Podcasts about Clonal

In this JCO Article Insights episode, Michael Hughes summarizes “International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al. published on June 09, 2025 along with an interview with author Dr Nikhil C. Munshi, MD. TRANSCRIPT Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I am interviewing Dr. Nikhil Munshi on the “International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma” by Avet-Loiseau et al. At the time of this recording, our guest has disclosures that will be linked in the transcript. While some patients with multiple myeloma live for decades after treatment, others exhibit refractory or rapidly relapsing disease irrespective of treatment administered. We term this “high-risk myeloma.” Multiple risk stratification systems have been created, starting with the Durie-Salmon system in 1975 and evolving with the advent of novel therapeutics and novel treatment approaches. In 2015, the Revised International Staging System (R-ISS) was introduced, which incorporated novel clinical and cytogenetic markers and remained, until recently, a mainstay of risk stratification in newly diagnosed disease. Myeloma as a field has, just in the past few years, though, undergone explosive changes. In particular, we have seen groundbreaking advances not only in treatments - the introduction of anti-CD38 agents and the advent of cellular and bispecific therapies - but also in diagnostic technology and our understanding of the genetic lesions in myeloma. This has led to the proliferation of numerous trials employing different definitions of high-risk myeloma, a burgeoning problem for patients and providers alike, and has prompted attempts to consolidate definitions and terminology. Regarding cytogenetic lesions, at least, Kaiser et al's federated meta-analysis of 24 therapeutic trials, published here in the JCO in February of 2025 and recently podcasted in an interview with associate editor Dr. Suzanne Lentzsch, posited a new cytogenetic classification system to realize a shared platform upon which we might contextualize those trial results. This article we have here by Dr. Avet-Loiseau, Dr. Munshi, and colleagues, published online in early June of this year and hot off the presses, is the definitive joint statement from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG). What is high-risk multiple myeloma for the modern era? The IMS and IMWG Genomics Workshop was held in July 2023 and was attended by international myeloma experts, collaborating to reach consensus based on large volumes of data presented and shared. The datasets included cohorts from the Intergroupe Francophone du Myélome (IFM); the HARMONY project, comprised of multiple European academic trials; the FORTE study, findings from which solidified KRd as a viable induction regimen; the Grupo Español de Mieloma Múltiple (GEM) and the PETHEMA Foundation; the German-Speaking Myeloma Multicenter Group (GMMG); the UK-based Myeloma XI, findings from which confirmed the concept of lenalidomide maintenance; Emory 1000, a large, real-world dataset from Emory University in Atlanta; the Multiple Myeloma Research Foundation Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) dataset; and some newly diagnosed myeloma cohorts from the Mayo Clinic. Data were not pooled for analyses and were assessed individually - that is to say, with clear a priori understanding of whence the data had been gathered and for what original purposes. Consensus on topics was developed based on the preponderance of data across studies and cohorts. In terms of results, substantial revisions were made to the genomic staging of high-risk multiple myeloma, and these can be sorted into three major categories: A) alterations to the tumor suppressor gene TP53; B) translocations involving chromosome 14: t(14;16) (c-MAF overexpression), t(14;20) (MAFB overexpression), and t(4;14) (NSD2 overexpression); and C) chromosome 1 abnormalities: deletions of 1p or additional copies of 1q. In terms of category A, TP53 alterations: Deletion of 17p is present in up to 10% of patients at diagnosis and is enriched in relapsed or refractory disease. This is well-documented as a high-risk feature, but the proportion of the myeloma cells with deletion 17p actually impacts prognosis. GEM and HARMONY data analyses confirmed the use of 20% clonal cell fraction as the optimal threshold value for high-risk disease. That is to say, there must be the deletion of 17p in at least 20% of the myeloma cells on a FISH-analysis of a CD138-enriched bone marrow sample to qualify as high-risk disease. TP53 mutations can also occur. Inactivating mutations appear to have deleterious effects similar to chromosomal losses, and the biallelic loss of TP53, however it occurs, portends particularly poor prognosis. This effect is seen across Myeloma XI, CoMMpass, and IFM cohorts. Biallelic loss is rare, it appears to occur in only about 5% of patients, but next-generation sequencing is nevertheless recommended in all myeloma patients. Category B, chromosome 14 translocations: Translocation t(14;16) occurs in about 2% to 3% of patients with newly diagnosed disease. In the available data, primarily real-world IFM data, t(14;16) almost always occurs with chromosome 1 abnormalities. Translocation t(4;14) occurs in about 10% to 12% of newly diagnosed disease, but only patients with specific NSD2 alterations are, in fact, at risk of worse prognosis, which clinically appears to be about one in every three of those patients. And so together, the CoMMpass and Myeloma XI data suggest that translocation t(4;14) only in combination with deletion 1p or gain or amplification of 1q correlates with worse prognosis. Translocation t(14;20) occurs in only 2% of newly diagnosed disease. Similar to translocation t(4;14), it doesn't appear to have an effect on prognosis, except if the translocation co-occurs with chromosome 1 lesions, in which case patients do fare worse. Overall, these three translocations - t(14;16), t(4;14), and t(14;20) - should be considered high-risk only if chromosome 1 aberrations are also present. In terms of those chromosome 1 aberrations, category C, first deletions of 1p: Occurring in about 13% to 15% of newly diagnosed disease, deletion 1p eliminates critical cell checkpoints and normal apoptotic signaling. In the IFM and CoMMpass dataset analyses, biallelic deletion of 1p and monoallelic deletion of 1p co-occurring with additional copies of 1q denote high-risk. In terms of the other aberration in chromosome 1 possible in myeloma, gain or amplification of 1q: This occurs in up to 35% to 37% of newly diagnosed disease. It upregulates CKS1B, which is a cyclin-dependent kinase, and ANP32E, a histone acetyltransferase inhibitor. GEM and IFM data suggest that gain or amplification of 1q - there was no clear survival detriment to amplification - is best considered as a high-risk feature only in combination with the other risk factors as above. Now, in terms of any other criteria for high-risk disease, there remains one other item, and that has to do with tumor burden. There has been a consensus shift, really, in both the IMS and IMWG to attempt to develop a definition of high-risk disease which is based on biologic features rather than empirically observed and potentially temporally dynamic features, such as lactate dehydrogenase. Beta-2 microglobulin remains an independent high-risk indicator, but care must be taken when measuring it, as renal dysfunction can artificially inflate peripheral titers. The consensus conclusion was that a beta-2 microglobulin of at least 5.5 without renal failure should be considered high-risk but should not preclude detailed genomic profiling. So, in conclusion, the novel 2025 IMS-IMWG risk stratification system for myeloma is binary. It's either high-risk disease or standard-risk disease. It's got four criteria. Number one, deletion 17p and/or a TP53 mutation. Clonal cell fraction cut-off, remember, is 20%. Or number two, an IGH translocation - t(4;14), t(14;16), t(14;20) - with 1q gain and/or deletion of 1p. Or a monoallelic deletion of 1p with 1q additional copies or a biallelic deletion of 1p. Or a beta-2 microglobulin of at least 5.5 only when the creatinine is normal. This is a field-defining work that draws on analyses from across the world to put forward a dominant definition of high-risk disease and introduces a new era of biologically informed risk assessment in myeloma. Now, how does this change our clinical approach? FISH must be performed on CD138-enriched samples and should be performed for all patients. Next-generation sequencing should also be performed on all patients. Trials will hopefully now begin to include this novel definition of high-risk multiple myeloma. It does remain to be seen how data from novel therapeutic trials, if stratified according to this novel definition, will be interpreted. Will we find that therapies being evaluated at present have differential effects on myelomas with different genetic lesions? Other unanswered questions also exist. How do we go about integrating this into academic and then community clinical practice? How do we devise public health interventions for low-resource settings? To discuss this piece further, we welcome the esteemed Dr. Nikhil Munshi to the podcast. Dr. Munshi is a world-renowned leader in multiple myeloma and the corresponding author on this paper. As Professor of Medicine at Harvard Medical School, Director of the Multiple Myeloma Effector Cell Therapy Unit, and Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute, he has presided over critical discoveries in the field.  Thank you for joining us, Dr. Munshi. Dr. Nikhil Munshi: Oh, it's my pleasure being here, Michael, to discuss this interesting and important publication. Michael Hughes: I had a few questions for you. So number one, this is a comprehensive, shall we say, monumental and wide-ranging definition for high-risk myeloma. How do you hope this will influence or impact the ways we discuss myeloma with patients in the exam room? And how do we make some of these components recommended, in particular next-generation sequencing, feasible in lower-resource settings? Dr. Nikhil Munshi: So those are two very important questions. Let's start with the first: How do we utilize this in our day-to-day patient care setting? So, as you know well, we have always tried to identify those patients who do not do so well with the current existing treatment. And for the last 30 years, what constitutes a myeloma of higher risk has continued to change with improvement in our treatment. The current definition basically centers around a quarter of the patients whose PFS is less than 2 to 3 years. And those would require some more involved therapeutic management. So that was a starting point of defining patients and the features. As we developed this consensus amongst ourselves - and it's titled as “International Myeloma Society, International Myeloma Working Group Consensus Recommendation” - this IMS-IMWG type of recommendation we have done for many years, improvising in various areas of myeloma care. Now, here, we looked at the data that was existing all across the globe, utilizing newer treatment and trying to identify that with these four-drug regimens, with transplant and some of the immunotherapy, which group of patients do not do as well. And this is where this current algorithm comes up. So before I answer your question straight, “How do we use it?” I might like to just suggest, “What are those features that we have identified?” There are four features which constitute high-risk disease in the newer definition. Those with deletion 17p with 20% clonality and/or TP53 mutation. Number two, patients with one of the translocations - t(4;14), t(14;16), or t(14;20) - co-occurring with 1q amplification or deletion 1p32. And that's a change. Previously, just the translocation was considered high-risk. Now we need a co-occurrence for it to be called high-risk. The third group is patients having biallelic deletion 1p32 or monoallelic deletion 1p32 along with 1q amplification. And finally, patients with high beta-2 microglobulin, more than or equal to 5.5 mg/dL, with normal creatinine less than 1.2 mg/dL. And the question, “How do we use this?” There are multiple areas where we incorporate high-risk features in our treatment algorithm. One of the first areas is where we would consider the induction regimen. If a patient has a high-risk disease, we would definitely consider a four-drug regimen rather than a three-drug regimen, although we are beginning to incorporate four-drug for all groups. That's one important thing. Number two, those are the patients where we do consider consolidation with transplant or maybe in the new world, considering some of the immunotherapeutic consolidation more early or more aggressively. Number three, these are the patients who get a little bit more maintenance therapy. So normally, lenalidomide might end up being our standard maintenance regimen. In patients who have high-risk disease, we incorporate either addition of daratumumab or the anti-CD38 targeting antibody and/or addition of proteasome inhibitor, either bortezomib or carfilzomib. So you would have multi-drug maintenance therapy in these patients. And in high-risk patients, we follow them with maintenance longer periods of time. One very critically important point to keep in mind is that to get the better outcome in high-risk disease, we must try to get them into MRD negativity because there is clear data that patients who do achieve MRD negativity, despite having high-risk disease, have a much superior outcome. They become near to standard-risk disease. And so, in high-risk patients, I would try to do whatever various options I have to try and get them into MRD-negative status. And when these patients relapse, we do not wait for the classic progression criteria to be met before we intervene. We would propose and suggest that we intervene earlier before the disease really blasts off. And so there are a number of areas in our setting where this high-risk definition will help us intervene appropriately and also with appropriate aggressiveness to achieve better outcome, to make this similar to standard-risk disease. Michael Hughes: Thank you, Dr. Munshi. And thoughts on how to really integrate this not only into academic centers but also lower-resource settings? Dr. Nikhil Munshi: So that's a very important question, Michael. And when we were developing this consensus, we were very cognizant of that fact. So wherever available, I think we are recommending that over a period of next 2, 3, 5 years, we should begin to switch over to sequencing-based methods because two components of this definition, one is TP53 mutation, which we cannot do without sequencing, and also reliably detecting deletion 1p requires sequencing-based method. So in the low-resource countries - and there are many in this world, and also even in our own country, patients may not be able to afford it - the older method with FISH or similar such technology, which is more affordable, is also acceptable for current time. They may miss a very small number of patients, maybe 2% to 3%, where these finer changes are not picked up, but a majority of this would be captured by them. So the current practice might still be applicable with some limitation in those patient populations, and that's what we would recommend. What is happening, fortunately, is that actually sequencing-based method is becoming cheaper. And in many centers, it is cheaper to do the sequencing rather than to do the FISH analysis. And so my hope is that even in low-resource centers, sequencing might be more economical in the end. It's, I think, the access to technology, which is a little bit limited currently, but it's hopefully becoming available soon. Michael Hughes: Thank you, Dr. Munshi. And staying for a minute and looking at the multiple myeloma subsets which might be missed by this really still very broad-ranging high-risk definition, at least by prior risk stratification systems, right, there is this group of patients who have standard-risk cytogenetics by R-ISS or R2-ISS, but they have primary refractory disease or they relapse early. We call these, as you are well aware, functionally high-risk disease. What proportion of previously FHR, functionally high-risk, myeloma patients do you expect to be captured by this novel definition? Dr. Nikhil Munshi: So I think the newer definition - and we can look at it both ways, but the newer definition should capture most of the functionally high-risk definition. To put it differently, Michael, there are patients who we know are, as you mentioned, functionally high-risk. Those are the patients who might have plasma cell leukemia, those who might have extramedullary disease, those who might not respond to our four-drug induction. If you don't respond to the four-drug induction, almost by definition, they are high-risk. However, a majority of them have one of the abnormalities that we are describing here. There would be a very small proportion which may not have. And if they do not have, we know one of the important components of this definition here is also that the genome, we know, keeps on evolving. So there may be a very small clone with the high-risk feature which was not obvious in the beginning. Following treatments or following relapse, that clone predominates, and now the patient's disease becomes high-risk.  So the definition would incorporate or would capture these functional high-risk patients, but as you said, in countries where resources are not available, using this functional high-risk would also be helpful and advantageous. Sometimes LDH ends up being a high-risk. In our studies, LDH has not come out to be high-risk anymore because the features we are describing captures most of those patients, but those alternatives, older, can still be considered if other newer techniques are not available. Michael Hughes: Got you. And in terms of these older definitions, yes, that incorporate tumor burden, these empirical observations about how myeloma presents, do you foresee any additional tumor burden indicators being added to future definitions of high-risk disease? Or do you instead see this particular definition as a major waypoint on the journey towards a fully biologically grounded definition of high-risk disease? Dr. Nikhil Munshi: I think your second part is what is going to happen. I think the tumor burden-related definition is being now replaced by the biological or genomic-based definition. And I think at some point, it will be quite fully replaced. One component not here, and it is because one thing, we don't have enough data; number two, we don't know how it will pan out, is also the influence of the microenvironment on the risk definition. For example, the immune system, the immune function, etc. But not enough data exists to suggest how it would change the current definition. So in future, would a definition be totally genomic or it could be more integrative? And my personal guess is that it would be more integrative and that some immune features might come into the picture, especially now that we are using immune-based therapy as a very important component of treatment - CAR T-cells, bispecific, and antibody-based treatments. What role the immune system plays in either supporting tumor or what role suppression of the anti-tumor immunity plays? They all will be important how patient outcomes end up being, and which in turn could translate into how patient's risk stratification might happen. So I think the older tumor burden-related definitions probably will become things of the past. What we have currently proposed and consensus developed is the new path forward, and over time, some microenvironmental influences, if defined and found to be important, may get some more incorporation if it compares favorably with the genomic features. Michael Hughes: Thank you, Dr. Munshi for that enlightening response.  To conclude the podcast, I'd like to look to the future and to the immediate future, what are the next steps for high-risk disease definition between now and discussing an integrated genomic-microenvironment-based definition? Will we see attempts to refine? Will we see a multi-level system, things like this? Dr. Nikhil Munshi: Yeah, so I think the current definition will be here to stay for the next 10 years or so. I think this has been developed using a large amount of data, so we do believe that this will remain fine. It has been validated now within the last six months by a few of the other studies. So there won't be a quick change. But we will try to, all of us will try to innovate. And as you very rightly bring up, the areas of research would include looking at the expression or transcriptomic component. Does that matter? And we do believe a small number of patients will have transcriptomic changes, not looked at the DNA changes, and may play a role. There are newer components, so long non-coding RNA, for example, is going to be an important component to look at, how it impacts the disease outcome, etc. There are also some of the proteomic-related changes which may become important in our studies. And then as we discussed, microenvironment and immunological changes. So these are the future areas of ongoing research where we all should collect data, and then in the next 5 to 10 years, we'll have another group meeting to see has anything changed or any of the features have become more important.  Most of the time, some of the older features are lost because they are not as critically high-risk, and the newer features come in. And so the historical background for just one second, there was a time when chromosome 13 was considered a high-risk disease. We now don't even mention it because it's not high-risk. The newer treatments have improved the outcome. t(4;14) used to be a high-risk disease. Now by itself today, in this definition by itself is not; it needs to be with something else. And so I think this is a great sign of progress. As we improve the treatment and outcomes, some of the features will become less important, new features will come up, and we'll need to keep on evolving with time and with technology and make it better for patients. Michael Hughes: Thank you so much, Dr. Munshi, for your wisdom, for your sagacity, for your historical perspective as well.  Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries. And be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit 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.  

In this episode, we are talking with Julia Moore, Communications Specialist at Bosman Family Vineyards, a South African winery at the forefront of ethical wine production and regenerative farming. With a 26% worker-ownership model, award-winning viticulture, and deep investment in education and inclusion, Bosman is redefining what sustainability in wine truly means. We explore the impact of shared ownership, the challenges and beauty of farming as a community, and the power of giving future generations opportunities beyond the vineyard. From vine nurseries to old vine Chenin Blanc, this conversation is rich in knowledge and purpose. Two wines are tasted during the episode: the affordable Generation 8 Chardonnay, supporting early childhood education projects, and the prestigious Optenhorst Chenin Blanc, sourced from the third-oldest Chenin vines in South Africa. Whether you're interested in equitable business models, viticulture innovation, or wines with purpose, this episode delivers inspiration in every sip. Episode Guide (Chapters) [02:30] - How Julia approaches wine storytelling as a communicator [04:47] - How the land shapes the vines [07:51] - The role of climate and vine age [09:30] - Ethical working and community impact [11:35] - Shared ownership: transforming life on the farm [14:25] - Vision for youth and long-term opportunity [17:32] - How many people live on the farm as a community [18:57] - Tasting Generation 8 Chardonnay — a fresh, unoaked white wine with expressive fruit and minerality. Available at Sainsbury's £9 (UK). [21:20] - How its sales support Bosman's education projects [26:19] - What happens in the vine nursery during winter [30:46] - Clonal selection and rootstock combinations [33:23] - Bosman named Winery of the Year in the Platter's Wine Guide [36:08] - Tasting Optenhorst Chenin Blanc 2023 — from 72-year-old dry-farmed bush vines. Around £25-30 per bottle. [38:59] - The story and power of old vines [41:06] - Pricing and exclusivity of Optenhorst; why it's a rare and age-worthy wine [49:01] - What the wine industry must do for equity and representation [51:46] - Bosman Family Vineyards and more information

In this episode of Hema Now, host Jonathan Sackier is joined by Paolo Gallipoli, Clinical Reader at the Centre for Haemato-Oncology at Barts Cancer Institute, to break down the biology, onset, and treatment of myeloid leukaemias. They detail common misconceptions about myeloid leukaemias, explain the differences between chronic myeloid leukaemia and acute myeloid leukaemia, and discuss Gallipoli's own research in the field, with a view towards future developments.  Timestamps  01:34 – Quickfire questions  06:55 – Potential careers  08:43 – Common misconceptions  11:34 – Best advice received  13:43 – Adaptive metabolic changes  16:45 – Chronic myeloid leukaemia vs acute myeloid leukaemia  19:20 – Recent publication  22:55 – Clonal hematopoiesis    27:13 – Treatment obstacles  29:18 – Future developments  31:01 – Gallipoli's three wishes 

In this week's episode we'll learn more about the ASCEND study, which investigated first-line asciminib in chronic phase chronic myeloid leukemia; a new risk score for myeloid neoplasm transformation in patients with clonal cytopenia of undetermined significance; and use of RHD genotyped D-positive blood transfusions in patients with sickle cell and unexpected anti-D antibodies.Featured ArticlesAsciminib Monotherapy as Frontline Treatment of Chronic Phase Chronic Myeloid Leukaemia - Results from the ASCEND StudyRisk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence Genotyped RhD+ red cells for D-positive patients with sickle cell disease with conventional RHD and unexpected anti-D 

In this week's episode we'll discuss the safety and efficacy of acalabrutinib, venetoclax and obinutuzumab in relapsed/refractory CLL; learn more about alternative donor transplantation for severe aplastic anemia and discuss clonal relapse dynamics in acute myeloid leukemia following allogeneic hematopoietic cell transplantation.Featured Articles: Acalabrutinib, venetoclax and obinutuzumab in relapsed/refractory CLL: Final efficacy and ctDNA analysis of the CLL2-BAAG trial Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT Clonal relapse dynamics in acute myeloid leukemia following allogeneic hematopoietic cell transplantation 

Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of unknown significance (CCUS) are considered precursor diseases to hematologic malignancies,... The post CHIP & CCUS: knowledge gaps, ongoing trials & recommendations for approaching patients with myeloid precursors appeared first on VJHemOnc.

In this week's episode we'll learn more about rare relapse-initiating stem cells in patients with MDS or AML in complete remission post-transplantation, discuss the role of interferon α in erythropoiesis in sickle cell disease, and learn more about how TNFα promotes clonal dominance of KIT D816V+ cells in mastocytosis.

BUFFALO, NY- January 10, 2024 – A new #editorial paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 24, entitled, “Exploring clonal hematopoiesis and its impact on aging, cancer, and patient care.” In this new editorial, researchers Julieta Elena Rodriguez, Jean Baptiste Micol and Capucine Baldini from Gustave Roussy discuss clonal hematopoiesis. Clonal hematopoiesis (CH) is a term that refers to the presence in blood cells of hematologic malignancy-associated somatic mutations without fulfilling the diagnostic criteria of hematologic disease. Emerging evidence suggests that CH is a consequence of an expansion of cells harboring initiating driver mutations, potentially linked to the aging hematopoietic system. While these detectable somatic mutations are rare in individuals under 40 years old, they become increasingly prevalent in the elderly population, a term called age-related clonal hematopoiesis (ARCH), reaching up to 18.4% in those aged 90 years or older. Aging itself is a significant stressor associated with CH, particularly in individuals over 70 years old. DNMT3A, TET2, and ASXL1 mutations are more common with advancing age. “Recent evidence also indicates that CH may play a role in solid tumors, such as an increased risk of incident lung cancer [4]. While initial studies associated CH mutations with worse survival outcomes [5], newer findings suggest that solid tumor patients with CH may experience longer survival [6]. However, the underlying mechanisms behind this relationship remain to be elucidated.” DOI - https://doi.org/10.18632/aging.205404 Corresponding author - Capucine Baldini - capucine.baldini@gustaveroussy.fr Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205404 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, clonal hematopoiesis, solid tumors About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Join us for our first episode of 2024 as we welcome Dr. Alex Bick, Assistant Professor of Medicine in the Division of Genetic Medicine at Vanderbilt University. In this episode, we will explore the impact of clonal hematopoiesis on cancer and cardiovascular health, examine the integration of genomics in healthcare and preventative medicine, and discuss a recent finding from the Million Veterans Program of a modifier variant in APOL1 kidney disease.

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Siddhartha Jaiswal, M.D., Ph.D., discusses clonal hematopoiesis and its impact on aging and diseases. Jaiswal highlights the role of genetic variations, focusing on a specific gene, TET2, and its link to clonal expansion. He explains that certain genetic variations can slow clonal expansion, potentially offering insights into treatments or interventions to mitigate its effects. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39260]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

Leonard Zon, M.D., discusses cutting-edge research on the intricate relationship between macrophages, stem cells, and the development of leukemia using the zebrafish model. He delves into the fascinating interactions between these cell types, highlighting the role of a "don't eat me" signal and the influence of the leukemic niche. Through cellular barcoding and single-cell RNA sequencing, he unveils a potential therapeutic target which may offer promising insights into treating leukemia by disrupting the stromal activities that support it. Zon showcases the power of zebrafish models in advancing our understanding of hematopoiesis and cancer, promising new avenues for research and treatment. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39064]

The 5th International Workshop on Acute Leukemias (iwAL 2023) took place in San Diego, CA, and brought together leading experts... The post iwAL 2023 Session I: Clonal hematopoiesis in AML, early detection and potential therapeutics appeared first on VJHemOnc.

In this week's episode, we'll learn more about poverty and relapse risk in children with ALL, discuss eligibility criteria and enrollment of diverse racial and ethnic populations in multiple myeloma clinical trials, and learn more about clonal hematopoiesis in VEXAS syndrome.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.13.548931v1?rss=1 Authors: Hobson, R., Levy, S. H. S., Flaherty, D., Xiao, H., Ciener, B., Reddy, H., Singal, C., Teich, A. F., Shneider, N. A., Bradshaw, E. M., Elyaman, W. Abstract: Recent murine studies have highlighted a crucial role for the meninges in surveilling the central nervous system (CNS) and influencing CNS inflammation. However, how meningeal immunity is altered in human neurodegeneration and its potential effects on neuroinflammation is understudied. In the present study, we performed single-cell analysis of the transcriptomes and T cell receptor repertoire of 72,576 immune cells from 36 postmortem human brain and leptomeninges tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimers disease, and Parkinsons disease. We identified the meninges as an important site of antigen presentation and CD8 T cell activation and clonal expansion and found that T cell activation in the meninges is a requirement for infiltration into the CNS. We further found that natural killer cells have the potential to negatively regulate T cell activation locally in the meninges through direct killing and are one of many regulatory mechanisms that work to control excessive neuroinflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Michael Diaz (@mdiazoncmd) and Dr. Namrata Chandhok (@NamrataChandhok) discuss the importance of genomic testing and how to understand and interpret test results when treating patients with myelodysplastic syndromes and clonal hematopoiesis. They also discuss the importance of selecting appropriate therapeutic agents to manage hematologic malignancies. This project is a collaboration between the American Society of Hematology, the Leukemia & Lymphoma Society, and the France Foundation. Access and complete the GENOM modules (for which you can claim CME and MOC credit) via ASH Academy On Demand! Music: "Happy Medium" performed by Zac Nelson, used under license from Shutterstock.

Commentary by Dr. Valentin Fuster

In this week's episode we'll discuss how azacytidine therapy influences the contributions of mutated HSC clones to hematopoiesis in MDS and CMML, learn more about the risk of venous thromboembolism in patients with adult-type diffuse glioma, and discuss the importance of 1p32 deletions as an independent and adverse prognostic factor in myeloma.

In this week's episode we'll discuss the benefits of early diagnosis and hematopoietic stem cell transplant in patients with hypomorphic RAG deficiency, learn more about EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy, and analyze the associations between clonal hematopoiesis and recurrent vascular events and death in patients with ischemic stroke. 

Dr. Jeremy Meier and Dr. Samuel Rubinstein of the University of North Carolina (UNC) Chapel Hill are the first and senior author, respectively, of a recently published review paper entitled Game of Clones: Diverse Implications for Clonal Hematopoiesis in Lymphoma and Multiple Myeloma. In this interview for Blood Cancer Awareness Month, Oncology Data Advisor's Editorial Board member Dr. Rahul Banerjee speaks with Dr. Meier and Dr. Rubinstein about their work in this area and the future of clonal hematopoiesis research in hematologic malignancies.

Commentary by Dr. Valentin Fuster

The relationship between mutations and precursor states in myelodysplastic syndromes (MDS) is a growing area of research, and advances in... The post Clonal hematopoiesis and pre-MDS states appeared first on VJHemOnc.

The relationship between mutations and precursor states in myelodysplastic syndromes (MDS) is a growing area of research, and advances in... The post Clonal hematopoiesis and pre-MDS states appeared first on VJHemOnc.

To download the transcript CLICK HERE PLEASE vote for me at The Peoples Choice Podcast Awards. Voting is open ONLY FOR JULY 2022. I am in the ‘ARTS' Category. CLICK HERE TO VOTE and thank you so much!! This is part 2 of my viticulture series. If you haven't heard part 1, go back to episode 98. However, if you are ready for part two, we are going be looking at rootstocks and clonal selections, then a little bit on vineyard design, how you choose your trellising for the vines. And in fact, training that vine, once you've done that. A small section on preparing your soils and then what you can do during the year, such as green harvesting and leaf stripping. You can choose to plant cover crops, put in an irrigation system, and you will most likely have to deal with pests and funguses, so this is discussed at the end giving a run down of what agrochemical farming is down to organics and then biodynamics.  If you want to skip ahead: 3.50: Rootstocks 8.17: Clonal selection 13.36: Vineyard design 15.33: Trellising choices 19.58: Training of the vine 22.53: Preparing of the soils 25.17: Weeds and cover crops 27.11: Irrigation 29.20: Leaf stripping and green harvesting 30.37: Pests and diseases 32.20: Prevention techniques and organic or biodynamic viticulture Fancy watching some videos on my youtube channel: Eat Sleep Wine Repeat Or come say hi at www.eatsleepwinerepeat.co.uk Or contact me on Instagram @eatsleep_winerepeat or on email: janina@eatsleepwinerepeat.co.uk Until next time, Cheers to you  

In this episode, we bring two experts in clonal hematopoiesis, Dr. Sid Jaiswal from Stanford University and Dr. Alex Bick from Vanderbilt University to dissect the biology, potential clinical implications, and future of clonal hematopoiesis.

This month on Episode 36 of Discover CircRes, host Cynthia St. Hilaire highlights original research articles featured in the April 29 and May 13 issues of Circulation Research. This episode also features a conversation with Dr Patricia Nguyen and Jessica D'Addabbo from Stanford University about their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self.   Article highlights:   Zanoli, et al. COVID-19 and Vascular Aging   Wang, et al. JP2NT Gene Therapy in a Mouse Heart Failure Mode   Harraz, et al. Piezo1 Is a Mechanosensor in CNS Capillaries   Zhao, et al. BAT sEVs in Exercise Cardioprotection   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cyndy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. And today, I'll be highlighting the articles from our April 29th and May 13th issues of Circulation Research. I also will speak with Dr Patricia Nguyen and Jessica D'Addabbo from Stanford University about their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self.   Cindy St. Hilaire:        The first article I want to share is titled Vascular Dysfunction of COVID 19 Is Partially Reverted in the Long-Term. The first author is Agostino Gaudio and the corresponding author is Luca Zanoli. And they're from the University of Catania. Cardiovascular complications, such as endothelial dysfunction, arterial stiffness, thrombosis and heart disease are common in COVID 19. But how quickly such issues resolve, once the acute phase of the illness has passed, remains unclear. To find out, this group examined aortic and brachial pulse wave velocity, and other measures of arterial stiffness in 90 people who, several months earlier, had been hospitalized with COVID 19. These measurements were compared with data from 180 controls, matched for age, sex, ethnicity and body mass index, whose arterial stiffness had been assessed prior to the pandemic. 41 of the COVID patients were also examined 27 weeks later to assess any changes in arterial stiffness over time. Together, the data showed arterial stiffness was higher in COVID patients than in controls. And though it improved over time, it tended to remain higher than normal for almost a year after COVID.   Cindy St. Hilaire:        This finding could suggest residual structural damage to the arterial walls or possibly, persistent low-grade inflammation in COVID patients. Either way, since arterial stiffness is a predictor of cardiovascular health, its potential longterm effects in COVID patients deserves further longitudinal studies.   Cindy St. Hilaire:        The second article I want to share is titled Gene Therapy with the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice. The first author is Jinxi Wang and the corresponding author is Long-Sheng Song from the University of Iowa. Junctophilin-2 is a protein with a split personality. Normally, it forms part of the heart's excitation contraction coupling machinery. But when the heart is stressed, JP2 literally splits in two, and sends its N-terminal domain, JP2NT, to the nucleus, where it suppresses transcription of genes involved in fibrosis, hypertrophy, inflammation and other heart failure related processes. However, if this stress is severe or sustained, the protective action of JP2NT is insufficient to halt the progressive failure. This group asked. "What if this N-terminal domain could be ramped up using gene therapy to aid a failing mouse heart?"   Cindy St. Hilaire:        To answer this question, they injected adenoviral vectors encoding JP2NT into mice either before or soon after transaortic constriction, or TAC, tack, which is a method of experimentally inducing heart failure. They found, in both cases, that the injected animals fared better than the controls. Animals injected before TAC showed less severe cardiac remodeling than control mice, while those treated soon after TAC exhibited slower loss of heart function with reduced ventricle dilation and fibrosis. These data suggest that supplementing JP2NT, via gene therapy or other means, could be a promising strategy for treating heart failure. And this data provides a basis for future translational studies.   Cindy St. Hilaire:        The third article I want to share is titled Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries. The first and corresponding author is Osama Harraz from the University of Vermont. Neurovascular coupling is the process whereby transient activation of neurons leads to an upsurge in local blood flow to accommodate the increased metabolic needs of the cell. It's known that agents released from active neurons trigger changes in local capillaries that prompt vasodilation, but how these hemodynamic changes are sensed and controlled is not entirely clear. This group suspected that the mechanosensory protein Piezo1, a calcium channel that regulates dilation and constriction of other blood vessels, may be involved. But whether Piezo1 is even found in the microcirculation of the CNS was unknown. This group shows that Piezo1 is present in cortical capillaries of the brain and the retina of the mouse, and that it responds to changes in blood pressure and flow.   Cindy St. Hilaire:        Ex vivo preparations of mouse retina showed that experimentally induced changes in hemodynamics caused calcium transients and related currents within capillary endothelial cells, and that these were dependent on the presence of Piezo1. While it is not entirely clear how Piezo1 influences cerebral blood flow, its pressure induced activation of CNS capillary endothelial cells suggest a critical role in neurovascular coupling.   Cindy St. Hilaire:        The last article I want to share is titled Small Extracellular Vesicles from Brown Adipose Tissue Mediate Exercise Cardioprotection. The first authors are Hang Zhao and Xiyao Chen. And the corresponding authors are Fuyang Zhang and Ling Tao from the Fourth Military Medical University. Regular aerobic exercise is good for the heart and it increases the body's proportion of brown adipose tissue relative to white adipose tissue. This link has led to the idea that brown fat, possibly via its endocrinal activity, might somehow contribute to exercise related cardioprotection. Zhao and colleagues now show that, indeed, brown fat produces extracellular vesicles that are key to preserving heart health. While mice subjected to four weeks of aerobic exercise were better protected against subsequent heart injury than their sedentary counterparts, blocking the production of EVs prior to exercise significantly impaired this protection. Furthermore, injection of brown fat derived EVs into the hearts of mice lessened the impact of subsequent cardiac injury.   Cindy St. Hilaire:        The team went on to identify micro RNAs within the vesicles responsible for this protection, showing that the micro RNAs suppressed an apoptosis pathway in cardiomyocytes. In identifying mechanisms and molecules involved in exercise related cardio protection, the work will inform the development of exercise mimicking treatments for people at risk of heart disease or who are intolerant to exercise.   Cindy St. Hilaire:        Lastly, I want to bring up that the April 29th issue of Circulation Research also contains a short Review Series on pulmonary hypertension, with articles on: The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure, by Olivier Boucherat; Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension, by Christopher Rhodes and colleagues; New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis, by Christophe Guignabert and colleagues; Group 3 Pulmonary Hypertension From Bench to Bedside, by Corey Ventetuolo and colleagues; and Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart, by Sudarshan Rajagopal and colleagues; and Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease, by Jessica Huston and colleagues.   Cindy St. Hilaire:        Today, Dr Patricia Nguyen and Jessica D'Addabbo, from Sanford University, are with me to discuss their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self. And this article is in our May 13th issue of Circulation Research. So, Trisha and Jessica, thank you so much for joining me today.   Jessica D'Addabbo:    Thank you for having us.   Patricia Nguyen:         Yes. Thank you for inviting us to your podcast. We're very excited to be here.   Cindy St. Hilaire:        Yeah. And I know there's lots of authors involved in this study, so unfortunately we can't have everyone join us, but I appreciate you all taking the time.   Patricia Nguyen:         This is like a humongous effort by many people in the group, including Roshni Roy Chowdhury, and Xianxi Huang, as well as Charles Chan and Mark Davis. So, we thank you.   Cindy St. Hilaire:        So atherosclerosis, it stems from lipid deposition in the vascular wall. And that lipid deposition causes a whole bunch of things to happen that lead to a chronic inflammatory state. And there's many cells that can be inflammatory. And this study, your study, is really focusing on the role of T-cells in the atherosclerotic plaque. So, before we get into the nitty gritty details of your study, can you share with us, what is it that a T-cell does normally and what is it doing in a plaque? Or rather, let me rephrase that as, what did we know a T-cell was doing in a plaque before your study?   Patricia Nguyen:         So, T-cells, as you know, are members of the adaptive immune system. They are the master regulators of the entire immune system, secreting cytokines and other proteins to attract immune cells to a diseased portion of the body, for example. T-cells have been characterized in plaque previously, mainly with immunohisto chemistry. And their characterization has also been recently performed using single cell technologies. Those studies have been restricted to mainly mirroring studies, studies in mice in their aortic walls, in addition to human carotid arteries. So, it is well known that T cells are found in plaque and a lot of attention has been given to the macrophage subset as the innate immune D. But let's not forget the T-cell because they're actually composed about... 50% in the plaque are T-cells.   Patricia Nguyen:         And we were particularly interested in the T-cell population because we have a strong collaboration with Dr Mark Davis, who's actually the pioneer of T-cell biology and was the first to describe the T-cell receptor alpha beta receptor in his lab in the 1970s. So, he has developed many techniques to interrogate T-cell biology. And our collaboration with him has allowed us and enabled us to perform many of these single cell technologies. In addition, his colleague, Dr Chen, also was pivotal in helping us with the interrogation and understanding of the T-cells in plaque.   Cindy St. Hilaire:        And I think one of the really neat strengths of your study is that you used human coronary artery plaques. So, could you walk us through? What was that like? I collect a lot of human tissue in my lab. I get a lot of aortic valves from the clinic. And it's a lot of logistics. And a lot of times, we're just fixing them, but you are not just fixing them. So, can you walk us through? What was that experimental process from the patient to the Petri dish? And also, could you tell us a little bit about your patient population that you sampled from?   Jessica D'Addabbo:    So, these were coronary arteries that we got from patients receiving a heart transplant. So, they were getting a heart transplant for various reasons, and we would receive their old heart, and someone would help us dissect out the coronary arteries from these. And then, we would process each of these coronary arteries separately. And this happened at whatever hour the hearts came out of the patient.   Jessica D'Addabbo:    So sometime, I was coming in at 3:00 AM with Dr Nguyen and we would be working on these hearts then, because we wanted the samples to be as fresh as possible. So, we would get the arteries. We would digest out the tissue. And then, we would have certain staining profiles that we wanted to look at so that we could put the cells on fax to be able to sort the cells, and then do all the downstream sequencing from there.   Cindy St. Hilaire:        So, in terms of, I don't know, the time when you get that phone call that a heart's coming in to actually getting those single cells that you can either send a fax or send a sequencing, how long did that take, on a good day? Let's talk only about good days.   Jessica D'Addabbo:    Yeah. A lot of factors went into that, sometimes depending on availability of things. But usually, we were ready with all of the materials in advance. So, I'd say it could be anywhere from six to 12 hours, it would take, to get everything sorted. Then, everything after that would happen. But that was just that critical period of making sure we got the cells fresh.   Patricia Nguyen:         So we have to credit the CT surgeons at Stanford for setting up the program or the structure, infrastructure, that enables us to obtain this precious tissue. That is Jack Boyd and Joseph Woo of CT surgery. So, they have enabled human research on hearts by making these tissues available. Because as you know, a transplant... They can say the transplant's happening at 12:00 AM, but it actually doesn't happen until 4:00 AM. And I think it's very difficult for a lab to make that happen all the time. And I think having their support in this paper was critical. And this has allowed us, enabled us, to interrogate kind of the spectrum of disease, especially focusing on T-cells, which are... They make a portion of the plaque, but the plaque itself has not like a million cells that are immune. A lot of them are not immune. So, enabling us to get the tissue in a timely fashion where they're not out of the body for more than 30 minutes enables us to interrogate these small populations of cells.   Cindy St. Hilaire:        That's actually the perfect segue to my next question, which is, how many cells in a plaque were you able to investigate with the single cell analysis? And what was the percentage again of the T-cells in those plaques or in... I guess you looked at different phases of plaque. So, what was that spectrum for the percentage of T-cells?   Patricia Nguyen:         So, for 10X, for example, you need a minimum of 10,000 captured cells. You could do less, but the utility of the 10X is maximized with 10,000. So, many times before the ability to multiplex these tissues, we were doing like capturing 5,000 for example. And the number of cells follows kind of the disease progression, in the sense that as a disease is more severe, you have more immune cells, in general. And it kind of decreases as it becomes more fibrotic and scarred, like calcified. So, it was a bit challenging to get very early just lipid-only cells. And a lot of those, we captured like 3000 or something like that. And efficiency is like 80% perhaps. So, you kind of capture…   Cindy St. Hilaire:        And also, how many excised hearts are going to have early athero? So, it's...   Patricia Nguyen:         Well, there are... nonischemics will have...   Cindy St. Hilaire:        Oh, okay. Okay.   Patricia Nguyen:         So, the range was nonischemic to ischemic.   Cindy St. Hilaire:        Oh great.   Patricia Nguyen:         So, about a portion... I would say one third of the total heart transplants were ischemic. And a lot of them were non ischemic. But as you know, the nonischemic can mix with ischemia. And so, they could have mild to moderate disease in the other arteries, for example, but not severe like 70%/90% obstruction.   Cindy St. Hilaire:        Wow. That's so great. That's amazing. Amazing sample size you have. So T-cell, it's kind of an umbrella term, right? There's many different types of T-cells. And when you start to get in the nitty gritty, they really do have distinct functions. So, what types of T-cells did you see and did you focus on in this study?   Jessica D'Addabbo:    So, the two main types of T-cells are CD4 positive T-cells and CD8 positive T-cells. And we looked at both of these T-cells from patients. We usually sorted multiple plates from each. And then, with 10X, we captured both. But our major finding was actually that the CD8 positive t-cell population was more clonally expanded than the CD4 population, which led us to believe that these cells were more important in the coronary artery disease progression and in the study that we were doing because for a cell to be clonally expanded, it means it was previously exposed to an antigen. And so, if we're finding these T-cells that are clonally expanded in our plaques, then we're hypothesizing that they were likely exposed to some sort of antigen, and then expanded, and then settled into the plaque.   Cindy St. Hilaire:        And when you're saying expansion, are you talking about them being exposed to the antigen in the plaque and expanding there? Or do you think they're being triggered in the periphery and then honing in as a more clonal population?   Patricia Nguyen:         So, that's a great question. And unfortunately, I don't have the answer to that. So basically-   Jessica D'Addabbo:    Next paper, next paper.   Patricia Nguyen:         Exactly. So, we... Interesting to expand on Jessica's answer. Predominantly what was found, as you said, was memory T-cells, so memory T-cells expressing specific markers, so memory versus naive. And these were effector T-cells. And memory meaning they were previously expanded by antigen engagement, and just happened to be in the plaque for whatever reason. We do not know why T-cells specifically are attracted to the plaque, but they are obviously there. And they're in a memory state, if you will. And some of them did display activation markers, which suggested that they clonally expanded to an antigen. What that antigen is, is the topic of another paper. But certainly, it is important to understand that these patients that we recruit, because they were transplant patients, they're not actively infected, right? That is a exclusionary criteria for transplants, right?   Patricia Nguyen:         So, that means these T-cells were there for unclear reasons. Why they're there is unclear. Whether they are your resident T-cells also is unclear, because the definition of resident T-cell still remains controversial. And you actually have to do lineage tracking studies to find out, "Okay, where... Did they come from the bone marrow? Did they come from the periphery? How did they get there?" Versus, "Okay. They were already there and they just expanded, for whatever reason, inside the plaque."   Cindy St. Hilaire:        So, your title... It was a great title, with this provocative statement, "T-cells are clonal and cross react to virus and self." So, tell us a little bit more about this react to virus and self bit. What did your data show?   Jessica D'Addabbo:    So, because of the way we sequenced the T-cell receptor, we were able to have paired alpha and beta chains. And because we knew the HLA type of the patients, we were able to put the sequences that we got out after we sequenced these through an algorithm called GLIPH, which allows us to look at the CDR3 region of the T cell receptor, which is the epitope binding region. And there are certain peptide. They're about anywhere from three to four amino acids long. These are mapped to certain binding specificities to known peptides. And so, basically, we were able to look at which epitopes were most common in our plaques. And we found that after comparing these to other epitopes, that these were actually more binding to virus. Patricia Nguyen:         So let me add to what Jessica stated, and kind of emphasize the value of the data set, if you will. So, this is, I believe, the first study that provides the complete TCR repertoire of coronary plaque, and actually any plaque that I know of, which is special because we know that there is specificity of TCR binding. It's more complicated than the antibody that binds directly from B cells to the antigen, because the T-cells bind processed antigen. So, the antigens are processed by antigen presenting cells like Dendritic cells and macrophages. And they have a specific HLA MHC class that they need to present to. And they need both arms, the antigen epitope and the MHC, to activate the T-cell. So unfortunately, it's not very direct to find the antigen that is actually activating the T-cell because we're only given a piece of it. Right?            Patricia Nguyen:         But we have provided a comprehensive map of all the TCRs that we find in the plaque. And these TCRs have a sequence, an immuno acid sequence. And luckily, in the literature, there is a database of all TCR specificities. Okay. So, armed with our TCR repertoire, we can then match our TCR repertoire with an existing database of known TCR specificities. Surprisingly, the matching TCRs are specific to virus, like flu, EBV and CMB. And also, because this was done in the era of COVID, we thought it would be important to look at the coronavirus database. We did find that there were matches to the coronavirus database. Even though our finding is not specific to SARS, it does lend to some potential mechanistic link there as well.   So, because this is all computational, it is important to validate. So, the importance of validation requires us to put the TCR alpha beta chain into a Jurkat cell, which is a T-cell line that does not have alpha beta chains on it, and then expose it to what we think is the cognate antigen epitote, with the corresponding HLA MHC APC. Because you don't have all those pieces, it will not work. Yes. So importantly, we did find that what we predicted to have the specificity of a flu peptide had specificity to a flu peptide.   Patricia Nguyen:         So then, the important question was, "Okay, these patients aren't infected, right? Why are these things here? Is there a potential cross reactivity with self peptides?"   Patricia Nguyen:         So luckily, our collaborator, Dr Charles Chan, was able to connect us with another computational algorithm that he was familiar with, whereby we were able to take the peptide sequences from the flu and match them with peptide sequencing from proteins that are self and ubiquitous. And we demonstrated, again, these T-cells were activated in vitro. That is why we concluded that there's a potential cross reactivity between self and virus that can potentially lead to thrombosis associated with viral infections. Of course, this all needs to be proved in vivo.   Cindy St. Hilaire:        Sure, sure.   Patricia Nguyen:         It's that first step for other things.   Cindy St. Hilaire:        The other big immune cell that we know is in atherosclerotic plaques and that's macrophages. And they can help to present antigens and things like that. And they also help to chew up the necrotic bits. And so, do you think that this T-cell component is an earlier, maybe disease driving, process or an adaptive process that goes awry as a secondary event? Patricia Nguyen:         So, I'm a fan of the T-cell. So... I'm with team T cell. I would like to think that it is playing an active role in pathology in this case and not a reactive role, in the sense of just being there. I think that the T-cell is actively communicating with other cells within the plaque, and promoting pro fibrotic and pro inflammatory reactions, depending on the T-cell. So, a subset of this paper was looking at kind of the interactions between the T-cell and other cells within the plaque, like macrophages and smooth muscle cells. And as we know, T-cells are activated and they produce cytokines. Those cytokines then communicate to other cells. And we found that, computationally, when you look at the transcriptome, there is a pro-inflammatory signature of the T-cell that resides in the more complex stage. And then, there's an anti-inflammatory signature that kind of resides in the transition between lipid and fibro atheroma, if you will.   Cindy St. Hilaire:        So, do you know, or is it known, how dynamic these populations are? Obviously, the hearts that you got, the samples you got, didn't have active infections. But do you know perhaps even how long ago they happened, or even how soon after there might be an infection or an antigen presented that you could get this expansion? And could that be a real driver of rupture or thrombosis?   Patricia Nguyen:         So, in theory, you would suppose that T-cells expanding and dividing and producing more and more cytokines would then lead to more macrophages coming, more of their production of proteinases that destroy the plaque. Right? So yes, in theory, yes. I think it's very difficult to kind of map the progression of T cell clonality in the current model that we have, because we're just collecting tissues. However, in the future, as organoids become more in science and kind of a primary tissue, where we can... For example, Mark Davis is making organoids with spleen, and also introducing skin to that.   Patricia Nguyen:         And certainly, we could think of an organoid involving the vasculature with immune cells introduced. And so, I think, in the next phase, project 2.0, we can investigate what... like over time, if you could model atherosclerosis and the immune system contribution, T-cells as well as macrophages and other immune cells, you can then kind of map how it happens in humans. Because obviously, mice are different. We know that mice... Actually, the models of transgenic mice do not rupture. It's very hard to make them rupture. Right?   Cindy St. Hilaire:        Well, if you stop feeding them high fat diet, the plaque goes away.   Patricia Nguyen:         For sure, for sure. So I think.. I mean, Mark Davis is a huge proponent of human based research, like research on human tissue. And as a physician scientist, obviously I'm more inclined to do human based research. And Jessica's going to be a physician someday soon. And I'm sure she's more inclined to do human based research. And certainly, the mouse model and in vitro models are great because you can manipulate them. But ultimately, we are trying to cure human diseases.   Cindy St. Hilaire:        Mice are not little humans. That's what we say in my lab. I similarly do a lot of human based stuff and it's amazing how great mice are for certain things, but still how much is not there when we need to really fully recapitulate a disease model.   So, my last question is kind of regarding this autoimmune angle of your findings. And that is, women tend to have more autoimmune diseases than men, but due to the fact that you are getting heart transplants, you've got a whole lot more men in your study than women. I think it was like 31 men to four women. But, I mean, what can you do? It's the nature of heart transplants. But I'm wondering, did you happen to notice...Maybe the sample size perhaps is too small, but were there any differences in the populations of these cells between women and men? And do you think there could be any differences regarding this more prevalence of autoimmune like reactions in women?   Patricia Nguyen:         So, that's an interesting question, but you hit it on the nose when you said "Your sample is defined mainly by men." And in addition, the samples that were women tend to have less disease. And they tend to be nonischemic in etiology. So, I think that kind of restricts our analysis. And perhaps, I guess, future studies could model using female tissues, for example, instead of only male. But the limitation of all human studies is sample availability. And perhaps, human organoid research can be less limited by that. And certainly, mouse research has become more evenly distributed of male and female mice.   Cindy St. Hilaire:        Yeah. Suffice it to say, human research is hard, but you managed to do an amazing and really important study. It was really elegant and well done. Congratulations on what is an epic amount of time. 12-hour experiments are no joke, and really beautiful data. So, thank you so much for joining me today, Dr Nguyen and Miss almost Dr D'Addabbo. Congrats and I'm really looking forward to seeing your future work.   Jessica D'Addabbo:    Thank you so much.   Patricia Nguyen:         Thanks so much.   Jessica D'Addabbo:    Thank you for having us. This is wonderful.   Cindy St. Hilaire:        That's it for the highlights from the April 29th and May 13th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page and follow us on Twitter and Instagram with the handle @Circres and #Discover CircRes. Thank you to our guests: Dr Patricia Nguyen, and soon to be Doctor, Jessica D'Addabbo, from Stanford University.   This podcast was produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Haler. And this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, visit aha journals.org.  

The 20th installment of the podcast commemorates 20 years of Attack of the Clones with a battalion of fans and friends sharing their Episode II recollections and reflections. From online spoiler forums and Celebration II to red carpet encounters and the hunt for the elusive “digi-proj,” 2002 springs back to life like an incredibly old frog dueling an evil retired Jedi in this retrospective on a movie created at a pivotal crossroads of cinematic art and technology.

MJ's guest today is owner of Ross Knoll Vineyard, Co-founder and Board Member for SommTV, and executive producer for SOMM Films, Diane Carpenter. In 2017 Diane and her husband David of 34 years cultivated their own vineyard in Sonoma County, California and planted 3000 Calera Clone Pinot Noir vines. Two years later, Diane and her colleagues created SommTV, where Diane has been an Executive Producer on Somm: Into the Bottle and SOMM 3. Diane is also Co-Founder and Board Member of Forgotten Man Films, where they produce the ongoing SOMM series. In this episode, MJ and Diane discuss her upbringing in England, meeting her husband, and moving to America. Diane details her journey through wine, from the glass that sparked her passion to getting her hands dirty in wine country for the first time to starting SommTV. She shares how she has balanced raising a family and pursuing a career.A huge thank you to Diane Carpenter! Check out her website and join her mailing list: www.dianecarpenter.orgFollow her on IG at @yourwinestylistThis episode's in studio wine:2020 Ross Knoll Rose Cuvee Chelsea ___________________________________________________________For insider info from MJ and exclusive content from the show sign up at Blackwineguy.comFollow MJ @blackwineguy Thank you to our sponsor: Taub Family Selections. Taub Family Selections is a dynamic fourth generation, family-owned wine import company with a truly enviable portfolio of fine wines from 11 countries. They are proud to represent an exceptional portfolio of high quality, terroir centric and historic producers from around the world, including Italy and France - where they have an exciting roster of burgeoning vignerons from Burgundy coming your way soon. Learn more at www.taubfamilyselections.comThank you to our sponsor: Independence Wine and Spirits - or IWS. IWS is one of the hot up and coming distributors of fine wines and spirits headquartered in New York City. Like Taub Family Selections, IWS is owned by the Taub family, who have re-entered the NY wholesale market, bringing the family back to its roots in distribution where they held court from 1951 – 2004. To learn more about IWS go to: https://independencewine.com Thank you to our sponsor: Ross Knoll Vineyard Wines is a female owned company which produces handcrafted wines with winemaker, Justin Seidenfeld, made from Pinot Noir grapes sourced from exceptional vineyards in the Russian River Valley. Go to rossknollvineyard.com and join their waitlist for the 2021 vintage Pinot Noir which will be released early 2022.Thank you to our sponsor: SOMM TV. SOMM TV is a streaming network focused on the world of wine, food, and travel. Many call it the "Netflix" of wine & food!Use code MJ60 at checkout and get your first year of SOMM TV at 60% off! That's only $20 for the whole year!Checkout Link: http://watch.sommtv.com/checkout?code=mj60&plan=yearly See acast.com/privacy for privacy and opt-out information.

Commentary by Dr. Anju Nohria

Dr. Nagourney today discusses how cancer is a clonal disease, and how that impacts potential treatm

Clonal hematopoiesis (CH) is an age-related, asymptomatic condition in which leukemia-associated somatic mutations are detected in the blood of individuals without a hematologic malignancy. In the nontransplant setting, CH is uniformly associated with adverse outcomes, including an elevated risk of developing hematologic malignancies and an increased risk of nonhematologic outcomes because of altered inflammatory signaling. Current evidence has thus been insufficient to resolve disagreement about whether to screen older candidate donors for CH, and some transplant centers have begun excluding donors found to have CH on the basis of the assumption that the adverse associations of native CH also apply in the context of transplant. This study performed a comprehensive analysis of samples from donors age 40 years or older to determine the impact of CH on overall recipient outcomes, risk of DCL, and measures of graft alloimmune activity. Article: https://ascopubs.org/doi/full/10.1200/JCO.21.02286

Ze wordt gezien als één van de hardnekkigste invasieve diersoorten: de marmerkreeft. Nu proberen onderzoekers te ontdekken of het diertje - dat zichzelf razendsnel voortplant - ons ook kan helpen.  Een behoorlijke plaag is het dier dat zich over de hele wereld heeft verspreid inmiddels. Terwijl het ooit begon met één oermoeder. Een afstammeling van de Noord-Amerikaanse rivierkreeft. Die moeder kwam in 1995 via een dierenmarkt in Duitsland in een aquarium terecht en daar begon ze aan haar leger van kinderen. Ze heeft inmiddels miljoenen nakomelingen die allemaal genetisch identiek zijn. Daar kwamen Duitse wetenschappers tot hun verbazing achter toen ze in 2018 het genoom van de moeder en andere marmerkreeften - die overal over de wereld werden teruggevonden - bestudeerden. Bijna geen genetische verschillen. Er komen bij de voortplanting van dit dier geen mannen kijken, dat kan ze zelf. Parthenogenese heet het. Eigenlijk is het gewoon klonen. Als je daarover nadenkt is het nogal apart dat veel diersoorten juist zoveel mogelijk genetische variatie nastreven om een gezonde populatie te krijgen, maar deze kreeft het zo bizar goed doet met nauwelijks genetische variatie.  Omdat dat klonen overeenkomsten heeft met hoe een tumor in een lichaam groeit is het dier sinds het onderzoek in 2018 ook een model voor kankeronderzoek. Maar wat moeten we er verder mee? Daar zijn wel wat ideeën voor.  Met dank aan dit uitgebreide artikel in The Guardian: ‘We started eating them': what do you do with an invasive army of crayfish clones? De paper uit 2018 vind je hier: Clonal genome evolution and rapid invasive spread of the marbled crayfish.  See omnystudio.com/listener for privacy information.