, K., Lew, G., Garimalla, S., Schock, S., Hu, J., Villegas, A., Conway, A., Fontenot, J., Zompi, S. Abstract: iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGF{beta} and ATRA. Using zinc finger nucleases, we demonstrated high non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs +/- HLA-A2 CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T cell proliferation in vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Targeting GITR in Cancer Immunotherapy – There Is No Perfect Knowledge

Oncotarget

Play Episode Listen Later Jun 21, 2023 3:36

A new research perspective was published in Oncotarget's Volume 14 on June 19, 2023, entitled, “Targeting GITR in cancer immunotherapy – there is no perfect knowledge.” In this new perspective, researchers Diwakar Davar and Roberta Zappasodi from the University of Pittsburgh Medical Center (UPMC), University of Pittsburgh, Weill Cornell Medical College, and Weill Cornell Graduate School of Medical Sciences discuss the glucocorticoid-induced TNFR-related protein (GITR), belonging to the TNFR superfamily (TNFRSF) and stimulating both the acquired and innate immunity. GITR is broadly expressed on immune cells, particularly regulatory T cells (Tregs) and natural killer (NK) cells. “Given its potential to promote T effector function and impede Treg immune suppression, GITR is an attractive target for cancer immunotherapy.” Preclinically, GITR agonists have demonstrated potent anti-tumor efficacy singly and in combination with a variety of agents, including PD-1 blockade. Multiple GITR agonists have been advanced into the clinic, although the experience with these agents has been disappointing. Recent mechanistic insights into the roles of antibody structure, valency, and Fc functionality in mediating anti-tumor efficacy may explain some of the apparent inconsistency or discordance between preclinical data and observed clinical efficacy. Overall, the clinical results obtained so far with GITR agonist agents have demonstrated specific immune effects in the expected immune cell populations based on preclinical studies. However, these effects have not produced substantial therapeutic activity in human cancer patients. A maturing understanding of the immune responses to GITR agonism in human cancer has clarified novel issues specific to drug development in this space including Ab structure (monospecific and bispecific mAbs and co-stimulatory GITR ligands), Ab valency, and Fc functionality. “This improved understanding of the immune responses to GITR agonism in patients should be kept in consideration for the design of novel rational combinations or treatment regimens in earlier disease settings where immunotherapy is gradually becoming the treatment of choice.” DOI - https://doi.org/10.18632/oncotarget.28461 Correspondence to - Diwakar Davar - davard@upmc.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28461 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, immunotherapy, programmed death-1 (PD-1), cytotoxic T-lymphocyte Antigen-4 (CTLA-4), glucocorticoid-induced TNFR-related protein (GITR) 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

Nuno Madeira do Ó, Reflection Therapeutics

Careers in Discovery

Play Episode Listen Later Apr 12, 2023 43:38

"Anybody can be a pair of hands, follow a protocol and do what they're told. If you want more than that, if you want to be a pair of hands with a brain, then you have to think differently." Nuno Madeira do Ó is the CEO of Reflection Therapeutics, a Biotech company harnessing the potential of Tregs to treat inflammatory diseases. Nuno shared the story of his career so far, and among other things we discussed pivoting a Biotech into a new disease area, transitioning from research into commercial roles and how a children's cartoon inspired a career in Life Sciences. Enjoy!

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Unlocking the Potential of Genomic Medicine to Treat Autoimmune and Inflammatory Diseases with Sandy Macrae Sangamo Therapeutics

Play Episode Listen Later Feb 20, 2023 16:14

Sandy Macrae, CEO of Sangamo Therapeutics, talks about the promise and limitations of genomic medicine to find the most effective and affordable treatments for patients with autoimmune and inflammatory diseases. Their CAR-Treg cell therapy platform allows T cells to be tracked throughout the body and activated to release chemicals and signals to reduce inflammation. Small molecule oral pills will always be used to treat diseases and vaccines to prevent them. The goal of genomic medicine is to eradicate the disease. Sandy explains, "We co-opted what's a very natural process and attached a whole series of things to it. The zinc finger gets us to the right bit of the DNA, and then we can either cut the DNA. We can turn it down, turn it off, replace a base, or replace a chunk of it. That's the advantage of the zinc fingers. It's natural. It's small. It's easily delivered and has a whole range of functions that allows us to choose the right tool for the right disease." "But there's going to be a growing space for diseases where there is a clear genetic influence or genetic participation in the disease, where a simple injection of a virus that takes the editing technology to the DNA can change the patient's course of their disease. I'm thinking of Sickle Cell Disease, where patients who were going into the hospital 10, 12, or 15 times a year are now not having any of those painful episodes. I'm thinking of Hemophilia, where they used to have to inject two or three times a week and have bleeding episodes, and they can now walk free and not worry about their bleeding." "But really, the excitement within Sangamo is the next-generation projects, the Tregs that we just spoke about, and a whole platform of brain-active conscription factors that we're working on." @SangamoTx #GenomicMedicine #GeneTherapy #CellTherapy #ZincFingers #Tregs #Tcells sangamo.com Download the transcript here

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Unlocking the Potential of Genomic Medicine to Treat Autoimmune and Inflammatory Diseases with Sandy Macrae Sangamo Therapeutics TRANSCRIPT

The Confident Clinician Podcast

Play Episode Listen Later Feb 20, 2023

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Reconsidering the Role of Melatonin in Rheumatoid Arthritis.

Play Episode Listen Later Sep 15, 2022 14:37

Recently a review article from 2020 caught my eye; Reconsidering the Role of Melatonin in Rheumatoid Arthritis. Sleep is a major issue for RA, and many patients and clinicians are turning to melatonin to aid with sleep issues, are we causing more harm than good? Melatonin has been known: as a powerful antioxidant and anti-inflammatory properties to help with regulating T cell responses, T helper (Th)1, Th17, and regulatory T cells (Tregs). to help modulate the circadian rhythm and enhance sleep On the flip side, there is evidence from animal studies showing there are receptors for melatonin on synovial macrophages which promote the release of some Th-1-type proinflammatory cytokines. It has also been pointed out that the higher blood concentrations of melatonin in arthritic patients, especially in the early morning, might explain the morning stiffness and joint swelling experienced by patients - but does that mean that melatonin should be completely avoided? So far most of that evidence is coming from animal studies but are they translating with similar outcomes in human RCT? Let's dive into 2 human trials to see how melatonin impacts your RA clients. Save the Date! Dr. Alison Danby, ND will be running a 1-day Autoimmune 101 Workshop for clinicians on Friday, October 21, 2022. Registration opens September 21st. Join our mailing list to make sure you are in the know to grab those Early Bird Savings. References: https://confident-clinician-club.s3.ca-central-1.amazonaws.com/The+Expert+Clinician/Autoimmune+101/TCC+Podcast/RA+%26+Melatonin+2007++(1).pdf https://confident-clinician-club.s3.ca-central-1.amazonaws.com/The+Expert+Clinician/Autoimmune+101/TCC+Podcast/RA+and+melatonin+-+2020+RCT+(1).pdf

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Papa Tregs Makes Three!

F Entertainment! with Rob Traegler

Play Episode Listen Later Aug 28, 2022 43:15

Olivia Newton-John bids farewell, "She-Hulk" smashes into streaming, Nick Nolte battles alcoholism and Rob's dad weighs in on everything from "Grease" to "Elvis".

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Alumni Spotlight: Cristin Berkey

IP Talk with Wolf Greenfield

Play Episode Listen Later Aug 18, 2022 8:17

We're pleased to feature Cristin Berkey in this episode of Wolf Greenfield's Alumni Spotlight series. Cristin was an associate at Wolf Greenfield from 2017-2019. Cristin currently serves as Senior Director of Intellectual Property and Contracts at Abata Therapeutics. Abata translates the biology of regulatory T cells (Tregs) into transformational medicines for patients with progressive multiple sclerosis and other serious autoimmune and inflammatory diseases. Here are some highlights from Cristin Berkey's turn in the Alumni Spotlight on IP Talk with Wolf Greenfield. 00:50 - Cristin's responsibility for managing IP strategy at Abata Therapeutics03:01 - An overview of T cells and their potential04:53 - The difference between being an in-house attorney and working at a law firm06:08 - Cristin's favorite Wolf Greenfield memory06:58 - Favorite place to get away07:22 - Light, heartwarming shows are a nice way to relax

ip senior director contracts alumni intellectual property berkey tregs

Can Salt Trigger Thyroid Autoimmunity?

Save My Thyroid

Play Episode Listen Later Aug 11, 2022 2:55

There are many health benefits associated with good quality sea salt, and it's something I recommend to my patients and personally add to my food regularly.At the same time, we know that too much salt can be problematic. Research shows that excessive salt consumption can increase Th17 cells and inhibit Tregs (the opposite of what we want to happen - check out last week's bonus episode for a quick summary).So, should everyone with Graves' disease and Hashimoto's avoid salt?Today I'm sharing the research around salt intake and autoimmunity and how you can safely consume salt as a part of your diet.In this episode, you'll learn:Why I regularly use and recommend sea saltWhat studies show about the correlation between a high-salt diet and autoimmunityMy recommendations for daily salt consumptionAs always, I hope you found this episode valuable, and I look forward to catching you in the next episode!To learn more, visit the show notes at https://savemythyroid.com/podcast/can-salt-trigger-thyroid-autoimmunity/.

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What are Th17 and Treg cells?

Save My Thyroid

Play Episode Listen Later Aug 4, 2022 3:10

T-helper 17 (Th17) cells and regulatory T cells (Tregs) play a role in developing autoimmune conditions like Graves' disease and Hashimoto's.Today I'm sharing everything you need to know about these cells since you'll hear me refer to them a lot in future podcast episodes.In this episode, you'll learn:Where Th17 and Treg cells originateThe role of Th17 and Treg cellsHow Th17 and Treg cells are connected to autoimmune conditionsNutrients, supplements, and natural agents that have been shown to increase regulatory T cells and decrease Th17 cellsTune in for next week's Q&A episode, where I'll discuss something many people commonly use in their homes that can increase Th17 cells.I hope you found this episode valuable, and I look forward to catching you in the next episode!To learn more, visit the show notes at https://savemythyroid.com/podcast/what-are-th17-and-treg-cells/.

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DrBeen#12 - Chronic Inflammation (Part 4) - T Regulatory Cells (June 17, 2022)

FLCCC Alliance

Play Episode Listen Later Jun 21, 2022 35:00

Long Story Short with Dr. Been Episode 12: Chronic Inflammation (Part 4) - T Regulatory Cells An important lecture in the chronic inflammation series that discusses T Regulatory cells (TRegs) and their function. Let's review this promising area of immunology. DrBeen: Medical Education Online https://www.drbeen.com/ Home - FLCCC | Front Line COVID-19 Critical Care Alliance https://covid19criticalcare.com/ For more references please see Odysee - https://odysee.com/@FrontlineCovid19CriticalCareAlliance:c/Chronic-Inflammation-T-Regulatory-Cells:3 Donate to the Front Line Covid-19 Critical Care Alliance, Inc.  To educate medical professionals and the public in safe and effective ways to prevent and treat COVID-19. Click here to make a donation: https://frontlinecovid-19criticalcarealliance.salsalabs.org/donate/index.html Buy FLCCC gear: https://supportflccc.store/ Subscribe to our mailing list on our website: http://flccc.net/signup Disclaimer: This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only. Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional.

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Ep. 28: “Exploring Regulatory T Cells” Featuring Dr. Michael Rosenblum

The Immunology Podcast

Play Episode Listen Later Apr 26, 2022 71:07

Dr. Michael Rosenblum is a Professor of Dermatology at the University of California, San Francisco. His lab seeks to to understand how immune responses are regulated in tissues and how this knowledge can be exploited for therapeutic benefit. They are currently investigating how Tregs control immune responses in tissues, as well as their “alternative” functions. He talks about early-life inflammation and type 2 helper T cells in the skin, and how Tregs can be manipulated to target autoimmune diseases and cancer.

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Coya Therapeutics: Treg Therapy in ALS

Endpoints

Play Episode Listen Later Mar 1, 2022 20:30

Regulatory T cells, also known as Tregs, are specialized cells that are part of the immune system. As the name implies, they help regulate the body's immune natural immune response, among other functions According to some studies, the dysregulation of TRegs may play a role in several neurodegenerative disease. Coya Therapeutics is a Texas based biotech company working to utilize TReg therapies to treat these diseases – including ALS. Their ALS treatment completed a Phase 2a study in 2021, with results to be published later in 2022. They are also planning a phase 2b study later this year. Today, on Endpoints, we're joined by Dr. Adrian Hepner, Coya's Chief Medical Officer, to talk about how TRegs might be able to help people with ALS, give an update on the Phase the phase 2a study, and discuss plans for the next steps. Support the show: https://www.als.net/donate/ See omnystudio.com/listener for privacy information.

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Episode 52 : Keep On Moving With Coach Tregs

Educate Motivate Inspire

Play Episode Listen Later Jan 11, 2022 56:39

In this episode of The MindBodyHealth Podcast I interview Mark Tregilgas aka Coach Tregs who is the founder of 30 Plus Mens Fitness and author of "Keep On Moving". Mark shares his rollercoaster journey in detail from feeling lost and depressed to using exercise and healthy lifestyle habits to change his life forever and has now spent many years positively impacting others and is one of the most respected and highly regarded coaches in the industry. In this conversation we destroy myths around weightloss, supplements, exercise and more. We stress the importance of creating a strong positive mindset and the importance of sleep and hydration. This episode is packed with personal stories, client success stories and lots of valuable tips and strategies to transform your life. Order a copy of Coach Tregs book https://www.amazon.co.uk/Keep-Moving-Coach-Tregs/dp/B09LGLN2NV/ref=tmm_pap_swatch_0?_encoding=UTF8&qid=1641892394&sr=8-1 Mark's Website http://www.30plusmensfitness.com Mark's Facebook Page https://www.facebook.com/30plusmensfitness Mark's Instagram http://www.instagram.com/30plusmensfitness Mark's Youtube https://www.youtube.com/user/30plusmensfitness I hope you enjoy this episode. Love to get your feedback and please give it a rating and a review. Website : http://www.davesheahanhighperformance.com Follow me on Instagram http://www.instagram.com/davesheahan1978 Follow me on Facebook http://www.facebook.com/DaveSheahanPage Follow me on Twitter http://www.twitter.com/davesheahan1 Follow me on Snapchat : username is davesheahan Subscribe to my Youtube Channel : http://www.youtube.com/user/homeworkoutsystem Follow me on Tiktok : https://vm.tiktok.com/ZSuHVEuC/ Whatsapp message me : +353 86 458 3216 Email me : dave@davesheahanhighperformance.com

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Episode 96: Jeff Bluestone, PhD

TheSugarScience Podcast- curating the scientific conversation in type 1 diabetes

Play Episode Listen Later Oct 21, 2021 32:20

Dr. Jeff Bluestone and others join us to discuss Tregs and Sonoma Bio. This episode is in Ask the Expert style Ask the Expert is a 30 minute digital cafe experience where scientists and grad students can meet up and exchange with thought leaders in the field of type one diabetes. Link below to sign up for a seat in the cafe! https://thesugarscience.org/ask-the-expert/

expert bluestone tregs

Episode 4: Coach Tregs podcast (episode 4)

Healthy mind healthy body

Play Episode Listen Later Sep 12, 2021 61:26

In this episode I speak to former Premier League footballer, Nigel Reo-Coker.Nigel started his career at Wimbledon before playing for West Ham United and captaining them in that famous 2006 F.A Cup final against Liverpool.He also played for Aston Villa, Bolton and Ipswich before spending the last few years of his career playing in the MLS in the States where he now resides with his wife and 3 young children.Nigel is one of the nicest guys I have spoken to and the banter and conversation just flowed.I hope you guys enjoy!Coach Tregs

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The Gary Null Show - 07.28.21

The Gary Null Show

Play Episode Listen Later Jul 28, 2021 58:49

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021. Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10. The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS). While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients. “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.” Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.” Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).” Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors." Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers. Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

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The Gary Null Show - 07.26.21

The Gary Null Show

Play Episode Listen Later Jul 26, 2021 58:56

Red and processed meat linked to increased risk of heart disease, study shows Oxford University, July 21, 2021 Globally, coronary heart diseases (caused by narrowed arteries that supply the heart with blood) claim nearly nine million lives each year1, the largest of any disease, and present a huge burden to health systems. Until now, it has been unclear whether eating meat increases the risk of heart disease, and if this varies for different kinds of meat. Researchers at the University of Oxford's Nuffield Department of Population Health have conducted the largest systematic review of the prospective evidence to date, including thirteen cohort studies involving over 1.4 million people. The study participants completed detailed dietary assessments, and their health was tracked for up to 30 years. The results are published today in Critical Reviews in Food Science and Nutrition. Overall, the evidence from the analysis indicated that: Each 50 g/day higher intake of processed meat (e.g. bacon, ham, and sausages) increased the risk of coronary heart disease by 18%. Each 50 g/day higher intake of unprocessed red meat (such as beef, lamb and pork) increased the risk of coronary heart disease by 9%. There was no clear link between eating poultry (such as chicken and turkey) and an increased risk of coronary heart disease. The findings may be because of the high content of saturated fat in red meat, and of sodium (salt) in processed meat. High intakes of saturated fat increase levels of harmful low-density lipoprotein (LDL) cholesterol, whilst excess salt consumption raises blood pressure. Both LDL cholesterol and high blood pressure are well-established risk factors for coronary heart disease. Previous work from the same research team has also indicated that even moderate intakes of red and processed meat are associated with increased risk of bowel cancer2. Dr. Keren Papier (Nuffield Department of Population Health), co-lead author of the study, said: "Red and processed meat have been consistently linked with bowel cancer and our findings suggest an additional role in heart disease. Therefore, current recommendations to limit red and processed meat consumption may also assist with the prevention of coronary heart disease." Dr. Anika Knüppel, from the Nuffield Department of Population Health and the other co-lead author of the study, added: "We know that meat production is a major contributor to greenhouse gas emissions and we need to reduce meat production and thereby consumption to benefit the environment. Our study shows that a reduction in red and processed meat intake would bring personal health benefits too." Currently in the UK, about 10 in 100 people would be expected to eventually die from coronary heart disease. Based on the findings from the present study and current red and processed meat intakes in the UK,4 if all these 100 people reduced their unprocessed red meat intake by three-quarters (for example from four times a week to one time a week), or if they stopped consuming processed meat altogether, deaths from coronary heart disease would decrease from 10 in 100 down to 9 in 100. The studies involved in this analysis were mostly based on white adults living in Europe or the U.S.. The research team say more data are needed to examine these associations in other populations, including East Asia and Africa. C is for Vitamin C -- a key ingredient for immune cell function Harnessing the combined power of Vitamin C and TET proteins may give scientists a leg up in treating autoimmune diseases La Jolla Institute for Immunology and Emory University, July 22, 2021 You can't make a banana split without bananas. And you can't generate stable regulatory T cells without Vitamin C or enzymes called TET proteins, it appears. Regulatory T cells (Tregs) help control inflammation and autoimmunity in the body. Tregs are so important, in fact, that scientists are working to generate stable induced Tregs (iTregs) in vitro for use as treatments for autoimmune diseases as well as rejection to transplanted organs. Unfortunately, it has proven difficult to find the right molecular ingredients to induce stable iTregs. Now scientists at La Jolla Institute for Immunology and Emory University School of Medicine report that Vitamin C and TET proteins can work together to give Tregs their life-saving power. "Vitamin C can be used to stabilize iTregs generated in vitro," says LJI Instructor Xiaojing Yue, Ph.D., who served as co-first author for the EMBO Reports study. "We hope that these kinds of induced Tregs can be used in the future for treatment of autoimmune diseases and organ transplantation." The recent study, led by LJI Professor Anjana Rao, Ph.D., and Emory Instructor Benjamin G Barwick, Ph.D., builds on the previous discovery that Vitamin C can enhance the enzymatic activity of TET proteins and prompt the generation of stable iTregs under lab conditions. This finding was encouraging, but the scientists did not want to work toward new autoimmune therapies without first analyzing the gene expression patterns and other key epigenetic features of the induced Tregs. "We wanted to study the entire system at a whole genome level using next generation sequencing technology to better understand the molecular features of these cells," says Yue. Study co-first author Daniela Samaniego-Castruita, a graduate student at LJI, spearheaded the analysis of gene expression and epigenetic changes in the iTregs. A major type of epigenetic modification involves the DNA itself through the addition or removal of molecules called methyl groups from cytosines, one of the four DNA bases. The methyl groups can be further oxidized by TET enzymes. All of these interactions can eventually change how cells "read" the DNA code. Another type of epigenetic change involves the alteration of DNA accessibility: whether DNA is loosely or tightly coiled. As the DNA coils unwind, regulatory regions become exposed which subsequently influence gene expression. In their analysis, the researchers found TET proteins are absolutely required for maintaining the gene expression and epigenetic features that make Tregs as what they are; and adding Vitamin C led to iTregs with similar similar gene expression and epigenetic features as normal "wild type" Tregs found in the body. The study also reveals an intriguing connection between TET enzymatic activity, Vitamin C and IL-2/STAT5 signaling. "In mice that are deficient for components of IL-2/STAT5 signaling, such as IL-2, IL-2 receptors or STAT5, the Tregs cannot develop properly or they can have impaired function," Yue says. The researchers demonstrate that on one hand, TET-deficiency in Treg cells leads to impaired IL-2/STAT5 signaling; on the other hand, Vitamin C confers iTregs enhanced IL-2/STAT5 signaling by increasing the expression level of IL-2 receptor and the functional form of STAT5, and STAT5 binding to essential regions in the genome, rendering these cells survive better in tough environments with low IL-2 supplementation. "We are looking for more small molecules to stabilize TET activity and generate induced Tregs that are even more stable," says Yue. "These induced Tregs could eventually be used to treat patients." "This research gives us a new way to think about treating autoimmune diseases," says Samaniego-Castruita. Resveratrol ameliorates high-fat-diet-induced abnormalities in liver glucose metabolism in mice via the AMPK pathway Hebei Medical Institute (China), July 19, 2021 A new study on high fat diet is now available. According to news originating from the Department of Internal Medicine by NewsRx correspondents, research stated, “Diabetes mellitus is highly prevalent worldwide.” Our news reporters obtained a quote from the research from Department of Internal Medicine: “High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase b (CaMKKb), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKb inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes.” According to the news editors, the research concluded: “These effects are mediated through the activation of AMPK by PP2A and CaMKKb.” Hundreds of chemicals, many in consumer products, could increase breast cancer risk List includes potential carcinogens that act by stimulating production of hormones that fuel breast tumors Silent Spring Institute, July 22, 2021 Every day, people are exposed to a variety of synthetic chemicals through the products they use or the food they eat. For many of these chemicals, the health effects are unknown. Now a new study shows that several hundred common chemicals, including pesticides, ingredients in consumer products, food additives, and drinking water contaminants, could increase the risk of breast cancer by causing cells in breast tissue to produce more of the hormones estrogen or progesterone. "The connection between estrogen and progesterone and breast cancer is well established," says co-author Ruthann Rudel, a toxicologist and research director at Silent Spring Institute. "So, we should be extremely cautious about chemicals in products that increase levels of these hormones in the body." For instance, in 2002, when the Women's Health Initiative study found combination hormone replacement therapy to be associated with an increased risk of breast cancer, women stopped taking the drugs and incidence rates went down. "Not surprisingly, one of the most common therapies for treating breast cancer is a class of drugs called aromatase inhibitors that lower levels of estrogen in the body, depriving breast cancer cells of the hormones they need to grow," adds Rudel. To identify these chemical risk factors, Rudel and Silent Spring scientist Bethsaida Cardona combed through data on more than 2000 chemicals generated by the U.S. Environmental Protection Agency (EPA)'s ToxCast program. The goal of ToxCast is to improve the ability of scientists to predict whether a chemical will be harmful or not. The program uses automated chemical screening technologies to expose living cells to chemicals and then examine the different biological changes they cause. Reporting in the journal Environmental Health Perspectives, Rudel and Cardona identified 296 chemicals that were found to increase estradiol (a form of estrogen) or progesterone in cells in the laboratory. Seventy-one chemicals were found to increase levels of both hormones. The chemicals included ingredients in personal care products such as hair dye, chemical flame retardants in building materials and furnishings, and a number of pesticides. The researchers don't yet know how these chemicals are causing cells to produce more hormones. It could be the chemicals are acting as aromatase activators, for instance, which would lead to higher levels of estrogen, says Cardona. "What we do know is that women are exposed to multiple chemicals from multiple sources on a daily basis, and that these exposures add up." The Silent Spring researchers hope this study will be a wakeup call for regulators and manufacturers in how they test chemicals for safety. For instance, current safety tests in animals fail to look at changes in hormone levels in the animal's mammary glands in response to a chemical exposure. And, although high throughput testing in cells has been used to identify chemicals that activate the estrogen receptor, mimicking estrogen, the testing has not been used to identify chemicals that increase estrogen or progesterone synthesis. "This study shows that a number of chemicals currently in use have the ability to manipulate hormones known to adversely affect breast cancer risk," says Dr. Sue Fenton, associate editor for the study and an expert in mammary gland development at the National Institute of Environmental Health Sciences. "Especially concerning is the number of chemicals that alter progesterone, the potential bad actor in hormone replacement therapy. Chemicals that elevate progesterone levels in the breast should be minimized." The researchers outlined a number of recommendations in their study for improving chemical safety testing to help identify potential breast carcinogens before they end up in products, and suggest finding ways to reduce people's exposures, particularly during critical periods of development, such as during puberty or pregnancy when the breast undergoes important changes. The project is part of Silent Spring Institute's Safer Chemicals Program which is developing new cost-effective ways of screening chemicals for their effects on the breast. Knowledge generated by this effort will help government agencies regulate chemicals more effectively and assist companies in developing safer products. Antioxidant activity of limonene counteracts neurotoxicity triggered by amyloid beta 1-42 oligomers in cortical neurons University of Naples (Italy), July 19, 2021 According to news reporting from Naples, Italy, by NewsRx journalists, research stated, “Many natural-derived compounds, including the essential oils from plants, are investigated to find new potential protective agents in several neurodegenerative disorders such as Alzheimer's disease (AD).” The news editors obtained a quote from the research from School of Medicine: “In the present study, we tested the neuroprotective effect of limonene, one of the main components of the genus * * Citrus* * , against the neurotoxicity elicited by Ab [ [1-42] ] oligomers, currently considered a triggering factor in AD. To this aim, we assessed the acetylcholinesterase activity by Ellman's colorimetric method, the mitochondrial dehydrogenase activity by MTT assay, the nuclear morphology by Hoechst 33258, the generation of reactive oxygen species (ROS) by DCFH-DA fluorescent dye, and the electrophysiological activity of K [ [V] ] 3.4 potassium channel subunits by patch-clamp electrophysiology. Interestingly, the monoterpene limonene showed a specific activity against acetylcholinesterase with an IC [ [50] ] almost comparable to that of galantamine, used as positive control. Moreover, at the concentration of 10 g/mL, limonene counteracted the increase of ROS production triggered by Ab [ [1-42] ] oligomers, thus preventing the upregulation of K [ [V] ] 3.4 activity. This, in turn, prevented cell death in primary cortical neurons, showing an interesting neuroprotective profile against Ab [ [1-42] ] -induced toxicity.” According to the news editors, the research concluded: “Collectively, the present results showed that the antioxidant properties of the main component of the genus * * Citrus* * , limonene, may be useful to prevent neuronal suffering induced by Ab [ [1-42] ] oligomers preventing the hyperactivity of K [ [V] ] 3.4.” Meditation And Yoga Change Your DNA To Reverse Effects Of Stress, Study Shows Coventry University (UK), July 22, 2021 Many people participate in practices such as meditation and yoga because they help us relax. At least those are the immediate effects we feel. But much more is happening on a molecular level, reveal researchers out of Coventry University in England. Published in the journal Frontiers in Immunology, this new research examined 18 studies on mind-body interventions (MBIs). These include practices such as mindfulness meditation and yoga. Comprehensively, these studies encompassed 846 participants over 11 years. The new analysis reveals that MBIs result in molecular changes in the human body. Furthermore, researchers claim that these changes are beneficial to our mental and physical health. Body's Response to Stress Causes Damage To elaborate, consider the effect that stress has on the body. When we are under stress, the body increases the production of proteins that cause cell inflammation. This is the natural effect of the body's fight-or-flight response. It is widely believed that inflammation in the body leads to numerous illnesses, including cancer. Moreover, scientists also deduct that a persistent inflammation is more likely to cause psychiatric problems. Unfortunately, many people suffer from persistent stress, therefore they suffer from pro-inflammatory gene expression. But there is good news! According to this new analysis out of Coventry, people that practice MBIs such as meditation and yoga can reverse pro-inflammatory gene expression. This results in a reduced risk of inflammation-related diseases and mental conditions. Lead investigator Ivana Buric from Coventry University's Centre for Psychology, Behaviour and Achievement stated: Millions of people around the world already enjoy the health benefits of mind-body interventions like yoga or meditation, but what they perhaps don't realise is that these benefits begin at a molecular level and can change the way our genetic code goes about its business. These activities are leaving what we call a molecular signature in our cells, which reverses the effect that stress or anxiety would have on the body by changing how our genes are expressed. Put simply, MBIs cause the brain to steer our DNA processes along a path which improves our wellbeing. More needs to be done to understand these effects in greater depth, for example how they compare with other healthy interventions like exercise or nutrition. But this is an important foundation to build on to help future researchers explore the benefits of increasingly popular mind-body activities. Large-scale study finds greater sedentary hours increases risk of obstructive sleep apnea Study finds that maintaining an active lifestyle can reduce the risk of OSA, encourages physicians to recommend exercise-based interventions for those at risk Brigham and Women's Hospital, July 22, 2021 A new study by investigators from Brigham and Women's Hospital examined the relationship between active lifestyles and the risk of obstructive sleep apnea (OSA). The study followed around 130,000 men and women in the United States over a follow-up period of 10-to-18 years and found that higher levels of physical activity and lower levels of sedentary behavior were associated with a lower risk of OSA. Their results are published in the European Respiratory Journal. "In our study, higher levels of physical activity and fewer hours of TV watching, and sitting either at work or away from home were associated with lower OSA incidence after accounting for potential confounders," said Tianyi Huang, MSc, ScD, an Associate Epidemiologist at the Brigham. "Our results suggest that promoting an active lifestyle may have substantial benefits for both prevention and treatment of OSA." OSA is a type of sleep apnea in which some muscles relax during sleep, causing an airflow blockage. Severe OSA increases the risk of various heart issues, including abnormal heart rhythms and heart failure. Using the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII) and Health Professionals Follow-Up Study (HPFS), the research team used statistical modeling to compare physical activity and sedentary hours with diagnoses of OSA. Both moderate and vigorous physical activity were examined separately and both were strongly correlated with lower risk of OSA, showing no appreciable differences in the intensity of activity. Moreover, stronger associations were found for women, adults over the age of 65 and those with a BMI greater than or equal to 25 kg/m2. "Most prior observational studies on the associations of physical activity and sedentary behavior with OSA were cross-sectional, with incomplete exposure assessment and inadequate control for confounding," said Huang. "This is the first prospective study that simultaneously evaluates physical activity and sedentary behavior in relation to OSA risk." This study also differs from others because of its large sample size and detailed assessment pf physical activity and sedentary behaviors. The research team was able to take many associated factors into account, making the findings more credible. The authors note that all collected data, both of OSA diagnosis and physical activity or sedentary behavior, were self-reported. While all study participants were health professionals, mild OSA is often difficult to detect and can remain clinically unrecognized. Furthermore, only recreational physical activity was taken into consideration, leaving out any physical activity in occupational settings. Sedentary behavior was only counted as sitting while watching TV and sitting away from home or at work. According to Huang, the next research steps would be to collect data using actigraphy, home sleep apnea tests and polysomnography, rather than self-reports. In light of the findings, investigators encourage physicians to highlight the benefits of physical activity to lower OSA risk. "We found that physical activity and sedentary behavior are independently associated with OSA risk," said Huang. "That is, for people who spend long hours sitting every day, increasing physical activity in their leisure time can equally lower OSA risk. Similarly, for those who are not able to participate in a lot of physical activity due to physical restrictions, reducing sedentary hours by standing or doing some mild activities could also lower OSA risk. However, those who can lower sedentary time and increase physical activity would have the lowest risk."

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How to increase your Regulatory T Cells or Tregs and improve your immune system.

Play Episode Listen Later Jul 22, 2021 11:16

Peripheral Regulartory T Cells are specialized cell that live in the gut. Tregs release anti-inflammatory cytokines that reduce inflammation in the body. Trees help maintain the balance of our immune system. Our immune system and emotional system is closely linked to physical health. Many believe that dysregulation of Tregs may lead to Autoimmune Disease.

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Episode 3: Coach Tregs podcast (episode 3)

coach states south pole ultramarathon deans dean karnazes tregs

Play Episode Listen Later Jul 13, 2021 43:21

In this podcast, I interview Ultra Marathon man, Dean Karnazes.At 58 years old Dean is a living legend who has run a marathon a day in 50 different States for 50 days on the bounce, run a marathon in the South Pole and once ran for 350 miles in just under 90 hours without sleep to name just a few things :)Tune in and listen to him tell his famous tale about how he turned his back on a comfy corporate yet unfulfilling career starting on the night of his 30th Birthday where he left a bar after drinking with friends and simply began to run into the night.That was the moment his life changed forever.Deans methodical approach to training, recovery and nutrition is incredible yet he talks about it in a very matter of fact way with zero arrogance.It was a joy to speak with someone who has inspired so much and continues to fire me up with what really can be achieved by the human body when the mind is conquered.Thank you Dean and keep inspiring.Coach Tregs

017 - Balancing T Cells - Th1, Th2, Th17, & Tregs

The Autoimmune Doc Podcast w/ Dr. Taylor Krick

Play Episode Listen Later Jul 1, 2021 35:10

T cells are a part of your immune system, which has many many important parts of course. T cells are particularly important in autoimmunity because the T CELLS ARE WHAT DO THE DAMAGE!!!In my last episode about Hashimoto's I talked about antibody levels and described how will antibodies "flag" something as bad so that immune cells can come destroy it, but antibodies have no destructive properties. The progression and destruction of autoimmune disease is determined by the level of T cell activity! T cells destroy the gut in autoimmunity. T cells destroy the joints in autoimmunity. T cells destroy the thyroid. T cells destroy the myelin of your nerves. THEY ARE IMPORTANT!!What type(s) are there? What do they do? How do I know if mine are working properly?This episode goes through all of that information! I go through the 4 most important polarizations of T cells: Th1 (fights intracellular infections)Th2 (produces mucus and expels allergens and parasites)Th17 (causes tissue-damaging inflammation)Regulatory T cells (Tregs), which are the peacemakers that dampen inflammationAutoimmunity ALWAYS has an imbalance of too much Th17 activity and not enough Treg activity, but what about Th1/Th2? Eventually MOST autoimmune patients will present with decreased Th1 and increased Th2, and in this episode I go through some of the details of how this happens, how the patient presents and how this needs to be handled clinically to get it under control!

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Episode 2: Coach Tregs podcast (episode 2)

Play Episode Listen Later Jun 26, 2021 49:59

In this episode Tregs interviews former Scottish international footballer Chris Iwelumo.Chris had a glittering career, spanning 19 years, starting at St Mirren in 1995, ending at Chester in 2014.He now works as a Talk Sport Radio presenter. Sit back, relax and enjoy this 50 minute interview from a larger than life character.Nice one Chris!Coach Tregs

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Episode 1: Coach Tregs Podcast (Episode 1)

Play Episode Listen Later Jun 13, 2021 124:35

I'm delighted to launch the all new Coach Tregs podcast!My first guest as you may know was former pro footballer and bloody good friend of mine, Wayne Thomas, who played for Torquay United, Stoke, Southampton and Burnley as well as a short spell in Greece.Here is our full 2 hour plus chat.EnjoyTregs

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Adipokine Mini Review I Daniel J. Guerra, PhD. 03 Feb 2021 Authentic Biochemistry Podcast Publications.

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Play Episode Listen Later Feb 4, 2021 29:26

*Adipose tissue is the endocrine organ that secretes “adipokines” *Nothing new to the Authentic Biochemistry crew; adipokines have been very well discussed here and their function as mediators of the feeding/appetitive/satiety response through the arcuate nucleus of the hypothalamus (POMCvNPY neurons) was most recently addressed. *Adipokines mediate the BMI, heart rate, serum glucose &fatty acid/TAG, and pro- inflammatory cytokine production;they are released by adipocytes (e.g. leptin and adiponectin) or preadipocytes, adipose tissue-infiltrated immune cells, or the gastric system Indeed, Th2 lymphocytes promote adipose glucose homeostasis by enhancing insulin sensitivity in adipocytes and browning/brown adipose tissue (BAT) activation but chronic inflammation of white adipose tissue (WAT) leads to the activation of pro-inflammatory pathways in adipocytes and resident immune cells following obesity involving the shutting down of Tregs and anti-inflammatory cytokines. Front Physiol. 2020; 11: 578966 Indian J Pharmacol. 2012 Mar-Apr; 44(2): 155–156. Cells. 2019 Mar; 8(3): 227. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

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Bep11 - Colonic Tregs and Mom

Antibuddies

Play Episode Listen Later Sep 20, 2020 66:00

In this episode, Eugenio, Jatin, and Natalie discuss about the a unique mode of non-genetic multigenerational inheritance in colonic Tregs. Check out our memes on Facebook (@antibuddies) and Twitter (@antibuddiesP). Join us on our monthly journal club at our YouTube channel: https://www.youtube.com/channel/UCxyrHotyyY3sSwcp1zigeCw Send us your queries/questions/suggestions at antibuddies1@gmail.com. Source: https://www.sciencedirect.com/science/article/abs/pii/S0092867420304931

Episode 20: Modify Tregs in Practice

Advanced Women's Health

Play Episode Listen Later Aug 26, 2020 28:10

Regulatory T cells are an incredibly important part of a healthy immune system. Many of the chronic diseases that we face including, autoimmune diseases, require modification of the immune system in order to support healing. In today's episode we discuss various pharmacological and natural methods that have been shown to regulate Tregs production and function. Research DiscussedMedical treatment can unintentionally alter the Treg compartment in patients with widespread pathophysiologic conditions https://ajp.amjpathol.org/article/S0002-9440(20)30369-2/fulltextThe role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A systematic reviewhttps://pubmed.ncbi.nlm.nih.gov/31550254/Metformin reduces autoimmune antibody levels in patients with Hashimoto's thyroiditis: A systematic review and meta-analysishttps://pubmed.ncbi.nlm.nih.gov/32741222/Promotion of regulatory T cell induction by immunomodulatory herbal medicine licorice and its two constituentshttps://www.nature.com/articles/srep14046Anti-inflammatory effects of the neurotransmitter agonist Honokiol in a mouse model of allergic asthmahttps://pubmed.ncbi.nlm.nih.gov/20889543/Modulation of Immune Function by Polyphenols: Possible Contribution of Epigenetic Factorshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738975/N‐acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double‐blind, placebo‐controlled trial†https://onlinelibrary.wiley.com/doi/full/10.1002/art.34502Immune Responses Regulated by Cannabidiolhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173676/Influence of Dietary Components on Regulatory T Cellshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276397/Stay in touch!Naturopathic Clinical Mentorship https://www.naturopathicmentorship.com/Next AWT Program launches September 14th - register now or book a call for more information! https://www.naturopathicmentorship.com/program-applicationAdvanced Women's Health website https://www.advancedwomenshealth.ca/My personal website and articles https://sarahwilsonnd.com/Finally Lose It purchase https://sarahwilsonnd.com/finallyloseitInstagram https://www.instagram.com/drsarah_nd/ Facebook https://facebook.com/sarahwilsonndLive in Ontario? Book an appointment! https://www.advancedwomenshealth.ca/book-nowOne on One professional consult

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Episode 6: Jennifer Bridge, PhD, Bluestone Lab, Anderson Lab, UCSF

TheSugarScience Podcast- curating the scientific conversation in type 1 diabetes

Play Episode Listen Later Aug 23, 2020 23:25

In this episode, Jennifer joins Nicole Phillips to discuss her research at UCSF in the Bluestone Lab and Anderson Lab. Jennifer's research focuses on understanding mechanisms regulating T-cell activation and studying an immunosuppressive population of T cells known as Tregs.

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Episode 19: Role of Regulatory T Cells in Healthy Pregnancies and Reproductive Diseases

Advanced Women's Health

Play Episode Listen Later Aug 12, 2020 29:56

Reproductive immunology is an area that all practitioners working in women's health should be familiar with. It is impossible to separate hormones from the immune system and research, like what we discuss today, is constantly evolving to show how important treating both systems is to the health of your patients. Whether you work with patients with endometriosis, recurrent pregnancy loss, preeclampsia or any other inflammatory conditions treating the immune system is foundational. In today's episode we review the different elements of the inflammatory response and discuss the connection between Tregs and hormones. Research DiscussedRole of Regulatory T Cells in Regulating Fetal-Maternal Immune Tolerance in Healthy Pregnancies and Reproductive Diseases https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333773/ Stay in touch!Naturopathic Clinical Mentorship https://www.naturopathicmentorship.com/Next AWT Program launches September 14th - register now or book a call for more information! https://www.naturopathicmentorship.com/program-applicationAdvanced Women's Health website https://www.advancedwomenshealth.ca/My personal website and articles https://sarahwilsonnd.com/Finally Lose It purchase https://sarahwilsonnd.com/finallyloseitInstagram https://www.instagram.com/drsarah_nd/ Facebook https://facebook.com/sarahwilsonndLive in Ontario? Book an appointment! https://www.advancedwomenshealth.ca/book-nowOne on One professional consult

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July 2020 Discover CircRes

Discover CircRes

Play Episode Listen Later Jul 16, 2020 21:17

This month on Episode 14 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the July 3 and July 17 issues of Circulation Research. This episode also features an in-depth conversation with Dr. Brenda Ogle and Drs. Molly Kupfer and Wei-Han Lin regarding their study, In Situ Expansion, Differentiation and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid. Article highlights: Wei, et al. Palmitoylation Cycling and Endothelial Maturity van Ouwerkerk, et al. Functional Variant Elements in Atrial Fibrillation Models Ibarrola, et al. Aldosterone in MVP Sharma, et al. Atherosclerosis Regression Requires Regulatory T Cells Cynthia St. Hilaire: Hi, welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr. Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. Today I'm going to share with you four articles selected from our July issues of Circulation Research, as well as have a discussion with Dr. Brenda Ogle and the first authors, Molly Kupfer and Wei-Han Lin, regarding their study, In Situ Expansion, Differentiation and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid. So first, the highlights. The first article I want to share with you is titled, "Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease." The first author is Xiaochao Wei, and the corresponding author is Clay Semenkovich from Washington University, St. Louis. Peripheral artery disease, or PAD for short, is a vascular occlusive disease of the lower extremities. It affects more than 2 million individuals globally, and its prevalence is ever increasing as our population ages. While statin therapy can be useful for combating coronary artery disease in peripheral artery disease patients, it does not prevent or reduce PAD patients' rates of lower extremity amputation. So looking to gain insights into the mechanisms underlying PAD, this team focused on the findings that circulating fibronectin and the dietary saturated fatty acid, palmitate, are associated with peripheral artery disease. They found this interesting as lipid modification proteins has been implicated in infections, premature aging, cancer and diabetes. One such protein modification is palmitoylation, which is the formation of a thioester bond between palmitate sand cysteine. Acyl-protein thioesterase 1, or APT1, is a depalmitoylase enzyme, which removes the fatty acid palmitate from protein. Using mouse models with inactivated endothelial APT1, as well as cell systems in arterial samples from humans with end stage peripheral artery disease, they tested whether deficiencies in palmitoylation cycling promotes endothelial instability, which is a hallmark of chronic arterial occlusive diseases. They discovered that as many as 10% of all proteins are palmitoylated. They found deficiency of APT1 in endothelial cells disrupts vascular homeostasis, in part by altering the intracellular trafficking of the small GTPase R-Ras. Impaired R-Ras membrane trafficking was rescued by modifying the palmitoylated R-Ras molecule to promote dissociation from membranes. These observations identify palmitoylation cycling as a potential therapeutic target in the treatment of peripheral vascular disease. The second article I want to highlight is titled, "Identification of Functional Variant Enhancers Associated with Atrial Fibrillation." The first author is Antoinette van Ouwerkerk, and the corresponding authors are Antoine de Vries and Vincent Christoffels, And they're from UMC Amsterdam. As we heard in our podcast last month with our interview with Dr. David McManus, atrial fibrillation, or AFib, is the most common form of arrhythmia, and is a major risk for heart failure, dementia, and stroke, and sudden death. Genome-wide association studies have revealed more than a hundred genetic loci linked to this condition, and many of these loci are found in non-coding regions, which are enriched for transcription factor binding sites and epigenetic modification sites, suggesting that these loci could potentially have gene regulatory roles. To test this idea, they use the method called self-transcribing active regulatory region sequencing, or STARR-seq, which is a method used to identify the sequences that act as transcriptional enhancers in a direct quantitative and genome-wide manner. They use STARR-seq to screen 12 of the strongest AFib linked regions of the genome, which contain more than 1600 individual aphid linked genetic variance, and they did this in cultured rat atrial monocytes. From this screen, they found approximately 400 regulatory elements, of which 24 exhibited variant-specific differences in regulatory activity. For one of these elements, upstream of the gene HCN4, deletion of the orthologous element in mice caused diminished transcriptional activity of the gene. Moreover, these variant-containing mice had brachycardia and sinus node dysfunction, both components of arrhythmia. This proof of principle study confirms that such a regulatory element screen could provide insight into the consequences of variants associated with AFib, or for that matter, many other diseases. The next article I want to share with you is titled, "A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse." The first author is Jaime Ibarrola, and the corresponding author is Natalia López-Andrés, and their work was completed at Sanitaria de Navarra in Pamplona, Spain. Mitral valve prolapse is a condition where blood leaks back into the left atrium of the heart, and it is the most common form of heart valve defects. The underlying pathology includes an overabundance of cells in the valve leaflet, so-called valve interstitial cells, or VICs. These activated VICs overproduce extracellular matrix protein, and the combination of increased numbers of VICs and increased amounts of extracellular matrix proteins contributes to the impairment of the structural integrity of the valve leaflet. The increase in VICs is due to excess proliferation, but also transformation of valve endothelial cells, so the cells that line the leaflet, valve endothelial cells, into mesenchymal like VICs. As a driver of endothelial to mesenchymal transition, aldosterone was suspected to play a role. Aldoesterone increased expression of VIC activation markers in cultured valve endothelial cells and increased production of certain extracellular matrix protein components. Spironolactone, an aldosterone inhibitor, prevented these effects, and importantly, prevented valve remodeling in a mouse model of mitral valve prolapse. The team showed that valve tissue from mitral valve prolapse patients taking aldosterone receptor inhibitors displayed less evidence of VIC activation and lower production of disease-regulated extracellular matrix components, than those not taking the drugs. These exciting results suggest aldosterone antagonists, already used for certain patients with heart failure or high blood pressure, may also benefit those with mitral valve prolapse. The last article I want to share before we switch to our interview, is titled, " Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression." The first author is Monika Sharma, and the corresponding author is Kathryn Moore, and they're from New York University. Atherosclerosis is a chronic inflammatory condition characterized by the buildup of fatty deposits in the artery walls, and monocytes and macrophages can infiltrate into these fatty deposits and contribute to the formation of plaque. Cholesterol-lowering drugs, like statins, promote the reduction of low-density lipoproteins in the blood, which can help to slow plaque growth, but they do not reverse disease progression. One possibility for changing the course of the disease is to develop therapies that can reduce plaque inflammation, and therefore, progression. With that goal in mind, this team investigated how the immunosuppressive activity of regulatory T cells, or Tregs, may influence the functions of plaque monocytes and macrophages. Using mouse models in which the disease can be reversed through aggressive lipid lowering, they found that depletion of the Treg population caused an increase in the numbers of monocytes and macrophages in the plaques, and resulted in poorer plaque regression. Indeed, these monocytes and macrophages proliferated more, remained in the plaques longer, and were less likely to adopt an anti-inflammatory pro-plaque resolving M2-like phenotype than plaque macrophages in mice with normal Treg numbers. Together, these results highlight the importance of Tregs for promoting plaque regression, and suggest future therapies aimed at boosting these cells, or indeed, M2 macrophages may enable atherosclerosis remission. Okay, so now we're going to switch over to the interview portion of our podcast. I have with me Dr. Brenda Ogle, who is a professor of biomedical engineering, and first authors Molly Kupfer and Wei-Han Lin, and they're from the University of Minnesota. And today we're going to be discussing their manuscript titled, "In Situ Expansion, Differentiation and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid." So thank you all for joining me today. Brenda Ogle: Thank you. Molly Kupfer: Thanks for having us. Wei-Han Lin: Thank you. Cynthia St. Hilaire: Great. I'm glad we can all do this remotely and nice and safe for COVID. So Dr. Ogle, you're the PI of the group, but Molly and Wei-Han, what stages of career are you at? Molly Kupfer: I just recently completed my PhD, so this work is sort of the culmination of that. Cynthia St. Hilaire: Oh, congratulations! Molly Kupfer: Yeah. Thank you. Cynthia St. Hilaire: Well done. Circ Research is a great thesis publication. Congratulations. Molly Kupfer: Thank you. Cynthia St. Hilaire: Wei-Han, how about you? Wei-Han Lin: So I'm a BME PhD student at the University of Minnesota. And I got my master degree in chemical engineering, but in Taiwan, and now I'm working with professor Brenda Ogle on cardiac tissue engineering stuff. Cynthia St. Hilaire: Excellent. So this is a beautiful paper. It's stunning. It has all sorts of wonderful parts, biological, biomechanical, great imaging, and essentially you created a 3D bio-ink that can be used to print and make a living pump, kind of a heart in a dish. And it's something that you're calling this human chambered muscle pump, or ChaMP, which I think is a great name. Can you please describe exactly what that is and why did you want to go about trying to make it? Molly Kupfer: Yeah, it might help if I give a little bit of context to this. So since the beginning, one of the central questions that the lab has been exploring is how do the cells of the heart interact with their environment, or the extracellular matrix, as we call it? We know that these interactions that occur at the cellular level are absolutely critical for cardiac function, both at the tissue and the organ level. And based on years of research studying how the extracellular environment modulates cellular function, we have now sought to apply what we've learned in order to engineer functional human cardiac tissues by recapitulating those very critical interactions in vitro. And actually, back in 2017, we published another study in Circulation Research, where we generated these contractile patches of cardiac tissue using a form of light-based 3D printing that allowed us to fabricate scaffolds with really high resolution micron-level features that were distributed in a way that mimics the native extracellular environment. And what we found is that by organizing the extracellular matrix in that way, we enabled the cells to organize themselves in the scaffold and form connections with each other and with the scaffold itself. And this was critical to achieving synchronous electromechanical function of the tissue as a whole. But these were very small millimeter scale tissues, and so for this new study, we sought to create something on a larger scale where you could incorporate some new geometric features such as chambers and the capacity for perfusion. And as you mentioned, using our knowledge of the interactions between cells and the extracellular matrix, we developed this unique bio-ink that could be used as a vehicle to 3D print these centimeter scale chambered tissue structures that are based on the geometry of the human heart. And so the tissues that resulted from this, the human chambered muscle pumps, or hChaMPs, exhibit thick, contiguous muscularization. They demonstrate electrical connectivity and pump function. And notably, this is the first time that this level of function and muscularization has been achieved in an engineered cardiac tissue of this level of geometric complexity. Cynthia St. Hilaire: So can you maybe talk a little bit about what do you mean by an ink, exactly? Is it actually printed? Is this like a printer that I could buy on Amazon? Obviously there's a huge biological component, but what are the actual technical things that you had to develop to make this chamber happen? Molly Kupfer: Yes. So we did use an extrusion-based 3D printing, which is similar to probably what people normally think about with 3D printing. Traditionally, it's been with plastics. In this case, we're printing with a bio-ink, which is essentially a formulation of proteins and other materials that we encapsulate the cells in, and then after that, we extrude it from a nozzle in a specific formulation or shape in order to create the structure. Cynthia St. Hilaire: So that's interesting. So in this mix, the cells are already in there as opposed to, I guess, some other things that people tend to call scaffolds where you kind of print that and then seed it? Molly Kupfer: Mm-hmm (affirmative). And in the example of the paper I discussed from 2017, that was an example where we printed a scaffold and put the cells in. But in this case, for such a large and complex structure, we actually mix the cells in prior to printing, and then we create the structure. Cynthia St. Hilaire: Wow. What's the timeframe of that? Like the cells, you got to digest them and mix things up and then print it. The cells, are they happy? Molly Kupfer: Yeah, that's a good question. So the actual printing process is quite fast, maybe a couple of minutes for this particular scale. We have to prepare, culture, the cells in advance and we're working with human-induced, pluripotent stem cells, so it takes time to grow them up, and then yes, we do detach them and singularize them, and we then mix them with the components. But overall, the actual printing process is relatively quick. Then it's a matter of maintaining the structure and culturing it and doing the differentiation as we did. And that takes weeks to do over time. But the actual process of making it, initially, is quite quick. Brenda Ogle: Challenging thing about this project was the fact that mature cardiac muscle does not transfer well. Meaning when you move it from a dish to an ink and then print it and ask it to start beating again, it doesn't typically happen. And that is because cardiomyocytes don't proliferate well, or make more of each other, and they also don't move well, or migrate. And so the premise on which most of this paper relies is on printing the stem cells first, letting them expand, sort of like they do with development, and then encouraging them to specify into cardiac cell types. Cynthia St. Hilaire: What's the bigger good that can come out of this? Why do we want to be able to do this in vitro, or even ex vivo heart in a dish? Brenda Ogle: The value is pretty tremendous because, suddenly we have a human model system in which we can perfuse volume, so volume can go in and come out, in which the cells experience those volume metric and fluid-induced forces that we haven't been able to study human cells in this way ever before. In the context of human disease, this is the first time we'll be able to look at onset of a particular disease, what was happening with onset, and then progression. And I think that is what is going to transform this field. Cynthia St. Hilaire: So what was the first one like? I'm thinking back to my graduate school and also my postdoc where I was involved in some disease discovery and I have a very vivid memory of the Western blot that proved the mutation that we found. And I literally ran down the hall holding the film. I'm imagining, maybe I'm projecting too much, but what was seeing that first one beat like? Molly Kupfer: You're not projecting. I feel like that well describes my experience. We had some early experiences where we would start to see beating areas under the microscope, but I think the moment, for me, was, I think there was one night I was working in the lab and I had some plates out, I was looking at stuff under the microscope going through just the mundane lab tasks, and I think I sort of saw it at the corner of my eye in the dish, something was moving. And that was the first time. Like I had watched parts of these things beat under a microscope all the time. I spent years looking at cardiomyocytes under a microscope, but that was the first time, for these hChaMPs, where I could actually see it moving just by my eye. Cynthia St. Hilaire: Wow. Molly Kupfer: And that was a really cool moment. Wei-Han Lin: Yeah. I was mostly working on the printing side, so the first time I realized the heart started beating, it's more like a shock to me, because I'm always printing the models or just the mold. But then really seeing those cells, or the whole structure, start to beat, was quite amazing. Cynthia St. Hilaire: Could you please tell me a bit about the 3D printing aspect of it? Is it like a shell like the outside of a balloon, or does it have an interior structure that helps dictates where the cell go? Can you explain what the printing is? Wei-Han Lin: So the structure we are printing is derived from MRI image stacks on a real human heart. And the image stack was segmented and reduce the size by 10 times, and then we convert the stack into the STL file, which is the standard operating format. And then we modify the model a little bit to make it into two chambers and with two vessels, and two connected chambers with two openings. And this is the heart we are using for the study. Cynthia St. Hilaire: Got it. So it's got kind of the big picture items of the heart. It's got two tubes going in and it's got two chambers and the fluid can flow between all of those aspects in a specific flow pattern. Wei-Han Lin: Exactly. Cynthia St. Hilaire: You said you have to differentiate them in a dish and you're adding different factors to do that. Do the cells like being in that scaffold, or do they want to seep out of that structure or is there something about the bio-ink that they're happy there? Molly Kupfer: You know, I think this bio-ink was, to a certain extent, optimized or designed such that the cells would be able to continue to attach and grow and remodel. So basically, for the most part, these components are biological materials. Some of them are just proteins. Some of them are proteins that have been modified with photo cross-linkable elements, but they still have these moieties that the cells can attach to. And over time we do see some remodeling and some extracellular matrix gets degraded and some gets deposited. Cynthia St. Hilaire: So have you gone to the next steps of something like single cell seq and trying to see what kind of cells you're getting in this? Or even maybe inputting different, the scaffold is getting one differentiation protocol, but are you possibly able to prime IPS cells such that they're maybe halfway to a vascular cell, or halfway to a cardiomyocyte cell, and then put them in the bio-ink? Brenda Ogle: That's a really interesting idea. I'm going to take that one. Cynthia St. Hilaire: Give me an acknowledgment. Brenda Ogle: So we've been thinking about that, the context of if expansion of IPS cells is the best way, for many cell types, how do we get multiple cell types and organize them? And you can imagine even just printing in specific areas, different cell types. Cynthia St. Hilaire: Oh, sure. Brenda Ogle: But the other thing we've thought about is delivering differentiation factor spatially. So almost printing a cell, but then printing that. depot of a factor, in the area that we wanted or in an arrangement that we want, and then releasing it when we want. And it's challenging for stem cell differentiation, because you really need no release, and then basically zero order release for two or three days, and then no release again. Cynthia St. Hilaire: Right. Brenda Ogle: So it's a challenging drug delivery problem, but we've been thinking a lot about it. Now priming the cells beforehand is another interesting approach. Cynthia St. Hilaire: Well, that's wonderful. I just want to congratulate you all again. Brenda Ogle: Thank you so much for having us. Cynthia St. Hilaire: Yeah, thank you so much. Wei-Han Lin: Thank you so much. Cynthia St. Hilaire: That's it for our highlights from the July issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and on Instagram with the handle @CircRes and #discovercircres. Thank you to our guests, Dr. Brenda Ogle, Dr. Molly Kupfer and Wei-Han Lin. This podcast is produced by Rebecca McTavish and Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host Dr. Cindy St. Hilaire, and this is Discover CircRes, you're on the go source for the most up-to-date and exciting discoveries in basic cardiovascular research.

Oncotarget - Indoximod Opposes The Immunosuppressive Effects Mediated By IDO And TDO

Oncotarget

Play Episode Listen Later Jun 23, 2020 5:06

Volume 11 Issue 25 of @Oncotarget reported that Indoximod has shaped the understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor, which controls transcription of several genes in response to different ligands including kynurenine. Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the Ah R. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme. Dr. Erik L. Brincks from NewLink Genetics Corporation as well as Lumos Pharma, Inc. said "Indoleamine 2,3-dioxygenase (IDO1) plays an important role in the regulation of acquired local and peripheral immune tolerance in normal and pathological scenarios." In cancer, IDO1 can be expressed either directly by the tumor cells or induced indirectly in host antigen presenting cells by the tumor. IDO1 expression by tumor cells has been associated with significantly worse clinical prognosis and reduced survival in malignant melanoma, pancreatic cancer, ovarian cancer, both pediatric and adult acute myelogenous leukemia, colorectal cancer, prostate cancer, endometrial cancer, and others. The cellular pharmacodynamic effects of IDO1 activity include the inhibition of antigen-specific CD8+ T cell proliferation, stimulation of differentiation of na�ve CD4+ T cells to Fox P3+ regulatory T cells, the activation of Tregs, and the recruitment of MDSC to the tumor. Both isomers are capable of restoring T-cell proliferation in an MLR assay with IDO+ dendritic cells as the stimulator cells, or in syngeneic antigen-dependent T-cell proliferation assays using IDO+ dendritic cells isolated from tumor-draining lymph nodes. L1m T is a competitive inhibitor and substrate of IDO1 enzymatic activity in cell-free assays using purified recombinant IDO1 enzyme, and in tumor cells treated with INFγ or in tumor cell lines transfected with expression vectors that encode IDO1 under the control of an heterologous promoter. The Brincks Research Team concluded in their Oncotarget Research Paper that these effects are independent on the Trp metabolizing activity of IDO and/or TDO but happen to oppose the effects of the enzymatic activity of IDO and TDO by multiple mechanisms that act on cell types commonly affected by the IDO and TDO pathways. Indoximod creates a Trp-sufficiency signal which leads to reactivation of MAP4K3 which leads to activation of mTORC1 activity, thus opposing and bypassing the effects of Trp deprivation that lead to GCN2 activation and MAP4K3 and mTOR inactivation. This effect requires a relatively high concentration of indoximod, is observed in both CD4+ and CD8+ T cells and leads to an increase in the proliferative capacity of activated effector and helper T cells. This effect takes place at clinically relevant concentrations of indoximod and is independent of IDO/TDO activity or exogenous Kyn, though it happens to oppose the Kyn/Ah R effects on T cell differentiation. Full text - https://www.oncotarget.com/article/27646/text/

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Dr. Mary J. Janatpour from Dynavax Technologies | Oncotarget

Oncotarget

Play Episode Listen Later Jan 31, 2020 11:16

The cover for issue 68 of Oncotarget features Figure 4, "Gene expression changes to the TME demonstrate sequential development of innate and adaptive immune responses," by Leong, et al. Intratumoral injection of SD-101 induces significant anti-tumor immunity in preclinical and clinical studies, especially when combined with PD-1 blockade. Combination therapy generated CD8+ T cell-dependent immunity leading to rejection of both non-injected and injected tumors and long-term survival, even in very large tumors. Dr. Mary J. Janatpour from Dynavax Technologies, Inc., Emeryville, CA 94608, USA said, "It has long been appreciated by cancer researchers that the phenotypic heterogeneity and progressive evolution of malignant tumors minimize the chance that any agent targeting a single molecular pathway could effectively cure advanced cancer." The authors have previously demonstrated in mouse tumor models that employing the innate immune system to prime a T cell response, in combination with checkpoint blockade, results in deep and durable anti-tumor efficacy. These high response rates were observed in both injected and non-injected tumor lesions and patients with PD-L1 negative tumors, indicating low levels of basal immune inflammation, responded as well as patients with PD-L1 positive tumors. Intratumorally administered SD-101 exerts its priming activity and ultimate orchestration of a systemic anti-tumor T cell response through multiple mechanisms. The production of interferon stimulates tumor cell killing by natural killer cells, with ensuing tumor antigen release, and induces chemokines that attract T cells back to the tumor bed. Low-dose cyclophosphamide decreases Tregs. Additional impacted biological activities have been described, such as: increased interferon production, induction of immunogenic cell death, increases in effector T cells, and increases in functional NK cells, ...likely to be complementary to SD-101 activity by virtue of modulation of the TME. By administering SD-101 locally, rather than systemically, the researchers demonstrate that localized SD-101 injection combined with systemically administered low-dose cyclophosphamide confers an anti-tumor response at non-injected sites. The Janatpour research Team concluded that taken together, the intratumoral SD-101 plus low-dose CY combination may complement existing checkpoint blockade therapies in patients to improve efficacy in the clinic and extend the benefits of immunotherapy to more patients. Full text - https://doi.org/10.18632/oncotarget.27322 Correspondence to - Mary J. Janatpour - mjanatpour@dynavax.com Keywords - TLR9, SD-101, cyclophosphamide, immune therapy, innate immunity About Oncotarget Oncotarget is a weekly, peer-reviewed, open-access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with @Oncotarget Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

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Dr. Guerra finishes the Treg lectures by drawing upon on a transcription factor molecular thread of Ariadne to deliver T cell lineage architechtonics.

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Play Episode Listen Later Aug 17, 2019 27:37

This is volume VI of the Tregs lecture narrative in which Dr. Guerra provides an introduction to a Diaeventontological process for navigating the labyrinth of T cell biochemistry. Published 17 August 2019. Authentic Biochemistry Podcast. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Innate lymphoid cells and the frank T lymphocyte family as controlled by cytokinogenesis, co-stimulation, and Tregs. Part I.Dr Dan Guerra

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Play Episode Listen Later Aug 4, 2019 28:07

Dr Dan Guerra presents "T regulatory Cells in Human Biology and Disease. An update on transcriptional control". Vol.I. This first segment introduces the elaborate nature of innate and acquired lymphoid cells and the transcription factors that drive lineage differentiation. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

30 Plus Mens Fitness Podcast - Episode 32

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Play Episode Listen Later Nov 7, 2018 41:00

In this episode Tregs interviews client online client Kieran Halfpenny from Ireland. Kieran joined us around the middle of the year in 2018 and has gone on to lose over 2 stone and drastically improve the quality of his life. After coming through 2 x Fat Dad to Fit Dad online programmes he is now a members club client and regularly joins Tregs on the live weekend workouts. We discuss his journey and how his weight loss has transformed his confidence and energy levels which has in turn benefited his young family enormously. He also bravely discusses a harrowing past experience which left him depressed and scarred for your years which he is now dealing with in a better head space due to his healthier lifestyle. It's another inspiring story of a normal guy who decided enough was enough and took the opportunity to change his life through health and fitness. Sit back, relax grab yourself a coffee and enjoy our chatter. As always I'd love your feedback. Keep Truckin Coach Tregs

30 Plus Men's Fitness Podcast Episode 31

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Play Episode Listen Later Nov 1, 2018 34:33

In this episode Tregs interviews client turned coach, Craig Warren from our 30+Hereford bootcamp. Craig originally joined us back at the start of 2017 when we ran a free transformation programme in his area. When he applied he said he wanted to be fitter to be able to run around with his kids. He has since gone on to lose over 3 stone in the last 18 months and recently qualified as a bootcamp coach so he could could lead the lads in Hereford. It's another inspiring story of a normal guy who decided enough was enough and took the opportunity to change his life through health and fitness. Sit back, relax grab yourself a coffee and enjoy our chatter. As always I'd love your feedback. Keep Truckin Coach Tregs

30 Plus Mens Fitness Podcast Episode 30

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Play Episode Listen Later Oct 15, 2018 21:56

In this episode Tregs interviews AJ from our 30+Berkshire bootcamp. AJ has dramatically turned his life around since finding us, losing over 2 stone and regaining energy so he can perform in work and also have a kick about with his son. However before he found us he was in a very dark place. In his own words "It go so bad, I walked up to a train station and was about to jump in front of a train, I'd had enough" I waited for the train, watched a few go by and thought "I'm having the next one" I blanked out. I stepped forwards. And then, an angel out of nowhere, an off duty copper, grabbed hold of my top and pulled me back. He wrestled me to the floor, hugged me and said "Son it's not worth it". What happened after this? You'll find out in this very episode. Well done on turning it around AJ and a big shout to coach Anthony for guiding him. As always I would love your feedback. Keep Truckin Coach Tregs

30 Plus Mens Fitness Podcast Episode 29