Podcasts about cd33

Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease.  I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida.  Our full disclosures are available in the transcript of this episode.  James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary.  But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting.  So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important.  Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission.  In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults.  I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate.  The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it.  The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting.  The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work.  Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved.  One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now.  So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field.  Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it.  And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't.  A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that.  I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results.  There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that.  John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets.  I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can.  I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that.  And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And 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 podcasts. 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. John Sweetenham  Dr. James Foran Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn  Disclosures:    Dr. John Sweetenham:    No relationships to disclose Dr. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview

In this week's episode we'll find out about longer term results from a pivotal trial of mosunetuzumab in relapsed/refractory follicular lymphoma, potential use of CD70 CAR T-cells that secrete an anti-CD33/anti-CD3 bispecific antibody as a therapy for acute myeloid leukemia, and how ferroptosis regulates hemolysis in stored red blood cells.Featured Articles:Long-term 3-year follow-up of mosunetuzumab in relapsed or refractory follicular lymphoma after ≥2 prior therapiesCD70 CAR T cells secreting an anti-CD33/anti-CD3 dual-targeting antibody overcome antigen heterogeneity in AMLFerroptosis regulates hemolysis in stored murine and human red blood cells

Today's Episode Dr. Raj talks with Dr. Rudy Tanzi about his work in Alzheimer's Disease research, his acronym SHIELD for evading its progression, and how his background as a musician has intersected with this work.  Today's Guest Dr. Tanzi is the Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, Co-Director of the Henry and Allison McCance Center for Brain Health, and Co-Director of the MassGeneral Institute for Neurodegenerative Disease at Massachusetts General Hospital. He also serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi received his BS (microbiology) and BA (history) at the University of Rochester in 1980 and his PhD (neurobiology) at Harvard Medical School in 1990. Dr. Tanzi co-discovered the first Alzheimer's disease (AD) gene, the amyloid precursor protein (APP) gene, and the two other early-onset familial AD genes, presenilin 1 and presenilin 2. As leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi identified several other AD genes, including CD33, the first AD gene shown to regulate neuroinflammation. He also discovered the Wilson's disease gene and other neurological disease genes. Dr. Tanzi's team was the first to use human stem cells to create three-dimensional neural-glial; cell culture organoids of AD, dubbed “Alzheimer's-in-a-Dish”. This model was the first to recapitulate all three key AD pathological hallmarks in vitro, and first to definitively show that amyloid plaques directly cause neurofibrillary tangles - and also made drug screening for AD faster and more cost-effective. Using this system, Dr. Tanzi has developed several novel therapies for AD including gamma secretase modulators targeting amyloid pathology and AMX0035, which was already successful in a clinical trial of ALS and now seeking FDA approval. Dr. Tanzi also discovered that beta-amyloid plays a functional role in the brain as an anti-microbial peptide, supporting a role for infection in AD pathology. Dr. Tanzi serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and numerous advisory and editorial boards. He has been named to TIME magazine's list of TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author who has co-authored the books Decoding Darkness, and the bestsellers Super Brain, Super Genes, and The Healing Self with Dr. Deepak Chopra. Dr. Tanzi has hosted several shows on public television, regularly appears on television news programs, and has testified to Congress on both Alzheimer's disease and brain health. About Dr. Raj Dr Raj is a quadruple board certified physician and associate professor at the University of Southern California. He was a co-host on the TNT series Chasing the Cure with Ann Curry, a regular on the TV Show The Doctors for the past 7 seasons and has a weekly medical segment on ABC news Los Angeles. Want more Dr. Raj? Check out the Beyond the Pearls lecture series! The Ultimate High Yield Bundle: The complete review of high-yield clinical medicine topics necessary for graduate medical education board exams including NBME, USMLE Steps 1/2/3, ITE and ABIM Boards. You can also listen to the Beyond the Pearls podcast. Check out our other shows: Physiology by Physeo Step 1 Success Stories The InsideTheBoards Study Smarter Podcast The InsideTheBoards Podcast Produced by Ars Longa Media To learn more about us and this podcast, visit arslonga.media. You can leave feedback or suggestions at arslonga.media/contact or by emailing info@arslonga.media. Produced by: Christopher Breitigan and Erin McCue. Executive Producer: Patrick C. Beeman, MD Legal Stuff The information presented in this podcast is intended for educational purposes only and should not be construed as professional or medical advice. Learn more about your ad choices. Visit megaphone.fm/adchoices

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.04.547548v1?rss=1 Authors: Eskandari-Sedighi, G., Crichton, M., Zia, S., Gomez, E., St. Laurent, C. D., Cortez, L. M., Patel, Z. H., Sidhu, G., Sarkar, S., Aghanya, V., Sim, V. L., Tan, Q., Julien, O., Plemel, J. R., Macauley, M. S. Abstract: Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-{beta} (A{beta}) deposition. Mice expressing CD33M have increased A{beta} levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to control 5XFAD mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.12.536603v1?rss=1 Authors: Capilla-Lopez, M. D., Deprada, A., Andrade-Talavera, Y., Martinez-Gallego, I., Coatl-Cuaya, H., Rodriguez-Alvarez, J., Rodriguez-Moreno, A., Parra-Damas, A., Saura, C. A. Abstract: Alzheimer' disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-{beta} (A{beta}) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubule-associated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to A{beta} pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to A{beta}/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g., APOE, BIN1, CD33, CLU, PICALM, PLCG2, PTK2B, TREM2, SORL1, USP6NL) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of A{beta} and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of A{beta} and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529353v1?rss=1 Authors: Borot, F., Humbert, O., Newby, G. A., Fields, E., Kohli, S., Radtke, S., Laszlo, G. S., Mayuranathan, T., Ali, A. M., Weiss, M. J., Yen, J. S., Walter, R. B., Liu, D. R., Mukherjee, S., Kiem, H.-P. Abstract: On-target toxicity to normal cells is a major safety concern with targeted immune and gene therapies. Here, we developed a base editing (BE) approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate (NHP) hematopoietic stem and progenitor cells (HSPCs) protects from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for novel immunotherapies with reduced off-leukemia toxicity. For broader applications to gene therapies, we demonstrated highly efficient ( greater than 70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in NHPs. In vitro, dual gene-edited cells could be enriched via treatment with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO). Together, our results highlight the potential of adenine base editors for improved immune and gene therapies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Study showing the time from diagnosis of AML to the start of intensive treatment indicate that a treatment delay has no negative prognostic impact. https://ashpublications.org/blood/article/136/7/823/460669/Does-time-from-diagnosis-to-treatment-affect-the RATIFY clinical trial showing the addition of midostaurin (FLT3 inhibitor) to 7+3 chemotherapy for AML https://www.nejm.org/doi/full/10.1056/nejmoa1614359 Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the European LeukemiaNet (ELN) https://ashpublications.org/blood/article/140/12/1345/485817/Diagnosis-and-management-of-AML-in-adults-2022 ASH 2022 abstract presenting Daunorubicin 60 Vs 90 mg/m2 https://ash.confex.com/ash/2022/webprogram/Paper157126.html ALFA-0701. The addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukemiahttps://www.thelancet.com/article/S0140-6736(12)60485-1/fulltext Quizartinib data presented at EHA 2022 https://library.ehaweb.org/eha/2022/eha2022-congress/356965/harry.erba.quizartinib.prolonged.survival.vs.placebo.plus.intensive.induction.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Amarker%3D1749%2Afeatured%3D17676 International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemiashttps://ashpublications.org/blood/article/140/11/1200/485730/International-Consensus-Classification-of-Myeloid The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasmshttps://www.nature.com/articles/s41375-022-01613-1  CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemiahttps://ascopubs.org/doi/10.1200/JCO.2017.77.6112?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed  Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remissionhttps://www.nejm.org/doi/full/10.1056/NEJMoa2004444

A study using chimeric antigen receptor (CAR)-T cells has proven to be safe for treating patients with relapsed or refractory acute myeloid leukemia (AML). The agent known as PRGN-3006 also brought remissions among patients who had chemotherapy for lymphodepletion prior to their CAR-T cell procedure (Abstract 4633). After the lead author of the new study, David Sallman, MD, from the Moffitt Cancer Center in Tampa, Florida, had reported the new findings at the 2022 Annual Meeting of the American Society of Hematology, OncTimes Talk correspondent Peter Goodwin interviewed him about the study and about the overall prospects of using CAR-T cells to treat AML. PRGN-3006 UltraCAR-T is a multigenic autologous chimeric antigen receptor (CAR)-T simultaneously expressing a CAR specifically targeting CD33; membrane bound IL-15 (mbIL15) for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. CD33 is over-expressed on AML blasts with lesser expression on normal hematopoietic stem cells. PRGN-3006 UltraCAR-T drug product is manufactured via an overnight process at medical centers using the Company's proprietary non-viral and UltraPorator systems and released for infusion in patients the next day. The decentralized, overnight UltraCAR-T manufacturing process, which does not use viral vectors or ex vivo activation and expansion of T cells, has the potential to address major limitations of current T cell therapies. PRGN-3006 UltraCAR-T has been granted Orphan Drug Designation and Fast Track Designation in patients with AML by the FDA. The Phase I/Ib clinical study is designed to enroll in two phases, an initial dose escalation phase followed by a dose expansion phase, to evaluate safety and determine the recommended Phase II dose of PRGN-3006 delivered via intravenous (IV) infusion without lymphodepletion (Cohort 1) or with lymphodepletion (Cohort 2). The study is also evaluating in vivo persistence and anti-tumor activity of PRGN-3006.

Today we are going to talk about sugar. What is sugar – what are the different types of sugars, how do they affect the body, our hormones, and also obviously how do they affect our blood sugar. We're going to talk about “natural” sugars vs processed sugars. We're also going to talk about carbohydrates. Why do they matter and how do they contribute to the total body's sugar burden. We are also going to address why we should even care about sugar. This is going to be a fun and interesting topic, at least in my opinion. I feel like it is a necessary subject so we are better informed and can make informed decisions regarding our intake of sugar, especially as we are in full swing of the holiday season. Just a quick disclaimer that this podcast is meant for educational purposes only and is not meant to diagnose or be a substitute for medical advice from your practitioner. I am a practitioner, but not your practitioner. **Follow me on Instagram: https://www.instagram.com/thefunctionalnursepractitioner/ ** Level up your products: https://www.ewg.org/ewgverified/ **Interesting articles for more information** Impact of sugar on the body, brain, and behavior: https://www.imrpress.com/journal/FBL/23/12/10.2741/4704 Pancreatic regulation of glucose homeostasis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892884/ Effect of different types of sugar on gut physiology and microbiota in overfed goose: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187246/pdf/main.pdf Impact of sugar on the body, brain, and behavior: https://www.imrpress.com/journal/FBL/23/12/10.2741/4704 Hidden in Plain Sight: https://sugarscience.ucsf.edu/hidden-in-plain-sight/ Yogurts vary widely in sugar content, survey shows: https://www.yogurtinnutrition.com/yogurts-vary-widely-in-sugar-content-survey-shows/ Coconut sugar: Is it good for you?: https://www.medicalnewstoday.com/articles/323047#impact-on-blood-glucose-levels What is maltodextrin and is it safe?: https://www.medicalnewstoday.com/articles/322426#which-foods-contain-maltodextrin Glycemic Index Research and GI News: https://glycemicindex.com/gi-search/ The lowdown on glycemic index and glycemic load: https://www.health.harvard.edu/diseases-and-conditions/the-lowdown-on-glycemic-index-and-glycemic-load Human brain sialoglycan ligand for CD33, a microglial inhibitory Siglec implicated in Alzheimer's disease: https://www.jbc.org/article/S0021-9258(22)00400-8/fulltext Increased Added Sugar Consumption Is Common in Parkinson's Disease: https://www.frontiersin.org/articles/10.3389/fnut.2021.628845/full High-Fat, High-Sugar Diet Disrupts the Preovulatory Hormone Surge and Induces Cystic Ovaries in Cycling Female Rats: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740526/

In this episode Dr Tanzi discusses whether Alzheimer's and other brain diseases are happening at a younger age and why that might be, along with his own protocol to maintaining a young and healthy mind! Dr. Rudolph Tanzi is the Director of the Genetics and Aging Research Unit, Co-Director of the McCance Center for Brain Health, Co-Director of the Mass General Institute for Neurodegenerative Disease, and Vice-Chair of Neurology (Research), at Massachusetts General Hospital, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi co-discovered the first three Alzheimer's disease genes, including APP and directs the Cure Alzheimer's Fund Alzheimer's Genome Project, which identified the first neuroinflammation-related Alzheimer's gene, CD33. He has also been developing therapies for treating and preventing AD using 3D human neural glial culture models of AD and is now testing them in various clinical trials. Dr. Tanzi has published over 600 papers, received numerous awards, including the Metropolitan Life Award, Potamkin Prize, Smithsonian American Ingenuity Award, and was one of the TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author, who co-authored “Decoding Darkness” “Super Brain”, “Super Genes”, and “The Healing Self”. He has also hosted three PBS shows and made numerous appearances on network and cable news and medical television shows. In his spare time, he plays keyboards for Joe Perry, Aerosmith and other musicians. Professor Tanzi's page at Harvard https://brain.harvard.edu/?people=rudolph-e-tanzi Books by Professor Tanzi https://amzn.to/3kyqxVQ Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being https://amzn.to/3zsenSl The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life https://amzn.to/3kwwwKx Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being https://amzn.to/3zx5h6Q Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease If you would like to support our channel, we'd love a coffee ☕…thank you! https://www.buymeacoffee.com/mhealthspan You can also find us on YouTube at https://www.youtube.com/c/modernhealthspan 15% off Bulletproof products at https://www.bulletproof.com/ with discount code HEALTHSPAN15. Renue By Science 10% discount code MHS at https://renuebyscience.com/all-products-2/ 10% off all products at DoNotAge with code MODERNHEALTHSPAN at https://donotage.org/

In this episode Dr Tanzi talks about some of the future potential options are to treat Alzheimer's once it has started and neural inflammation has set in. Dr. Rudolph Tanzi is the Director of the Genetics and Aging Research Unit, Co-Director of the McCance Center for Brain Health, Co-Director of the Mass General Institute for Neurodegenerative Disease, and Vice-Chair of Neurology (Research), at Massachusetts General Hospital, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi co-discovered the first three Alzheimer's disease genes, including APP and directs the Cure Alzheimer's Fund Alzheimer's Genome Project, which identified the first neuroinflammation-related Alzheimer's gene, CD33. He has also been developing therapies for treating and preventing AD using 3D human neural glial culture models of AD and is now testing them in various clinical trials. Dr. Tanzi has published over 600 papers, received numerous awards, including the Metropolitan Life Award, Potamkin Prize, Smithsonian American Ingenuity Award, and was one of the TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author, who co-authored “Decoding Darkness” “Super Brain”, “Super Genes”, and “The Healing Self”. He has also hosted three PBS shows and made numerous appearances on network and cable news and medical television shows. In his spare time, he plays keyboards for Joe Perry, Aerosmith and other musicians. Professor Tanzi's page at Harvard https://brain.harvard.edu/?people=rudolph-e-tanzi Books by Professor Tanzi https://amzn.to/3kyqxVQ Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being https://amzn.to/3zsenSl The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life https://amzn.to/3kwwwKx Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being https://amzn.to/3zx5h6Q Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease If you would like to support our channel, we'd love a coffee ☕…thank you! https://www.buymeacoffee.com/mhealthspan You can also find us on YouTube at https://www.youtube.com/c/modernhealthspan 15% off Bulletproof products at https://www.bulletproof.com/ with discount code HEALTHSPAN15. Renue By Science 10% discount code MHS at https://renuebyscience.com/all-products-2/ 10% off all products at DoNotAge with code MODERNHEALTHSPAN at https://donotage.org/

In this episode Professor Tanzi talks about SHIELD, his acronym for the things that you can do to protect your brain. S - Sleep, H - Handle Stress, I - Interactions with friends, E - Exercise, L - Learn new things and D - Diet and we dive into detail on a few of them. Dr. Rudolph Tanzi is the Director of the Genetics and Aging Research Unit, Co-Director of the McCance Center for Brain Health, Co-Director of the Mass General Institute for Neurodegenerative Disease, and Vice-Chair of Neurology (Research), at Massachusetts General Hospital, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi co-discovered the first three Alzheimer's disease genes, including APP and directs the Cure Alzheimer's Fund Alzheimer's Genome Project, which identified the first neuroinflammation-related Alzheimer's gene, CD33. He has also been developing therapies for treating and preventing AD using 3D human neural glial culture models of AD and is now testing them in various clinical trials. Dr. Tanzi has published over 600 papers, received numerous awards, including the Metropolitan Life Award, Potamkin Prize, Smithsonian American Ingenuity Award, and was one of the TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author, who co-authored “Decoding Darkness” “Super Brain”, “Super Genes”, and “The Healing Self”. He has also hosted three PBS shows and made numerous appearances on network and cable news and medical television shows. In his spare time, he plays keyboards for Joe Perry, Aerosmith and other musicians. Professor Tanzi's page at Harvard https://brain.harvard.edu/?people=rudolph-e-tanzi Books by Professor Tanzi https://amzn.to/3kyqxVQ Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being https://amzn.to/3zsenSl The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life https://amzn.to/3kwwwKx Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being https://amzn.to/3zx5h6Q Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease If you would like to support our channel, we'd love a coffee ☕…thank you! https://www.buymeacoffee.com/mhealthspan You can also find us on YouTube at https://www.youtube.com/c/modernhealthspan 15% off Bulletproof products at https://www.bulletproof.com/ with discount code HEALTHSPAN15. Renue By Science 10% discount code MHS at https://renuebyscience.com/all-products-2/ 10% off all products at DoNotAge with code MODERNHEALTHSPAN at https://donotage.org/

In this episode Professor Tanzi talks about the causes of Alzheimer's, from the plaques and tangles to neural inflammation, and what treatments exist for these symptoms. Dr. Rudolph Tanzi is the Director of the Genetics and Aging Research Unit, Co-Director of the McCance Center for Brain Health, Co-Director of the Mass General Institute for Neurodegenerative Disease, and Vice-Chair of Neurology (Research), at Massachusetts General Hospital, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi co-discovered the first three Alzheimer's disease genes, including APP and directs the Cure Alzheimer's Fund Alzheimer's Genome Project, which identified the first neuroinflammation-related Alzheimer's gene, CD33. He has also been developing therapies for treating and preventing AD using 3D human neural glial culture models of AD and is now testing them in various clinical trials. Dr. Tanzi has published over 600 papers, received numerous awards, including the Metropolitan Life Award, Potamkin Prize, Smithsonian American Ingenuity Award, and was one of the TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author, who co-authored “Decoding Darkness” “Super Brain”, “Super Genes”, and “The Healing Self”. He has also hosted three PBS shows and made numerous appearances on network and cable news and medical television shows. In his spare time, he plays keyboards for Joe Perry, Aerosmith and other musicians. Professor Tanzi's page at Harvard https://brain.harvard.edu/?people=rudolph-e-tanzi Books by Professor Tanzi https://amzn.to/3kyqxVQ Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being https://amzn.to/3zsenSl The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life https://amzn.to/3kwwwKx Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being https://amzn.to/3zx5h6Q Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease If you would like to support our channel, we'd love a coffee ☕…thank you! https://www.buymeacoffee.com/mhealthspan You can also find us on YouTube at https://www.youtube.com/c/modernhealthspan 15% off Bulletproof products at https://www.bulletproof.com/ with discount code HEALTHSPAN15. Renue By Science 10% discount code MHS at https://renuebyscience.com/all-products-2/ 10% off all products at DoNotAge with code MODERNHEALTHSPAN at https://donotage.org/

Dr. Rudolph Tanzi is the Director of the Genetics and Aging Research Unit, Co-Director of the McCance Center for Brain Health, Co-Director of the Mass General Institute for Neurodegenerative Disease, and Vice-Chair of Neurology (Research), at Massachusetts General Hospital, and the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi co-discovered the first three Alzheimer's disease genes, including APP and directs the Cure Alzheimer's Fund Alzheimer's Genome Project, which identified the first neuroinflammation-related Alzheimer's gene, CD33. He has also been developing therapies for treating and preventing AD using 3D human neural glial culture models of AD and is now testing them in various clinical trials. Dr. Tanzi has published over 600 papers, received numerous awards, including the Metropolitan Life Award, Potamkin Prize, Smithsonian American Ingenuity Award, and was one of the TIME100 Most Influential People in the World. Dr. Tanzi is a New York Times bestselling author, who co-authored “Decoding Darkness” “Super Brain”, “Super Genes”, and “The Healing Self”. He has also hosted three PBS shows and made numerous appearances on network and cable news and medical television shows. In his spare time, he plays keyboards for Joe Perry, Aerosmith and other musicians. Professor Tanzi's page at Harvard https://brain.harvard.edu/?people=rudolph-e-tanzi Books by Professor Tanzi https://amzn.to/3kyqxVQ Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being https://amzn.to/3zsenSl The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life https://amzn.to/3kwwwKx Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being https://amzn.to/3zx5h6Q Decoding Darkness: The Search For The Genetic Causes Of Alzheimer's Disease If you would like to support our channel, we'd love a coffee ☕…thank you! https://www.buymeacoffee.com/mhealthspan You can also find us on YouTube at https://www.youtube.com/c/modernhealthspan 15% off Bulletproof products at https://www.bulletproof.com/ with discount code HEALTHSPAN15. Renue By Science 10% discount code MHS at https://renuebyscience.com/all-products-2/ 10% off all products at DoNotAge with code MODERNHEALTHSPAN at https://donotage.org/

Dr. Guenther Koehne is the Deputy Director and Chief of Blood and Marrow Transplant and Hematologic Oncology at the Baptist Health South Florida Miami Cancer Institute. They are part of a clinical trial for an approach that protects healthy cells from the toxic side-effects of targeted blood cancer treatments with a focus on acute myeloid leukemia (AML). Guenther explains," And then, we have the opportunity to administer medications or CAR-T cells, for example, post transplantation, that are specifically targeting CD33, which then presumably allows us to specifically target residual leukemia cells." "So, my institution, Miami Cancer Institute, and before that, I was at Memorial Sloan Kettering Cancer Center, where I implemented the purification of stem cells from the stem cell product, from the donor stem cell product, allowing to deplete the T cells and other cells that were not necessarily needed for a successful transplant while we have a purified stem cell population. And on this clinical trial, we can now use the purified stem cells and send them to a specified laboratory to silence or down regulate the expression of CD33, using CRISPR technology so that the end product after this step will include a donor-derived stem cell population that is CD33 negative." #MiamiCancerInstitute #VorBio #CellTherapy #BloodCancers #AML #AcuteMyeloidLeukemia #AML #Leukemia #ClinicalTrial #Miami miamicancerinstitute.com Listen to the podcast here

Dr. Guenther Koehne is the Deputy Director and Chief of Blood and Marrow Transplant and Hematologic Oncology at the Baptist Health South Florida Miami Cancer Institute. They are part of a clinical trial for an approach that protects healthy cells from the toxic side-effects of targeted blood cancer treatments with a focus on acute myeloid leukemia (AML). Guenther explains," And then, we have the opportunity to administer medications or CAR-T cells, for example, post transplantation, that are specifically targeting CD33, which then presumably allows us to specifically target residual leukemia cells." "So, my institution, Miami Cancer Institute, and before that, I was at Memorial Sloan Kettering Cancer Center, where I implemented the purification of stem cells from the stem cell product, from the donor stem cell product, allowing to deplete the T cells and other cells that were not necessarily needed for a successful transplant while we have a purified stem cell population. And on this clinical trial, we can now use the purified stem cells and send them to a specified laboratory to silence or down regulate the expression of CD33, using CRISPR technology so that the end product after this step will include a donor-derived stem cell population that is CD33 negative." #MiamiCancerInstitute #VorBio #CellTherapy #BloodCancers #AML #AcuteMyeloidLeukemia #AML #Leukemia #ClinicalTrial #Miami miamicancerinstitute.com Download the transcript here

NEWS: Sugar-studded protein is key to an Alzheimer's cure | The Brighter Side (01:38) In a bit of “reverse engineering” research using brain tissues from five people who died with Alzheimer's disease, Johns Hopkins Medicine researchers say they discovered that a special sugar molecule could play a key role in the development of Alzheimer's disease. This could indicate the molecule, known as a glycan, to be used as an early diagnostic test. And opens a way to perhaps prevention of the disease Cleaning up the disease-causing forms of amyloid and tau is the job of the brain's immune cells, called microglia. Earlier studies found that when cleanup is impaired, Alzheimer's disease is more likely to occur.  Thought to be caused by an overabundance of a receptor on the microglia cells, called CD33. Past studies by the researchers showed that for CD33, these “connector” molecules are special sugars.These molecules are ferried around the cell by specialized proteins that help them find their appropriate receptors.  The protein-glycan combination is called a glycoprotein.  The researchers, to find out more about the glycoproteins, obtained brain tissue from five people who died of Alzheimer's disease and from five people.Among the many thousands of glycoproteins they gathered from the brain tissues, only one connected to CD33. What was this mysterious glycoprotein?The researchers determined the protein component's identity by taking its “fingerprint” using mass spectroscopy, which identifies protein building blocks. Then they compared the molecular makeup of the protein with a database of known protein structures. The research team was able to conclude the protein portion of the glycoprotein was receptor tyrosine phosphatase (RPTP) zeta. Further experiments showed that the brain tissue of the five people who died with Alzheimer's disease had more than twice as much RPTP zeta S3L as the donors who did not have the disease. Implying that this glycoprotein may be connecting with more CD33 receptors than a healthy brain, limiting the brain's ability to clean up harmful proteins. Gonzalez-Gil Alvarenga, Ph.D., first author on the study stated:“Identifying this unique glycoprotein provides a step toward finding new drug targets and potentially early diagnostics for Alzheimer's disease.”   A Surprising Link Between Immune System and Hair Growth | Neuroscience News (07:36) Salk scientists have uncovered an unexpected molecular target of a common treatment for alopecia, a condition in which a person's immune system attacks their own hair follicles, causing hair loss. Corresponding author of the study, Ye Zheng, associate professor in Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis, stated:“For the longest time, regulatory T cells have been studied for how they decrease excessive immune reactions in autoimmune diseases … Now we've identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration completely separate from suppressing immune response.” Initially the researchers were interested in researching the roles of regulatory T cells and glucocorticoid hormones in autoimmune diseases.They did not function together to play a significant role in any of these conditions.  Thought they'd have more luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The scientists induced hair loss in normal mice and mice lacking glucocorticoid receptors in their regulatory T cells.After two weeks, the researchers saw the normal mice grew their hair back, while the ones lacking the receptors struggled to grow it back The findings suggested that some sort of communication must be occurring between regulatory T cells and hair follicle stem cells to allow for hair regeneration.They continued to investigate how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples. They found that glucocorticoids instruct the regulatory T cells to activate hair follicle stem cells, which leads to hair growth. Depends on a mechanism whereby glucocorticoid receptors induce production of the protein TGF-beta3, all within the regulatory T cells. TGF-beta3 then activates the hair follicle stem cells to differentiate into new hair follicles, promoting hair growth.  This study revealed that regulatory T cells and glucocorticoid hormones are not just immunosuppressants but also have a regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.     Engineers devise clever system for EVs to share charge—while driving | Anthropocene (13:34) The charging station expansion isn't keeping up with the growing number of EVs on the road.The number of EVs on the road per public charging point globally rose to 9.2 at the end of last year, from 7.4 at the end of 2020, according to a study by BloombergNEF analyst Ryan Fisher on the state of public charging infrastructure. In a new study, engineers propose a way around this conundrum: EVs that share charge with each other while driving. In their vision, cars with low batteries could buy some charge from others with extra to spare, all without stopping. Could be orchestrated via a cloud-based control system Electrical and computer engineer Prabuddha Chakraborty the University of Florida and his colleagues propose a two-battery system for EVs.A large, slow-charging lithium-ion battery would drive the car,  A smaller, fast-charging battery would be used for on-the-go charging.  Once powered up, the small battery would transfer its charge to the car's main battery.  “Just like in your computer you have fast cache memory—but it's expensive—so you have other type of high-capacity memories that are slower,” said Tamzidul Hoque, a professor of electrical engineering and computer science at the University of Kansas The cloud-based system idea:Monitor charge levels of electric cars.  If a car's power is starting to run low, the network would alert it to other cars nearby with enough charge to sell.  Once two cars are matched with owner consent, cables would connect them for charging and they would be locked at the same speed until the power transfer is complete. Yet even in a well-planned, dynamic peer charging network, the researchers found in simulations that the total charge of the network will slowly deplete.To try to get around this idea, they propose the concept of mobile charging stations: large battery-loaded trucks that would recharge multiple vehicles at once.  Like military jets being refueled in-flight by tanker aircraft.  Using popular traffic modeling software they were able to simulate their idea somewhat.They found that it would eliminate range anxiety and re-charging wait time, and reduce EV cost by eliminating the need to have big batteries.   Scientists Use Vegetable Oil Byproduct to Remove Heavy Metals From Contaminated Water | EcoWatch (20:27) Scientists from Nanyang Technological University, Singapore, collaborating with ETH Zurich, Switzerland (ETHZ), have discovered a way to turn byproduct from vegetable oil production into a membrane that filters out heavy metals from water. Ali Miserez, study author and professor at Nanyang Technological University, stated:“Water pollution remains a major global issue in many parts of the world…Heavy metals represent a large group of water pollutants that can accumulate in the human body, causing cancer and mutagenic diseases. Current technologies to remove them are energy-intensive, requiring power to operate, or are highly selective in what they filter.” The researchers noticed that proteins in peanut and sunflower oil waste byproducts, called oilseed meals, were useful in attracting heavy metal ions.Turned the oilseed meals' proteins into nano-sized protein amyloid fibrils, which strongly attract heavy metal ions.  Combined these amyloid fibrils with activated carbon and tested the filters on three types of metal: platinum, chromium and lead. The membranes were 99.89% effective at filtering out all of the heavy metals from water, with the best results for platinum and lead. The membrane made from waste byproduct proteins is a low-cost option that requires little energy for decontamination, and the researchers say this innovation could work all over the world for water purification.  “Recovering precious platinum, which costs US$33,000/kg, only requires 32 kg of protein, while recovering gold, which is worth almost US$60,000/kg, only requires 16 kg of protein. Considering that these proteins are obtained from industrial waste that is worth less than US$1/kg, there are large cost benefits,” Miserez explained. Because of the simple technology, this filtration membrane is readily scalable, according to the researchers.   Tesla launches new virtual power plant that pays Powerwall owners to help end brownouts | Electrek (25:30) Tesla has launched a new virtual power plant in partnership with PG&E in California that will pay Powerwalls owners to help stabilize the electric grid and end brownouts in California. What is a virtual power plant?Consists of distributed energy storage systems, like Tesla Powerwalls, used in concert to provide grid services and avoid the use of polluting and expensive peaker power plants. Tesla has partnered with PG&E to launch a new version of its virtual power plant that will actually compensate people participating:The company's statement: “Become a part of the largest distributed battery in the world and help keep California's energy clean and reliable. Opt-in to the Tesla Virtual Power Plant (VPP) with PG&E and your Powerwall will be dispatched when the grid needs emergency support. Through the Emergency Load Reduction Program (ELRP) pilot, you will receive $2 for every additional kWh your Powerwall delivers during an event. Adjust your Backup Reserve to set your contribution, while maintaining backup energy for outages.” Depending on the events and the number of Powerwalls homeowners have, they could earn anywhere from $10 to $60 per event or even more for bigger systems. The extra capacity your Powerwall provides could help avoid or reduce blackouts in a severe emergency. This way, Powerwall can keep the lights on for both you and your community. Tesla said that it has about 50,000 Powerwalls that could be eligible for this VPP, which add up to a significant 500 MWh of energy capacity than can be distributed in any event.

Emergencies happen in hematology and oncology. This is a fact. But how do we manage these emergencies? Look no further. In this episode, we'll talk about one of the key hematologic malignancies that you'll encounter as a fellow, one that requires immediate action to reduce mortality: acute promyelocytic leukemia (APL or APML)- Acute Promyelocytic leukemia (APL or APML):**Stay tuned for our upcoming “part two” and “chemotherapy basics” episodes for more information on non-acute management of this disease**APL is a true hematologic emergency! Although this is a very curable form of leukemia, it is associated with high rates of severe DIC and high mortality in the period immediately following diagnosis***Untreated, can see pulmonary or cerebrovascular hemorrhage in up to 40% of patients***10-20% incidence of hemorrhage-related mortality in the initial period***Statistically significant increase in mortality at 30 days with just a 12-hour delay in initial hematologist consultation- Disease basics:** Rare subtype of AML(

Dr. Tanzi is the Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, Co-Director of the Henry and Allison McCance Center for Brain Health, and Co-Director of the MassGeneral Institute for Neurodegenerative Disease at Massachusetts General Hospital. He also serves as the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School. Dr. Tanzi received his B.S. (microbiology) and B.A. (history) at the University of Rochester in 1980 and his Ph.D. (neurobiology) at Harvard Medical School in 1990. Dr. Tanzi was a key member of the teams that discovered the first Alzheimer's disease (AD) gene, the amyloid precursor protein (APP) gene, and the two other early-onset familial AD genes, presenilin 1 and presenilin 2. As leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi identified several other AD genes, including CD33, the first AD gene shown to regulate neuroinflammation in AD. He also discovered the Wilson's disease gene and several other neurological disease genes. Dr. Tanzi's team was the first to use human stem cells to create three-dimensional mini human brain organoids of AD, dubbed “Alzheimer's-in-a-Dish”. This model was the first to recapitulate all three key AD pathological hallmarks. He and his team have successfully used these organoids to screen for approved drugs and natural products that can stop AD brain pathology. Dr. Tanzi has developed several novel therapies for AD including gamma secretase modulators targeting amyloid pathology (Phase 1 planned 2021) and AMX0035, which was already successful in a clinical trial of ALS and now under priority review for approval at the FDA. Dr. Tanzi also discovered that beta-amyloid plays a functional role in the brain as an anti-microbial peptide, supporting a potential role for infection in the etiology of AD. Dr. Tanzi serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and on numerous scientific advisory and editorial boards. He has published over 600 research papers and is one of the top 50 most cited neuroscientists in the world. He has received the highest awards in his field, including the Metropolitan Life Foundation Award, Potamkin Prize, Ronald Reagan Award, Oneness in Humanity Award, Silver Innovator Award, the Smithsonian American Ingenuity Award, the Brain Research Foundation Award, and the Kary Mullis Award for Medical Research. He has also been named to TIME magazine's list of TIME100 Most Influential People in the World. Dr. Tanzi is also a New York Times bestselling author, who has co-authored the books Decoding Darkness, and bestsellers, Super Brain, Super Genes, and The Healing Self. Dr. Tanzi joins us to mark The One Way Ticket Show's 10th anniversary for our special series--a “one way ticket to optimal mental, physical and spiritual well-being”. On this episode of the program, Dr. Tanzi's conversation with Host Steven Shalowitz includes why today is rapidly becoming the golden age for solving age related brain diseases, lifestyle changes we can make to reduce the risk of Alzheimer's and questions around the brain-consciousness connection. Dr. Tanzi is just one of the engaging personalities featured on The One Way Ticket Show. During the regular season of the program, Host Steven Shalowitz explores with his guests where they would go if given a one way ticket, no coming back. Their destinations may be in the past, present, future, real, imaginary or a state of mind. Steven's guests have included: Nobel Peace Prize Winner, President Jose Ramos-Horta; Legendary Talk Show Host, Dick Cavett; Law Professor, Alan Dershowitz; Fashion Expert, Tim Gunn; Broadcast Legend, Charles Osgood; International Rescue Committee President & CEO, David Miliband; Former Senator, Joe Lieberman; Playwright, David Henry Hwang; Journalist-Humorist-Actor, Mo Rocca; SkyBridge Capital Founder & Co-Managing Partner, Anthony Scaramucci; Abercrombie & Kent Founder, Geoffrey Kent; Travel Expert, Pauline Frommer, as well as leading photographers, artists, chefs, writers, intellectuals, etc.

I am so excited to interview Melissa. Now, here is a hard working person running for Congress to serve LA County communities from Malibu to Palos Verdes. Melissa is a Texas-born Jew who has a lot of international experience studying Afghanistan & Pakistan in addition to working as an actress and screenwriter. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/realpeopleusa/support

In this episode we speak with Larry Fitzgibbon the co-founder and CEO of Tastemade. We focus in on the success of short term content from SnapChat to the viral TikTok and how to leverage your audience for massive success. Creative Disruption Podcast with Ricky Ray Butler and Derral Eves Insights and stories from leading creators, writers, producers and marketers on how the worlds of advertising, entertainment, and data science are converging. Subscribe To YouTube

The cover for issue 39 of Oncotarget features Figure 4, "Apoptosis assay of NRXN1-targeted ADC at IC50 dose calculated by growth inhibition curves," by Yotsumoto, et al. which reported that the authors identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1. The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines. The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines. Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy. Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research. Dr. Daiya Takai from The University of Tokyo Hospital and Dr. Takuma Yotsumoto from The University of Tokyo Graduate School of Medicine said, "Small cell lung cancer (SCLC) accounts for 10–15% of lung cancer, and its prognosis has remained relatively dismal for years." Considering the high sensitivity of SCLC to chemotherapy, the selective delivery of a cytotoxic agent using ADC could be a novel treatment strategy for SCLC. Five ADCs have been approved by The Food and Drug Administration: Brentuximab vedotin for Hodgkin lymphoma Ado-trastuzumab emtansine for HER2-positive metastatic breast cancer Inotuzumab ozogamicin for acute lymphoblastic leukemia Gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia, and Trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2-based regimens in a metastatic setting. In SCLC, DLL3, a cell surface Notch ligand that appears to be a direct downstream target of ASCL1, has been identified as a novel target for ADCs. In this study, the Oncotarget authors aimed to identify novel molecular targets for ADCs in SCLC. They herein report that NRXN1-mediated ADC exhibited anti-tumor activity in vitro, and thus NRXN1 could be a novel target of ADCs for SCLC. The Takai/Yotsumoto Research Team concluded in their Oncotarget Research Paper "we identified NRXN1 as a new target for ADCs by screening membrane proteins using a computational-biological approach. The combination of the primary anti-NRXN1 monoclonal antibody and the secondary ADC exhibited anti-tumor activity in an NRXN1-expression dependent manner. NRXN1 could be a novel potential target of ADCs for SCLC that is worth further research." Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27718 Full text - https://www.oncotarget.com/article/27718/text/ Correspondence to - Daiya Takai - dtakai-ind@umin.ac.jps and Takuma Yotsumoto - tyotsumoto-ths@umin.ac.jp Keywords - antibody-drug conjugates, small cell lung cancer, novel molecular targets, NRXN1, cell adhesion molecule 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 https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

A few words and a poem too. #blacklivesmatter #nojusticenopeace Campaign Zero: Organization that utilizes research-based policy solutions to end police brutality in the U.S. https://www.joincampaignzero.org/ Unicorn Riot: Nonprofit media collective dedicated to exposing the root causes of social, economic, and environmental issues. https://unicornriot.ninja/ George Floyd Memorial Fund: The official GoFundMe to support the Floyd family. https://www.gofundme.com/f/georgefloyd Minnesota Freedom Fund: Community-based fund set up to pay criminal bail and immigration bonds for individuals who have been arrested while protesting police brutality. This has become one of the most prominent bail funds, providing relief to protesters in Minneapolis seeking justice for George Floyd. https://minnesotafreedomfund.org/ Submit your poetry and flash fiction today for the Creative Drive Podcast: https://idlewy.blog/you/

Ira Pastor, ideaXme life sciences ambassador, interviews Dr. Rudolph Tanzi, Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital. Ira Pastor Comments: On this episode we are going to journey back to the topic of Alzheimer’s disease (AD), projected to affect over a 100 million people worldwide by mid century.  Dr. Rudolph Tanzi: Dr. Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH), and has been investigating the genetics of neurological disease since the 1980s when he participated in the first study that used genetic markers to find a disease gene for Huntington's disease. In 1990, Dr. Tanzi received his Ph.D. in neurobiology at Harvard Medical School, where his doctoral thesis was on the discovery and isolation of the first Alzheimer's disease gene - the amyloid precursor protein (APP), published in 1987 in Science. Dr. Tanzi's work in Alzheimer's disease research: Dr Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including those responsible for Wilson’s disease. Dr Tanzi also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and leader of the Cure Alzheimer's Fund Alzheimer’s Genome Project, where he has carried out multiple genome wide association studies (GWAS) of thousands of Alzheimer’s families leading to the identification of novel AD candidate genes, including CD33, and ADAM10 genes. Dr Tanzi has also worked on the role of zinc and copper in AD, on gamma secretase modulators for the prevention and treatment of Alzheimer's, and on human stem cells to create an “Alzheimer’s-in-a-Dish”, three-dimensional neural culture system, that was the first to recapitulate both pathological hallmarks of Alzheimer’s disease. Dr. Tanzi has published over 500 scientific papers, including the top three most cited papers in the field of Alzheimer's disease research. Dr. Tanzi also co-authored the books "Decoding Darkness: The Search the Genetic Causes of Alzheimer's Disease", the New York Times Best Selling book “Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being”, "Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being", and "The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life" with Deepak Chopra. Dr. Tanzi in the Media Dr. Tanzi has made numerous television appearances on shows such as CBS This Morning and Dr. Oz. He also hosts the shows "Super Brain with Dr. Rudy Tanzi", "Super Genes with Dr. Rudy Tanzi" and "The Brain Body Mind Connection with Dr. Rudy Tanzi and Dr. Deepak Chopra" on PBS television. In addition to his work in AD and brain health, Dr. Tanzi has wide ranging musical pursuits. Dr Tanzi professionally plays keyboards, most recently with Joe Perry and Aerosmith. He also co-wrote the song tribute to Alzheimer's patients called "Remember Me", performed by singer Chris Mann. He plays keyboards on the albums: "Aerosmith: Music from Another Dimension", and "Joe Perry: Switzerland Manifesto." On this episode we will hear from Dr Tanzi about: His background; how he developed an interest in neurobiology and the domain of AD. His work on the Alzheimer's Disease - Infectious Disease connection and the Alzheimer's Disease - Neuro-inflammation connection. His work with stem cells and regenerative medicine. His work in the area of aging, brain health and the "psycho-biologic" aspects of health and wellness. About mental health and self care during the COVID-19 crisis. Credits: Ira Pastor interview video, text, and audio. Follow Ira Pastor on Twitter:@IraSamuelPastor If you liked this interview, be sure to check out ourinterviewexploring the viral causes of Alzheimer's! Follow ideaXme on Twitter:@ideaxm On Instagram:@ideaxme Find ideaXme across the internet including on iTunes,SoundCloud,Radio Public,TuneIn Radio,I Heart Radio, Google Podcasts, Spotify and more. ideaXme is a global podcast, creator series and mentor programme. Our mission: Move the human story forward!™ ideaXme Ltd.

Hyperstyles. CD33 | Full-On Fusion | Tracklist can be found at: https://soundcloud.com/lentej/ Enjoy and dance on!

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Acute Leukemias Update — Part 2: Our interview with Dr Ravandi highlights the following topics as well as cases from his practice: Impact of genetic mutations and cytogenetic alterations on prognosis and therapy selection for patients with AML (00:00) Initial workup for patients with newly diagnosed AML (03:38) Biologic rationale for, activity of and approval of venetoclax in combination with hypomethylating agents for patients with AML who are 75 or older or have comorbidities (05:48) Integration of venetoclax with hypomethylating agents into the clinical algorithm for AML (10:50) Approach to therapy for older patients with AML and FLT3 mutations(12:43) Management of toxicities associated with venetoclax combined with a hypomethylating agent (15:08) RATIFY: Results of a Phase III trial evaluating midostaurin with 7 + 3 induction and high-dose cytarabine consolidation and as maintenance therapy for patients with newly diagnosed AML and FLT3 mutations (18:25) Efficacy of sorafenib, quizartinib or gilteritinib for patients with AML and FLT3 mutations (21:57) Side effects and spectrum of activity of gilteritinib, quizartinib and midostaurin (25:09) Case: A 70-year-old man with AML and NPM1 and FLT3 mutations receives azacitidine in combination with venetoclax and sorafenib as third-line therapy (29:06) Case: A 44-year-old woman with AML and an IDH2 mutation receives enasidenib (31:32) Perspective on the potential use of enasidenib or ivosidenib in the first-line setting (34:52) Mechanism of action and efficacy of CPX-351 in patients with therapy-related AML or AML with myelodysplasia-related changes (37:45) Clinical experience with CPX-351 (40:23) Role of gemtuzumab ozogamicin in the treatment of CD33-positive AML (42:57) Activity of the recently approved hedgehog inhibitor glasdegib in combination with low-dose cytarabine for newly diagnosed AML in patients aged 75 or older or those with comorbidities (46:27) Case: A 75-year-old woman with AML and significant comorbidities is enrolled on a clinical trial of decitabine with venetoclax (47:58) Case: A 76-year-old woman with ALL experiences a complete remission with blinatumomab as second-line therapy (51:46) Mechanism of action and efficacy of blinatumomab for ALL (55:52) Activity and tolerability of CAR T-cell therapy for ALL (57:50) Cytokine release syndrome and neurologic toxicities associated with CAR T-cell therapy and blinatumomab (59:52) Perspective on the role of tyrosine kinase inhibitors in the treatment of Philadelphia chromosome-positive ALL (1:02:09) Efficacy of gemtuzumab ozogamicin in patients with high-risk APL (1:04:46)   Select publications

The Carolina Desis were invited back to their alma mater to speak to a class about the Religion & Politics in India from 1800s to the Present, taught by Dr. Mou Banerjee. Thank you to the students: Lucas, Amy, Ethan, Darian, Liam, and Aaron (special thanks to Aaron for bringing us this opportunity) for the fantastic conversation! This episode is a highlight reel of the various topics we discussed. Shout out to Yash Mistry for editing this month’s episode! Disclaimer: all of the opinions expressed during the discussions are very much our personal opinions as the Carolina Desis and do not represent Clemson University, in any way.

University of Alberta chemistry researcher, Matthew Macauley, speaks about new findings on a protein call CD33 which, it's believed, has an impact on the development of alzheimers disease.

Prof Erba speaks with ecancertv at ASH 2016 about phase 1b trials of combining standard chemotherapy with a CD33 antibody-drug conjugate against acute myeloid leukaemia. He describes the drug design, patient characteristics and response rates, including adverse events with a tendency towards low-grade nausea and diarrhoea, and considers the significant benefits to patient outcomes after a single round of treatment.

Dr Fathi talks to ecancertv at EHA 2016 about an ongoing phase I trial that looks at the use of vadastuximab talirine (SGN-CD33A; 33A) in combination with standard therapies (azacitidine, decitabine) in older AML patients who have declined intensive frontline therapy.

Professor Gert Ossenkoppele from VU University Medical Center talks to ecancer TV about the treatment of acute myeloid leukaemia (AML) in elderly patients. Professor Ossenkoppele notes that standard treatment for elderly patients has mostly stayed the same in the last 30 years. Thus there is an urgent medical need for improvements in this patient group. In contrast, improvements have been made in treatments for younger patients, to whom more intensive treatments can be given. Many promising drugs interfering with the signal transduction pathways of AML cells are currently in phase I and II clinical trials, for example, trials involving gemtuzumab, a monoclonal antibody against anti-CD33. Data with tipifarnib, a farnesyltransferase inhibitor, are also outlined. Professor Ossenkoppele notes that epigenetic modulation of AML cells provides another potential avenue of treatment, with decitabine showing a survival benefit in elderly patients, and the potential place of this drug in therapy is addressed. Furthermore, the promise of allogenic stem cell transfers in the elderly using a reduced intensity conditioning regimen is outlined. Molecular prognostic tools could also be used to help treatment decision-making in older patients.

Background: The capacity of patient's Natural Killer cells (NKs) to be activated for cytolysis is an important prerequisite for the success of antibody-derived agents such as single-chain triplebodies (triplebodies) in cancer therapy. NKs recovered from AML patients at diagnosis are often found to be reduced in peripheral blood titers and cytolytic activity. Here, we had the unique opportunity to compare blood titers and cytolytic function of NKs from an AML patient with those of a healthy monozygotic twin. The sibling's NKs were compared with the patient's drawn either at diagnosis or in remission after chemotherapy. The cytolytic activities of NKs from these different sources for the patient's autologous AML blasts and other leukemic target cells in conjunction with triplebody SPM-2, targeting the surface antigens CD33 and CD123 on the AML cells, were compared. Methods: Patient NKs drawn at diagnosis were compared to NKs drawn in remission after chemotherapy and a sibling's NKs, all prepared from PBMCs by immunomagnetic beads (MACS). Redirected lysis (RDL) assays using SPM-2 and antibody-dependent cellular cytotoxicity (ADCC) assays using the therapeutic antibody Rituximab (TM) were performed with the enriched NKs. In addition, MACS-sorted NKs were analyzed for NK cell activating receptors (NCRs) by flow cytometry, and the release of TNF-alpha and IFN-gamma from blood samples of both siblings after the addition of the triplebody were measured in ELISA-assays. Results: Patient NKs isolated from peripheral blood drawn in remission produced comparable lysis as NKs from the healthy twin against the patient's autologous bone marrow (BM) blasts, mediated by SPM-2. The NCR receptor expression profiles on NKs from patient and twin were similar, but NK cell titers in peripheral blood were lower for samples drawn at diagnosis than in remission. Conclusions: Peripheral blood NK titers and ex vivo cytolytic activities mediated by triplebody SPM-2 were comparable for cells drawn from an AML patient in remission and a healthy twin. If these results can be generalized, then NKs from AML patients in remission are sufficient in numbers and cytolytic activity to make triplebodies promising new agents for the treatment of AML.

Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123(dim) and CD11c- CD123(high)) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2-1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class It molecules, CD33 and low levers of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc gamma RIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming. Copyright (C) 2000 S. Karger AG, Basel.