Podcasts about pi3

In this episode of The Metabolic Classroom, Dr. Ben Bikman explores the metabolic effects of estrogens, particularly their role in glucose metabolism.Estrogens, mainly produced in the gonads, play a crucial role in regulating blood glucose by enhancing insulin sensitivity. Dr. Bikman explained that estrogens improve insulin signaling through pathways such as PI3 kinase and AKT, which are essential for glucose uptake in muscle and fat tissues. Additionally, estrogens activate AMP-activated protein kinase (AMPK), further promoting glucose uptake and maintaining healthy blood glucose levels.Estrogens also suppress glucose production in the liver by inhibiting key enzymes involved in gluconeogenesis, helping to prevent excess glucose release into the bloodstream. In contrast, progesterone decreases insulin sensitivity and promotes insulin resistance, counteracting some of estrogen's beneficial effects. This hormonal interplay affects glucose metabolism during the ovarian cycle, with estrogen-dominant phases being more favorable for glucose control.During menopause, the significant drop in estrogen levels leads to increased insulin resistance and shifts in fat storage, often resulting in more central fat accumulation. While hormone replacement therapy (HRT) can mitigate some of these changes, it comes with risks that need careful consideration. Ben emphasizes the significant role of estrogens in glucose metabolism and their broader impact on metabolic health, especially in women.https://www.insuliniq.com 01:19 - Overview of Estrogens and Progesterone02:20 - Cholesterol as the Precursor to Sex Hormones03:34 - The Role of Aromatase in Estrogen Production04:32 - Understanding the Family of Estrogens05:56 - Estrogens and Glucose Metabolism: Key Signaling Pathways06:54 - Insulin Signaling Pathway Overview08:57 - How Estrogens Enhance Insulin Sensitivity10:04 - The Role of AMPK in Glucose Uptake12:11 - Estrogens' Dual Mechanism in Regulating Glucose Levels13:18 - The Impact of Estrogens on Liver Glucose Production15:33 - Estrogens' Role in Suppressing Gluconeogenesis17:07 - Why Women Have Lower Risk of Type 2 Diabetes19:28 - Metabolic Effects During the Ovarian Cycle21:54 - Progesterone's Influence on Insulin Resistance and Fat Storage25:16 - The Shift in Fat Storage Patterns Post-Menopause26:16 - Hormone Replacement Therapy: Metabolic ConsiderationsPI3K activation leads to the phosphorylation of Akt, a key protein in glucose metabolism, which promotes the translocation of GLUT4 (glucose transporter type 4) to the cell membrane, facilitating glucose uptake into muscle and adipose tissue: https://www.sciencedirect.com/science/article/pii/S155041311930138X?via%3Dihub AMPK acts as an energy sensor and helps maintain cellular energy balance, which is crucial in regulating glucose and lipid metabolism: https://link.springer.com/article/10.1007/s12013-015-0521-z Progesterone increases blood glucose levels by enhancing hepatic gluconeogenesis. This effect is mediated by the progesterone receptor membrane component 1 (PGRMC1) in the liver, which activates gluconeogenesis pathways, leading to increased glucose production, especially under conditions of insulin resistance: https://www.nature.com/articles/s41598-020-73330-7 Hosted on Acast. See acast.com/privacy for more information.

JCO PO author Dr. Samuel J. Klempner shares insights into his JCO PO article, “PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity across 28-8, 22C3, and SP263 assays”. Host Dr. Rafeh Naqash and Dr. Klempner discuss assessing the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer samples. TRANSCRIPT  Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center. Today we are excited to be joined by Dr. Samuel J. Klempner, Director of Gastro Esophageal Medical Oncology and Assistant Professor at Harvard Medical School Mass Gen Cancer Center and author of the JCO Precision Oncology article, “PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity Across 28-8, 22C3, and SP263 Assays.” At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Klempner, welcome to our podcast and thanks for joining us today.  Dr. Samuel J. Klempner: Happy to be here. Thanks for having me. Dr. Abdul Rafeh Naqash: For the sake of this podcast, we'll be using our first names. So, Sam, it was great to see you at ASCO recently, where I believe you presented these data as an abstract as well. Dr. Samuel J. Klempner: Yes, we had a poster presentation for this paper, which was published in parallel with the meeting. Dr. Abdul Rafeh Naqash: Congratulations, and I'm very happy that you chose JCO PO as the destination for these data. So we're going to be talking about a lot of different things today in the context of gastric cancer, which I know you treat very often in your clinic. So could you tell us what the treatment landscape for advanced gastric cancer currently is? Because that goes into the context of why I believe you and your colleagues went ahead with this project.  Dr. Samuel J. Klempner: Yeah, happy to. As you know, unfortunately, half or more of our patients, by the time they come to medical attention for a gastric or GE junction or esophageal adenocarcinomas, unfortunately have advanced disease, often metastatic at presentation. So we have this large population of patients with advanced disease, and over the last couple years, we've actually made some substantial advances in the management and survival of this population. This has been mainly driven by biomarker selection, whether it be adding immunotherapy on top of HER2 therapy, whether it be testing for claudin and seeing the results with claudin directed therapies. And perhaps the vast majority of patients are potentially eligible for immune checkpoint inhibitors. We've seen several phase three trials, perhaps highlighted by CheckMate 649, KEYNOTE 859, rationale studies confirming that there are populations of patients who derive significant survival advantages from the addition of anti PD-1 on top of chemotherapy. So the landscape has really evolved into a biomarker directed world, which is exactly what we hope, because ultimately, the goal is, of course, to match patients with the best drugs at the right time. And that's really the background of where this analytical effort came from.  Dr. Abdul Rafeh Naqash: Thank you for giving us that overview. Going to the second part, which, as you mentioned in your initial overview about the role of immunotherapy, and as we all know, immunotherapy has changed the treatment landscape for a lot of different tumor types. And as clinicians, we often see or ask, what is the PD-L1 positivity for, let's say, lung cancer, which is what I treat, and gastric cancer, which is what you treat. Some of the nuances that we don't necessarily go into when we're looking at those reports is the combined positivity score, the tumor proportion score, or the tumor area positivity. Could you give us an understanding, for the sake of our audience or for the sake of our trainees who might be listening to this podcast, what the CPS, or what the TAP  mean and where they are used in the treatment landscape for biomarker selection in the context of gastric cancer? And how do you approach the different cutoffs for CPS when you're treating an individual in the standard of care setting for gastric cancer? Dr. Samuel J. Klempner: For sure, happy to. So I think eventually it all comes back to patients. When we're sitting in a clinic room with the patient, we want to be able to have features about the tumor that's going to tell us if a therapy is more or less likely to work, maybe if there's a prognostic implication so we have predictive and prognostic biomarkers. And PD-L1 expression does not appear to be particularly prognostic, but it does appear to be predictive of benefit from immune checkpoint inhibitors. Therefore, all of the phase 3 trials that we've seen in some way have linked the biomarker expression to outcomes, whether it's the primary endpoint, whether it's post hoc retrospective analyses, etc. What we've seen is that all of these phase 3 trials have largely used different antibodies to define PD-L1 strata within the trial. So whether that's 22C3,  whether it's 28-8, whether it's 263, those are the predominant antibody clones used to examine PD-L1 expression in tumor samples. And it's been pretty clear across these large phase 3 trials that there is a trend with increasing PD-L1 expression and increasing magnitude of benefit. We see this in the improved hazard ratios in the CPS greater than five or greater than ten versus less than one, etcetera.  However, the scoring systems have varied. There is TPS tumor positivity, which only accounts for tumor cells. There is combined positive score, which accounts for tumor cells and mononuclear infiltrates and involves counting cells. And then perhaps the most recent one is the tumor area positivity, which is essentially a non counting method to look broadly at the area of the sample that is expressing PD-L1. It was on this background that we said, is there analytical concordance among the main antibodies? Our work does not address whether there is difference in clinical outcomes between testing 28-8 and 22C3 and SP263. It is simply a pure analytical comparison of the three antibodies. Is a CPS 5, when you call it by 28-8, somewhat agreeable to a TPS or a TAP greater than five with the same antibody and with a different antibody. So we felt that this was kind of a question that hadn't really been fully addressed in the field and may help contextualize results for clinicians and ultimately cross trial comparisons.  Dr. Abdul Rafeh Naqash: Thank you for that explanation. And you bring forth a very important question. And I remember this example of a patient with lung cancer who had tissue NGS done, and they had a limited gene panel with PD-L1 testing sent that showed a PD-L1 of close to 15 or 20%, and then another NGS panel with a different antibody, suggesting that they had a PD-L1 of close to 60-70%, which significantly changes the overall approach for treatment in the context of blood cancer. Is that something that you experience in gastric cancer also, in terms of variability for CPS, determining what treatment combinations you might be able to put an individual patient on? Dr. Samuel J. Klempner: It's rare that we have samples at any institution tested in multiple methods, but these types of papers and others had looked at some stuff similar and prior to our publication, but we know that there is both spatial heterogeneity. So if you test a tumor versus metastasis, you may have different PD-L1 scoring even in regions of large samples, like surgical resections, there will be some intra tumor heterogeneity in regions of expression. And then we also know that sometimes after therapy, for example, post radiation, there's some data that at the time of surgery, the PD-L1 expression may be higher than what the presurgical sample was. So there's a lot of variables that are factored in. But one thing that wasn't really well known is, across the standard antibodies, how well is the inter assay comparison? There had been some work from a group in Singapore, a very nice paper suggesting that at the higher cut points, the agreement was pretty good across the assays, CPS greater than 5 and greater than 10, and maybe slightly less so at the lower. They had used a different method, which was not really what is standard, and they had used multiplex immunofluorescence or IHC. This is not a validated method for PD-L1 scoring. So that was an open question, sort of. Although they laid a very important piece of data down, we wanted to use the most standard assays and essentially do a very similar analysis, but using the standard scoring criteria. Dr. Abdul Rafeh Naqash: Very interesting. So, could you walk us through the approach of how you looked at this question, what kind of samples you used and what kind of testing algorithms you implemented to look at the cross validation of these three different antibodies? Dr. Samuel J. Klempner: The antibodies were chosen primarily because those are the standard ones that either have companion diagnostics or have been used most commonly in phase 3 trials. So 22C3 has most commonly been linked to pembrolizumab, 28-8 to nivolumab, and 263 used with Roche and Genentech trials primarily. And so we selected the antibodies based on the common use. We selected the scoring systems of CPS and TAP, again based on the most commonly used and validated scoring algorithms in gastric cancer. And then, although most patients in clinic and metastatic disease present with biopsy samples from the primary tumor, there may be some limitations in biopsy samples in terms of small amount of material and ability to reliably count 100 cells, etc., for CPS. So we actually use surgically resected samples from a commercial biobank, 100 samples, and essentially 28-8 was really the reference. And we picked samples that, using 28-8 CPS PD-L1 expression represented the entire spectrum, meaning we had CPS less than 1, we had greater than 1 and less than 5, greater than 5 and less than 10, and greater than 10, so that we could compare across these different strata, because those are the most common strata that have been used in clinical trials and linked to magnitude of benefit. Dr. Abdul Rafeh Naqash: And something that, interestingly, I see here when we go to some of the results, and I'm pretty sure you'll talk about the concordance, is the correlation coefficient seems to increase as the percentage positivity increases for a certain antibody. Could you try to help us understand why that might be the case? Is it because it's easier for the pathologist to look at the slide when there is a certain level of positivity that crosses a certain threshold? Or could there be some other factors that are not well understood. Dr. Samuel J. Klempner: Yeah, it's a totally good question, and I think it's something that's seen in other IHC biomarkers as well. If you look at HER2, you'll see some similar trends. The agreement at IHC 3+ is pretty good and greater than it is at lower cut points. And having talked to multiple pathologists, and I'm not a pathologist, we had three pathologists scoring all of these samples, and essentially, it's what you might expect. It is just easier when there's a lot of the marker. It is easier to judge the high extremes of the strata. So the agreement at greater than 10 is quite good, and this has already been shown by others. It's just an easier thing to score for anyone. The agreement is better across all of the assays at higher cut points, whether it's TAP greater than 10% or CPS greater than 10%. And you can see that pretty clearly in our data, and it's also been shown in other data sets looking at roughly similar questions in other tumor types.  Dr. Abdul Rafeh Naqash: Going to the interesting results that you have in this paper, could you highlight for us some of the important findings that you had and put them into context of what their clinical implications may be? Dr. Samuel J. Klempner: Yeah, I think I'll start with the clinical implications so that what clinicians, and we're both clinicians, what we want to know is, if I have a report that says the CPS is greater than 1 and it's done with a 22C3 test, is that also likely to be greater than one if it had been done with a 28-8 test or scored with a different algorithm - CPS versus TAP? So, essentially, some degree of confidence on the interchangeability between the assays themselves, that is really the clinical implication. And so, to accomplish this, we set out to basically do the comparisons you'd have to do to convince yourself that that is true. So you take samples against a reference range, in this case, across the PD-L1 strata, you pick a reference test, in this case, 28-8, you have one pathologist be the start, and then you compare other pathologists against each other and that person, and you look. And in the pathology literature, they have strata of agreement which tend to go from poor, moderate, good to excellent. And these are sort of accepted standards in the pathology world about inter reader agreement. So between one pathologist and another, and things that are moderate or good are considered essentially acceptable at interchangeable levels.  And so, as you suggested, at the higher cut points, the agreement is very good. The clinical interpretation of that is that if you get a TAP greater than 10% scored on a 22C3 antibody on a Dako staining system, you can feel relatively confident that that would also be called a TAP or a CPS greater than 10 by a 28-8 antibody, suggesting there is good agreement between the two antibodies at that cut point. As you move down, there is a little bit less agreement, and that is consistent with what's been shown before. But in our data set, the agreement was still pretty good across all three of the antibody clones, even at the lower cut point, so greater than 1% for TAP or CPS greater than 1. And that provides, I think, some reassurance to clinicians that whatever test their own pathology lab is using, if it's one of these three assays, they can provide some degree of confidence that what they're seeing would be similar to what they were seeing if it had been done with another test. Dr. Abdul Rafeh Naqash: I think that that is very important, because even though we do want broad testing in general for metastatic tumors, as you probably will agree with, but there's a lot of practices still that institutions tend to do their own testing with limited gene panels or even IHCs. So I think to put that in the context of your study, as you said, if you have a certain antibody that is positive, as you've shown, then that also likely means that with another antibody that your institution may not test for, it's likely the tumor sample is likely going to be positive at a similar level.  So I think you also used digital pathology as part of this project, even though that may not be the most important aspect. As we move slowly and steadily towards artificial intelligence and machine learning, could you tell us how you incorporated the digital assessments and how you utilize them to correlate with the pathologist assessment and the futuristic perspective of how we could eventually try to incorporate digital pathology assessments for this kind of staining approach, which might limit interobserver operability differences as well as time constraints? Dr. Samuel J. Klempner: I hope I can do this part justice, because, again, I'm not a pathologist. But the digital imaging analysis was really essentially used as a quality check and verification tool in our own paper. Our intent was not to establish DIA directly as a superior methodology to TAP or CPS, but simply to provide ourselves some degree of confidence in the staining pattern and distribution across the three assays, and whether or not this would generate significant differences in what the PD-L1 score would have been called. And so, the bottom line is, the digital imaging analysis suggested there were very minor differences across the three assays in terms of, like, percent cell positivity, which is one of the main readouts, and the mean difference was actually quite small. So we felt that the digital imaging analysis, which was really considered somewhat exploratory in our own work, supported what we saw with the pathology comparators read in traditional methods. I think it sets somewhat of an initial pilot data benchmark to say that maybe we can think about moving tools like digital imaging analyses forward in terms of PD-L1 scoring approaches in the future. But it does not provide adequate data to say that we can do this now or we have enough samples and enough comparisons to say that, “Hey, for sure, digital imaging is equivalent to pathology reading.” I think that we're getting there and our data supports that that may ultimately be the conclusion, but for us it was really essentially an orthogonal support and sanity check for our traditional approach, which is, of course, a pathologist based scoring. So supportive and suggestive, but not definitively conclusive. Dr. Abdul Rafeh Naqash: Definitely early days for visual pathology assessments, but I think that it's a very rapidly evolving field, and hopefully we'll see more of this in the next few years, as well as incorporating some assessments into clinical trials.  Now, shifting away from your honorary pathologist role as part of this project to your actual role as a clinician investigator/clinician scientist, could you tell us your career trajectory, how you started, how you've self paced yourself, and how you've tried to mentor certain different individuals in your current role? Dr. Samuel J. Klempner: Yeah, I remember my grandfather and other people telling me, just try to leave it a little bit better than you found it. And so that's, I think, a guiding principle. I hope that at the end of my own career, I can leave oncology a little bit better than when I started. I think the best way to do that is to mentor and train the next generation who are going to drive these practices. I started, like many others, personally touched by cancer in my family, which started me on a journey towards oncology, was somewhat frustrated by the lack of options available to my mom, and then became deeply interested in the science and how come we knew so little about cancer, so spent a fair amount of time in labs, and had a really formative experience with Lew Cantley looking at PI3 kinase resistance and signal transduction, and wanted to learn to speak the language and interact with people driving the lab based work. And that's been something I've tried to keep as central to my career as someone who has a very strong translational interest.  And so I try to think of ways that I think we can learn from every single patient and every subgroup. I mean, for example, in our own work here, it's very unclear if there's a biology linked to the different PD-L1 strata. So for example, does a PD-L1 CPS greater than 10 tumor have a very high interferon gene signature? Or are there features of the T cells that are different between a CPS 10 or higher versus a less than 1? So PD-L1 is a biomarker, but is it really telling us about biology? And so these are the types of questions that I try to stimulate in all the residents and fellows and hopefully it will drive translational projects. But I think just having the conversations and asking the questions and talking to people. I mean, I love the ASCO Career Lounge and always try to do that when possible. I know you do the same. I think staying curious is really the thing that I try to remain in life and also in my career and have fun and enjoy with your colleagues. And I think that will make us all better researchers and ultimately translate to better outcomes for our patients, which is, of course, why we all do this. Dr. Abdul Rafeh Naqash: Wonderfully said Sam, thank you so much. Thanks again for choosing JCO PO as the final destination for your work. Hopefully we see more of the similar work that you do in your field in JCO PO. And thank you for talking to us about your journey as well.  Dr. Samuel J. Klempner: Yes, thanks for having me. I'll talk to you sometime soon.  Dr. Abdul Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.   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.     Disclosures Dr. Klempner Stock and Ownership Interests TP Therapeutics Nuvalent, Inc Honoraria Merck Serono Consulting or Advisory Role Atellas Pharma Bristol-Myers Squibb Merck Daiichi Sankyo/UCB Japan Sanofi/Aventis Mersana Exact Sciences Novartis SERVIER AstraZeneca Amgen I-Mab iho Oncology    

The landscape of medication to treat ER+, HER2 negative or low is changing rapidly as patients experience progression on CDK4/6 inhibitors and look for next steps.  Now that biomarker testing is more readily available (both tissue and liquid), there are more options particularly in the PI3 kinase pathway.  In this episode we will discuss biomarker testing, the PI3 kinase pathway, and an exciting new patient initiative, the PIK3CA Pathbreakers.

Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo:  You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike  fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us.   Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of  1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it's very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer.  Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you're talking about? Dr. Hope Rugo:  The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo:  I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope,  is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn't really show a whole lot that the company wanted to pursue.  So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that's a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting.  I think that probably these early-stage trials are going to end up being big; they're going to have be clean. I'm guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we're not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow.  How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson:  I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo:  That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thanks so much.   Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Follow today's speakers:     Dr. Hope Rugo  @hoperugo  Dr. Nancy Davidson     Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Nancy Davidson: No Relationships to Disclose    

On this week's episode of the Dairy Edge, Sarah Higgins, Ruminant and Equine Veterinary Manager with MSD, discusses Bovine Respiratory Disease (BRD) but in particular Bovine Coronavirus. Sarah first explains BRD and the risk factors that predispose animals to the disease.  Bovine Coronavirus is a coronavirus, though it is not associated with COVID-19 having been first identified in the 1970s.  Research has shown a very high prevalence of the disease both across Europe and in Ireland and it is associated with ‘opening the gate' for other BRD elements such as RSV, Pi3 and mannheimia haemolytica.  Given its prevalence and its gateway action, MSD have recently released a vaccine for administration from birth to counteract this virus. Sarah then discusses herd health planning with the farm's vet to establish a strong vaccination programme to deal with issues that occur on the farm. With reducing antimicrobial availability, vaccination strategies to maximise the health of the herd will be important Sarah finishes by saying that while antimicrobials will still be required to treat disease when it occurs, the use of the right product at the right rate for the right length of time, is an important contribution farmers can make to reducing the risk associated with antimicrobial resistance along with an appropriate vaccination strategy. For more episodes from the Dairy Edge podcast go to the show page at: https://www.teagasc.ie/animals/dairy/the-dairy-edge-podcast/ The Dairy Edge is a co-production with LastCastMedia.com

Sarah Higgins, Ruminant & Equine Manager with MSD joins Stuart Childs on this week's Dairy Edge podcast to talk about Bovine Respiratory Disease (BRD) and its impact.  Sarah outlines what BRD is, how it impacts on animals and what people can do to reduce the impact it has on their herds. Sarah explains that while vaccination from the day of birth against RSV and Pi3 is now possible, this alone is not going to solve respiratory issues on farms and farmers need to take a broader view of trying to limit the effect of the disease. Finally, Sarah spoke about coughing cows and explained that this is in effect another symptom of BRD on farms with increased resistance to lung worm doses a significant causal effect on some farms.  She cautioned that people need to consult with their own veterinary practitioner to develop an appropriate strategy to deal with BRD on their own farms. For more episodes from the Dairy Edge podcast go to the show page at: https://www.teagasc.ie/animals/dairy/the-dairy-edge-podcast/ The Dairy Edge is a co-production with LastCastMedia.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.29.526107v1?rss=1 Authors: Attisano, L., Christova, T., Ho, S. K. Y., Liu, Y., Gill, M. Abstract: The establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning and formation of neuronal circuitry. Here, we demonstrate that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, loss of Ltk and/or Alk yields a striking multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk results in a delay in neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and there is a disruption of the axon tracts in the corpus callosum. Mechanistically, we show that loss of Alk and Ltk increases cell surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which acts to activate downstream PI3 kinase signalling to drive the excess axon phenotype. Thus, our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioural abnormalities. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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

Today N3M0 and M1L3S face off against PI3 and MANCH3ST3 of the stars in the nutshells. Who will win eternal bragging rights over the other podcast? Make sure to leave a 5 star review on Apple Podcasts and Spotify and send in an email to be featured in the next episode. Check Out Their Stuff! Podcast- Brawl Stars in a Nutshell Our Stuff Patreon: patreon.com/eternalbrawl YT- Eternal Brawl, DynaMI Brawl Stars Email- eternalbrawlpodcast@gmail.com Club- Eternal Brawl #2RL22LCLG Friend Code- #2U2RCRURV(Nemo) | #8YJ92Y8P0(Miles) Website- anchor.fm/eternal-brawl Other Eternal Podcasts- Eternal Royale- by Little D, Eternal Tunes- by Jude --- Send in a voice message: https://anchor.fm/eternal-brawl/message

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Henry. Dr. Lynn Henry: Thank you very much for inviting me to participate. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Henry, do you have any relevant disclosures that are related to this guideline topic? Dr. Lynn Henry: No, I do not. Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update? Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time. When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included. The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well. Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing? Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone. This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations. Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma. Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor. Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor. Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations? Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation. Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline. Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations? Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor. This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums. In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor. The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants. Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency? Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time. Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer? Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test. At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy. The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater. Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use. Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high? Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab. In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs. In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used. Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden? Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions. However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically. Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables. So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment. Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase? Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions. So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer. Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA? Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression. Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question. Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells? Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer. To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer. Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations? Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer. Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers. Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future. Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer? Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients. Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers. Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry. Dr. Lynn Henry: Thank you so much! Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   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.  

On this week's podcast, we'll review a recent analysis of phase 3 daratumumab studies looking at the prognostic impact of sustained minimal residual disease, or MRD negativity in patients with multiple myeloma. Next, we'll hear more about a novel thrombolytic agent targeting von Willebrand factor that may represent a promising approach for the treatment of thrombotic thrombocytopenic purpura. We'll conclude with a study demonstrating that PI3 kinase inhibitor duvelisib can be used to enhance the in vivo efficacy of CAR T cells in CLL.

Join Scott as he discusses #CircuitPython2022, answers questions and chats with ladyada. Support Scott and Adafruit by purchasing hardware from https://adafruit.com Chat with me and a lot of others on the Adafruit Discord at https://adafru.it/discord. Deep Dive happens every week. Normally Fridays at 2pm Pacific. Next week is on Friday. All notes are available on GitHub with links into the videos. Thanks to @askpatrickw and @dcd for making and maintaining the notes: https://github.com/adafruit/deep-dive-notes/ 0:00 Getting Started 3:44 welcome 4:30 camera product mode - microprocessors running circuitpyton 9:17 CP 2022 planning review / introduction 12:30 First blog https://blog.adafruit.com/tag/circuitpython2022/ 14:10 Plans for time off in April - maybe Aug-Oct 16:50 Initially BLE on ESP work 17:00 https://blog.adafruit.com/2022/01/13/scotts-circuitpython2022-tannewt/ 22:39 difference from Arduino, difference from ESP? 23:50 Reading out display data in hardware testing. 25:00 BitmapSaver library can save a screenshot. Then CPython code running on a PC can use PIL to compare it with "known good" copies of the image. 24:42 updates in UF2 repo for display 26:55 Python easy to read? 28:05 Arduino Leonardo-type board with built in Bluetooth. I want to build a Bluetooth Macropad, but I can't find any documentation that helps me. Do you know where can I go to find this? 29:38 USB Host / would love Pi 400 self contained 30:55 Async Networking 31:13 Testing 31:24 tracking “regressions” - things that used to work - github issues labels 33:4Are regressions board or port specific, or are they general regressions 34::52 hoping non-iDevices will get some love for BLE workflows. I've been unable to get code.circuitpython.org working on neither Android or PC 35:22 Android and iOS updates to older apps 36:30 Maybe the community can identify "Port Champions" (or maybe the chip mfgers can step in here) 37:45 Automation and testing 38:41 Rosie-ci in adafruit github 39:42 sommersoft RosiePi repo https://github.com/physaCI 40:43 ,,, using Python to develop API for the ESP family of hardware? 41:40 Is there anything that Gerry does other people could easily replicate for testing? 42:22 What is the timeline for ESP32-S3 gets Arduino support https://github.com/espressif/arduino-esp32/issues/5594#issuecomment-1001514885 43:00 RPi CP baremetal question for you: are Pi3 and/or Pi400 on the map? 45:00 Any pointers/examples of OTA update of CP devices? 46:42 thoughts on simulated hardware for testing 47:44 P400's C port works for gadget mode I think 49:07 This would only replicate what CP “thinks” is displayed on the screen. What about knowing if there is a bus error like we saw on this?: 49:40 not a priority, but any more thoughts on allowing either FS access to the OTA partitions if folks want, or a way to disable OTA to reclaim more flash space for those that want? 50:27 OTA update process 51:30 is OTA exclusive to ESP? 52:29 IDF support ( table posted to discord at 2:48 PST ) 53:15 switch to desktop / learn guide / Circuitpyton-on-raspberry-pi-bare-metal-no-os 55:50 github repo pull requests pr 5858 56:35 pr 5662 58:45 ​Do you have a ESP32-S3-DevKitC-1-N8R8 yet? I got one but it has Octal PSRAM so builds online don't work yet. Hope it becomes a build target. 1:03:20 downloading the latest CP 1:04:26 Authy two factor authentication demo! 1:05:20 wifi on the S3 https://github.com/espressif/arduino-esp32/issues/5594#issuecomment-1001514885 1:06:00 Cat woke up :-) 1:07:00 split out target specific configs pr 5853 1:08:18 make board menuconfig 1:09:44 switch cp to core 1 on S3 pr 5860 1:11:00 Blinka mascot 1:11:50 grokked - slang for understood 1:12:39 Lady Ada dialed in 1:16:40 grok, ping, foobar, and other lang 1:18:37 Lady Ada on screen 1:19:17 HDMI output from microcontrollers 1:20:30 HDMI on pico 1:23:00 https://github.com/Wren6991/PicoDVI 1:25:00 retro look 640x480 by doubling 320x240 1:25:40 use rPi, since FPGAs are unavailable 1:27:00 composite video 1:29:20 PS2 keyboards 1:29:50 BRAM = Block Ram 1:30:00 ML on Raspberry pi 4 - demos and learn guides 1:31:20 TensorFlow vs TensorFlow Lite 1:32:30 ML is statistics in Disguise 1:37:08 Lady Ada signed off 1:38:30 Access to high res camera on raspberry pi ? 1:39:20 Add floppy IO - pr 5832 1:40:22 not getting past the rainbow screen - perhaps GDB could help 1:42:20 caught up on discord 1:43:30 Touch TFT - can we remove it ? 1:53:00 Minute with NimBLE ( espressif.com ) 1:59:00 WiFi workflow discussion - web REPL 2:00:00 difference between sockets and ports 2:02:50 Deep Dives notes auto publish in a few hours 2:03:16 housekeeping wrap-up - next week deep dive on S3 2:04:10 2pm Friday next week 2:04:43 Pet the cat 2:05:23 thanks again

In this episode, AABP Executive Director Dr. Fred Gingrich is joined by Dr. Justin Kieffer, former chair of the AABP Committee on Pharmaceutical and Biologic Issues (CPBI). Dr. Kieffer led a team of AABP members in the development of the first bovine vaccination guidelines produced by AABP. We discuss the development of this resource document that is available exclusively to AABP members to assist them in developing vaccine protocols for beef and dairy operations. We discuss how veterinarians can consult with producers in optimizing the immune response to vaccines as well as minimize adverse events and what to do if there is an adverse event. Dr. Kieffer updates us on the implementation of the single tier vaccine labeling in 2015 by USDA APHIS. CPBI developed a list of core vaccines for cattle which includes BVD, IBR, BRSV, PI3 and Clostridial pathogens. The vaccine guidelines discuss each pathogen's disease considerations, type of vaccines that are available, outbreak mitigation, and vaccine scheduling notes. The document provides this information for all core and risk-based vaccines that can be considered for cattle. Dr. Kieffer states that veterinarians should inform their producers that no vaccine is completely safe, no vaccine is completely effective and no vaccine is always indicated. AABP recommends that producers utilize the expertise of the veterinarian of record to develop and monitor vaccine protocols to improve the health, welfare and productivity of the cattle in their care. We encourage feedback from members on the guideline by emailing fred@aabp.org. If you are a current AABP member, you can view the vaccine guidelines by going to the AABP Committee Resources page and opening the Pharmaceutical and Biologic Issues section. You will find the guideline as a downloadable PDF at the bottom of the CPBI resources page. The link for the USDA APHIS veterinary biologics product summaries to view vaccine data for the single-tier labeling claim is located here. Practical immunology and beef and dairy vaccine protocolsChris Chase2021 AABP Recent Graduate Conference Proceedings The vaccine guidelines developed by CPBI is an example of AABP providing practical resources for members. If you are not an AABP member and you are working with cattle, we welcome you to join our organization. You can join AABP or renew your dues to become a current member, by going to this link. Have a podcast suggestion or feedback? Email  haveyouherd@aabp.org 

Hallo Leute, heute gehen wir noch einmal detaillierter auf Nicos Opnsense Setup ein und warum ich meine Fritzbox 7412 als DSL Modem wieder heraus geschmissen habe. Außerdem erzähle ich von einem Dienst um (fast) jeden Scanner, netzwerkfähig zu bekommen mit einen einfachem Webfrontend, welches auch auf dem Handy gut funktioniert und einen Pi3 als Server, um den Dienst laufen zu lassen. Als letztes sprechen wir noch über ein paar Tipps, um bei euren Proxmox Host, Strom zu sparen. Viel Spaß beim Zuhören! Links: Scanserverjs Zyxel VMG1312-b30a - DSL Router/Modem PVE "use pointer for tablet" deaktivieren Proxmox CPU Governor ändern Zyxzel VMG1312-b30a Telekom Firmware OPNsense Selfhosted-Adventures Links wie Twitter & Blog

Dr. Hayes interviews Dr. Pamela Goodwin on her work in metabolism and cancer.   TRANSCRIPT SPEAKER 1: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement [MUSIC PLAYING]   SPEAKER 2: Welcome to JCO's Cancer Stories, The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of this shows, including this one, podcast.asco.org. Today my guest on this podcast is Pam Goodwin. Dr. Goodwin was instrumental in the consideration of metabolism, exercise, and diet for prevention and/or treatment of breast, and for that matter, other cancers. Dr. Goodwin received her undergraduate medical degree from the University of Ottawa, and then she did a residency in internal medicine at the University of Toronto, where she also did a year residency in pathology, which I was unaware of. She went on to train in oncology at Princess Margaret Hospital in Toronto, and she spent a year as a research fellow with, in my opinion, the legendary Dr. Norman Boyd. She's on a clinical appointment at Mount Sinai Hospital in Toronto, where she directed the breast program for 15 years. And she's remained on faculty for the University of Toronto since 1986, where she is now the Marvelle Koffler Chair in breast research and a professor in the departments of medicine and clinical epidemiology. She's won many, many awards for her contributions to science, but perhaps most germane to this discussion-- and I was unaware-- she was named a star in nutrition and cancer by the United States National Cancer Institute a few years ago. She's authored over 200 peer reviewed papers. And she serves as the current editor in chief of the Journal of the National Cancer Institute Cancer Spectrum, and she's also deputy director of JNCI. By the way, she receives research funding in collaborations with Epic Science but has no other declarations of conflicts. Dr. Goodwin, welcome to our program today. PAM GOODWIN: Thank you. It's a pleasure to be here. SPEAKER 2: So let's start with a [INAUDIBLE] question that I ask almost everybody in this series. And that is, tell us a little about yourself and why oncology. Was there a light bulb that went on, or you knew you were going to be an oncologists from the time you were in kindergarten? PAM GOODWIN: Well, I was born in Ottawa. And when I was a young girl at five years old, we moved into the country. And it was just outside of Ottawa, but it's now called Kanata. But at the time, it was a very rural area. And I started my education in a one-room schoolhouse. By the time I was halfway through my schooling, they put a division down the middle of the room and it became a two-room schoolhouse. But from the very beginning, I remember in grade 1 sitting at the back of my row-- each grade had a row-- and I would listen to the lesson from my row. And the teacher would move to the next row, and I would listen to that lesson, and then I would listen to the next lesson. I always wanted to learn more. I became interested in oncology for a reason that many oncologists have. My mother had cancer and died when I was still in school. And-- jeez, still emotional. And it really made me realize that-- at the time, cancer was almost uniformly fatal. It made me realize that there was a lot of work to be done in the area of cancer. So I very early on decided that I was going to do medicine and that I was going to do oncology, and I never looked back. SPEAKER 2: So neither of your parents was a physician? PAM GOODWIN: No, no. My mother actually worked in the finance department on Parliament Hill for the government of Canada. And my father, in the 1950s, worked on computers for the Department of National Defense. So no medical people there at all. SPEAKER 2: Well, at least it sounds like there was some science behind you. And when you went into oncology then, were you just dedicated to breast cancer because of the history you just gave us, or was there somebody who talked you into being a breast cancer person? PAM GOODWIN: I think Norman Boyd had one of the biggest influences me. My mother didn't have breast cancer, she had myeloma. But Norman, at the time, was at Princess Margaret Hospital and was very interested in diet and breast cancer risk. And I was very interested in the role of the patient in cancer from the very beginning. I thought I might end up doing research in quality of life, because that was an emerging field at the time. But I became very interested in the host factors in obesity, metabolism. And I chose to focus on how these factors impacted the clinical course of cancer for the most part, and I focused on breast cancer. At the time, it was way, way out there to work in this area. And one of my biggest challenges as a new investigator and a new staff person was to be sure that people didn't think I was a little bit of a quack by working in this area. SPEAKER 2: Actually, I have two follow up questions for that, and I'll get to that in just a moment. But can you tell us a little more about Dr. Boyd. I mentioned him earlier as being legendary, but a lot of our listeners may not know who he is and what he's done. PAM GOODWIN: So Norman Boyd was a medical oncologist at Princess Margaret Hospital who became a clinician scientist over the years. He was very interested in the role of dietary fat in breast cancer and actually conducted a randomized trial of dietary fat reduction, which, unfortunately, didn't show a beneficial effect on breast cancer. But he was one of the grandfathers of the mammographic density breast cancer risk association. And he did a very large amount of work confirming that association, quantifying that association, and identifying how it made independent contributions to breast cancer risk over and above family history, for example. SPEAKER 2: I want to say, I have-- obviously, I think you can tell-- enormous respect for Dr. Boyd. He's truly a giant. However, he's caused more trouble in the United States than he knows, because every woman has a mammogram. If she has dense breasts, she gets a little piece of paper saying, speak to your doctor about this. And then we say, I don't know what to do about that. PAM GOODWIN: That's right. That's right. That happens in Canada sometimes too. SPEAKER 2: So you've talked about Dr. Boyd being a stimulus. And you sort of hinted on this. Were there obstacles? I can imagine mentors at the time at Princess Margaret or other places saying, are you crazy? This will go nowhere. You're wasting your career. PAM GOODWIN: Well, I think a lot of people thought that it was a little bit crazy. I think a lot of people thought that it was possibly these people were being under dosed with chemotherapy, that the obesity cancer link wasn't a true biologic association. And that's one of the reasons that I have practiced at a general hospital my whole life. At a general hospital, we have a very strong diabetes and endocrinology department. And they fully understood that these factors could be important. They had seen the impact of diabetes on a host of organs-- end organ disease in the kidney, for example-- and they were very open to this type of research. And I was actually recruited to Mount Sinai Hospital by a guy called Lou Siminovitch, who was a molecular biologist. He had just set up a new research institute at Mount Sinai Hospital. And even though he was not an MD, he wasn't a clinician, he would look at all of my grants and ask the most important question, find the fatal flaw that needed to be fixed before it went in. And Lou continued to support me throughout my career. He died just a couple of weeks ago just shy of his 101st birthday. SPEAKER 2: Oh my. That's great. So you mentioned your grants. Was it hard to get funded early on when you started this? PAM GOODWIN: With some organizations, yes it was. But I think because I always presented this as a biologic association and my focus, at least early on, was to try to identify what was the biologic link between obesity and breast cancer, I think my grants were somewhat better received. I think I always had hypotheses relating to the biomarkers and not just to the prognostic association. Now it wasn't always easy, because my first study was a prospective study of obesity and breast cancer. And towards the middle of the 1990s, we confirmed the association and we looked at biomarkers. We collected fasting blood during the study. We looked at biomarkers focusing on insulin, because there was some emerging evidence that insulin might be associated with cancer. And we actually showed that insulin was strongly associated with obesity and was a stronger predictor of breast cancer recurrence and death than obesity. So as a young staff person-- I think I was an associate professor at the time-- I wrote that up and I sent it to The New England Journal of Medicine, thinking that I really had a great finding there. And New England gave me three reviews. Two of them were glowing. They were fantastic, really nothing to change. And the third one said, I see nothing wrong with this paper, I simply don't believe the results. And New England rejected it. SPEAKER 2: It's always the third reviewer. PAM GOODWIN: That's right. But it took another three years to get it published in JCO. And it's now my most highly cited paper, so go figure. SPEAKER 2: That's interesting. So you talked a bit about the biology. Again for our listeners, my impression is not just that obese people get cancer, but that there is an underlying biology that connects them. Can you go through what your work to show that, and others for that matter. PAM GOODWIN: Yeah, so it's a really complicated association. And the biology of obesity is complicated. There is an alteration or a change in adipose tissue in individuals that are obese, and that's associated with a change in physiology. And both of those factors can then impact the development and prognosis or clinical course of breast cancer. We focused more on the physiology. We've looked at insulin, which I think is now accepted as a growth factor in breast cancer. Most breast cancers express insulin receptors on their surface and insulin that is circulating signals with those receptors to turn on the PI3 kinase pathway. Hyperglycemia, which is associated with obesity, may also change cellular metabolism. And there's a lot of people that have been focusing on inflammation in the adipose tissue. Andy Dannenberg's group in New York has probably been the main people in this area. We've recently looked at that, and we've actually found-- Martin Chang, a pathologist who worked with me at Sinai, and he's now in Vermont, he recently found that the type cellular response to obesity that occurs in adipose tissue may actually determine the physiologic response to obesity and whether obesity impacts breast cancer outcomes. So in other words, if there are CD68 positive macrophages in adipose tissue, you're going to have insulin resistance and you're going to have poor breast cancer outcomes. But for another woman who has the same BMI, if she has an absence of those CD68 positive macrophages in the adipose tissue, she will not have insulin resistance and she will not have worse breast cancer outcomes. So we're trying to focus there on what is the link between the adipose tissue response and the physiologic response and what drives that. SPEAKER 2: I think almost everybody listening to this podcast knows that over the last 15 or 20 years, we've really broken breast cancer into a number of different kinds of cancers. In fact, I really believe that they all happen to be different cancers that happen to start in one anatomic site-- the breast-- as opposed to being all breast cancers. Have you seen differences in the emergence or potential treatment of different subtypes related to obesity or obesity management? PAM GOODWIN: So in some of our earlier work, we actually found that obesity was "perhaps" a little bit more prognostically important in ER negative breast cancer. And I put the word perhaps in quotation marks there. I think more recent work has not shown that, and that obesity contributes across the spectrum of breast cancer. To the extent that obesity impacts are related to estrogen, then you're going to see a greater impact in hormone receptor positive breast cancer. But the association is really seen across the spectrum of breast cancers. SPEAKER 2: So another question that raises-- and others have addressed this-- do you think it's obesity or specific types of diets that are the culprit? PAM GOODWIN: I think it's obesity. I think diet contributes to body size, and I think the composition of the diet may play a role in the response to obesity. But I think that if you are normal weight and have non-obese physiology, the dietary composition doesn't matter quite as much. I think right now when people are looking at diet, they're no longer looking at the fat content of the diet. They're looking at whether it's a healthy diet, whether there are legumes and nuts and healthy oils, but they're also looking at the glycemic index of the diet. I think all of that contributes, but my read is that obesity is the primary driver of this association. SPEAKER 2: And do you think that once you have obesity, it's too late, losing doesn't help. In other words, this is something that's imprinted early on, because I do want to get into treatment too, but especially for prevention. PAM GOODWIN: So that's an unknown. Steve Hursting's group has actually done an experiment where they had mice that were either fed a normal diet and weren't obese, or were fed an obesogenic diet and became obese. And the ones that became obese, a group of them, half of them were put back on the normal diet and they became non-obese. And then they injected all three groups with cancer cells. And what they found was that the currently obese and the formerly obese mice had tumor growth that was the same and was much greater than the mice that were never obese. And they also found patterns of DNA methylation and gene expression in the mammary fat pad that was similar in the formerly obese and the currently obese mice and different from the never obese mice. That suggests that, perhaps, there may be some carryover after weight loss. But I think we need to be very, very careful. The tumor cells were injected almost immediately after the weight loss. And these were mice, they weren't people. People, I think, are a little bit more complex than mice. SPEAKER 2: I mean, this raises-- actually, I have to say that this entire series for me has been, what if I was in a cab with these people who have been experts and pioneers in a field and I can just ask ask them any questions I want to. These are questions I've been wanting to ask you for 20 years, but we never had the opportunity. So the other thing is it's a little bit like early pregnancy. We know there is something about early pregnancy that imprints a cancer reduction compared to late pregnancy. And as you know the Russos have worked on this for years and years. And I've wondered if that's the case with obesity, but now I'm going to [INAUDIBLE] myself instead of you. It's just something I've thought about for a long time. PAM GOODWIN: We're not going to know until we get the results of some studies. The BWEL study led by Jennifer Ligibel looks at weight loss after breast cancer diagnosis. It's fully accrued. It's a randomized trial. It will give us some definitive information. But our group did a small randomized trial called the LISA study, which were reported out about a year ago. And in that study, we actually showed that there was a reduced risk of breast cancer recurrence in women that were randomized to the dietary-- the weight loss intervention arm. The hazard ratio was 0.71. We'd hypothesized a hazard ratio of 0.76. So it looked good, but we did not complete accrual on that study. So we didn't have the power to conclude that the effect that we saw was actually significant. But I actually think that those results are-- I think they're going to lead us in the direction that we hope to see in the BWEL study. In other words, I think that the effect of obesity will not be fully baked in and that there may be some ability to reverse it. We know that losing even 10% of weight will reduce insulin, for example, by 20% to 30%. We know we can see major changes in physiology when we see weight loss. SPEAKER 2: So in your work with [INAUDIBLE], so go back to biology, and you had an opportunity then to look at things like methylation patterns before and after weight loss in cancer cells, or what's getting turned on. You talked about the CILs in macrophage infiltration, but are there things going on in the cancer cells themselves-- or the normal cells for that matter-- that make them more or less susceptible to going on to become nasty cancers? PAM GOODWIN: So that's a little bit beyond my focus. In the BWEL study, blood is being collected repeatedly. So we'll at least be able to look at those changes in lymphocytes, for example. When you're looking at the adjuvant setting, there's no tumor to rebiopsy. And I'm not convinced that the obesity link is the same in the metastatic setting as it is in the adjuvant setting. Once you get into the metastatic setting, the presence of tumor itself may alter metabolism and may impact a lot of the factors that we're looking look at. SPEAKER 2: I'd like to ask you to look forward a little bit now too, because especially in your early work with epidemiology and a focus on lifestyle changes and weight loss, do you think that's going to be where the magic bone will be, or will it be a drug that people can take? I know you've worked quite closely with the Metformin. And imagine you looked in a crystal ball here, I know it's cloudy, but maybe you can give us some insight. PAM GOODWIN: Well, we've looked at Metformin initially because it was an insulin lowering drug. And then Grahame Hardie identified the AMP kinase mechanism of action, and now there's a host of direct antitumor effects that have been reported with Metformin. I think that Metformin in many ways is an anti-obesity physiology drug. It improves much of the physiology associated with obesity. As you know, we've done work showing that it lowers insulin in non-diabetic patients who have breast cancer. We've also done a neoadjuvant window of opportunity study, where patients were given Metformin for the two weeks between diagnosis and definitive surgery. And we showed that Metformin actually lowered T67 and increased apoptosis in the cancer cell. So that was the time when we could look at the cancer cells before and after drug administration. So I think we may see some direct-- or we may see some tumor effects. As you know, we have the large MA-32 adjuvant trial-- 3,600 patients-- which is about to be analyzed. It will likely be analyzed in the next two to three months, and we'll have a definitive answer as to whether Metformin will improve breast cancer outcomes. And because we're looking at contralateral breast cancers, we can also look at whether it impacts the development of breast cancer. SPEAKER 2: At night, do you look up at the ceiling and worry about things like everolimus and alpelisib that actually block the insulin pathway, and then we see hyperglycemia? I don't know if you've treated many people with alpelisib, but hyperglycemia is one of the major consequences of that. Could we actually be in a vicious cycle with using these drugs, or am I reaching too far? PAM GOODWIN: No, I worry about it. I do. It's the same with the IGF1 receptor blockers. I think that sometimes we don't look at the impact of a drug that we believe targets the tumor on the patient's physiology, and the patient's physiology may then actually impede the ability of the drug to treat the breast cancer. If we look at the use of, for example, aromatase inhibitors in premenopausal women, they raise the estrogen levels and the tumor may progress more quickly. We have an example of that. And I think whenever we're doing anything, we need to look beyond the drug itself to the impact-- the drug and the tumor to the impact it has on the patients. I mean, one of the really interesting things that I've seen recently is that some of the PD-L1 inhibitors, when you look at them used to treat cancers other than breast cancer-- I don't think we have this information yet in breast cancer-- being obese actually predicts a better response. So there's something about the synergy between the PD-L1 inhibitor and the obese physiology that makes the PD-L1 inhibitor work better. And some people think it's leptin that is playing a role, but I don't think that's been definitively established. SPEAKER 2: I was not aware of that. Actually, when I was at the Dana-Farber, Chuck Scher, who discovered PD, Platelet-Derived, growth factor, was an endocrinologist. He's a PhD, but he's an endocrinologist by training. And he used to tell me the cancer is just endocrinology gone wild, so you need to understand endocrinology if you're going to be an oncologist. And I'm learning that in spades now 40 years later. PAM GOODWIN: Well, when it comes to breast cancer, yeah, that might be true. Only-- SPEAKER 2: Well, especially in breast cancer, I think. Let's get away from breast cancer for just a moment. I'm towards the end here. And what do you think the role for obesity and diet in other cancers? Do you see such a strong association? And do you have optimism that the kinds of things you're doing in breast cancer will spill over to the others? PAM GOODWIN: So I think obesity is important for cancer in general. I think obesity is associated with increased risk of most types of cancer. And I think it's even more important in cancers like endometrial cancer than it is in breast cancer. I think that what we're learning about obesity and breast cancer will be applicable to multiple other types of cancers. One of the big things we need to think about, though, is that we're in the midst of an obesity epidemic. And at some point, this becomes a societal issue. Obesity is a bad thing for cancer. It's a bad thing for many other illnesses too. And it's probably contributing to a shortened life expectancy for obese individuals. And we need, as a society, at least in the developed world, to start thinking about what we are going to do to try to reduce obesity, to try to get people to eat healthy and to eat proper portion sizes, and to become physically active or to be more physically active. I put that in a very blunt way, but I think these issues extend far beyond breast cancer, far beyond cancer, and really into our general health and well being. SPEAKER 2: Yes, I agree. I've been fond of saying that I think obesity is the smoking of the next generation. I think we're going to pay the piper for this. PAM GOODWIN: I think you're absolutely right. And I think we have a generation that's coming up that maybe has never known proper portion size and knows, at a theoretical level, about healthy eating but doesn't understand how to put it into place and follow a healthy diet and be physically active. And because the obesity epidemic is really just the last generation or generation and a half, we should be able to turn it around. This is not something that's baked into our genes. This is something that we, as a society more so than as individuals, [INAUDIBLE]. SPEAKER 2: Well, and I think when we finally do recognize that and understand how to treat the obesity, people will remember that you were at the forefront-- I don't want to age you-- but 30 or 35 years ago when the whole field got started. So thank you for your courage in going that way. Many of us took the path of least resistance. I don't think you did. Anyway, so thanks for taking time to speak with us today, very much appreciated. And thanks for all you do for the field, and most importantly for our patients. I'm fond of saying that to almost all of our speakers. Without the people who have been on this series, we wouldn't be where we are today. So I'm very appreciative of it. Have a good day. Buh-bye. PAM GOODWIN: You too. Buh-bye. SPEAKER 2: Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org. [MUSIC PLAYING]

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Drag From The LEFT w/ your hosts Avery Ware & Juanita Bind'Em, a weekly digital series where we dish all things drag and pop culture through a radical leftist perspective. On this week's episode of #DragFTL we discuss #RPDR Season 13 Episode 8, the sanctity of “lipsync for your life”, and $herry Pi3. Drag from the LEFT and Call'n/Call Out are recorded live every Sunday at 6PM EST with your hosts @AveryWare and @JuanitaBindem on Stereo App. Drag From the LEFT is available everywhere podcasts are streamed: https://linktr.ee/DragFTL Tune in for our after show, Call'n/Call Out, Uploaded Wednesdays @ 5PM. --- Support this podcast: https://podcasters.spotify.com/pod/show/drag-from-the-left/support

What if there were a single company that could connect hospital electronic health record systems to a massive genomic testing and analytics platform? It would be a little like Amazon Web Services (AWS) for healthcare—an enabling platform for anyone who wants to deploy precision medicine at scale. That's exactly what Joel Dudley says he's now helping to build at Tempus.When Harry last spoke with Dudley in January 2019, he was a tenured professor of genetics and genomics at the Icahn School of Medicine at Mount Sinai Medical Center and director of the Institute for Next Generation Healthcare. But later that same year, Dudley was lured away to Tempus, founded in 2015 by Eric Lefkofsky, the billionaire co-founder of Groupon. Tempus is building an advanced genomic testing platform to document the specific gene variants present in patients with cancer (and soon other diseases) in order to match them up with the right drugs or clinical trials and help physicians make faster, better treatment decisions. In this week's show, Harry gets Dudley to say more about Tempus's business—and explain why it was an opportunity he couldn’t turn down.You can find more details about this episode, as well as the entire run of MoneyBall Medicine's 50+ episodes, at https://glorikian.com/moneyball-medicine-podcast/Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:• Launch the “Podcasts” app on your device. If you can’t find this app, swipe all the way to the left on your home screen until you’re on the Search page. 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Thanks!TRANSCRIPTHarry Glorikian: The last time I had Joel Dudley on the show in January 2019, he didn’t sound like a guy who was looking for a new job. At the time, he was a professor of genetics and genomics at the Icahn School of Medicine at Mount Sinai, and the director of the Institute for Next Generation Healthcare. He was publishing breakthrough papers on the use of advanced statistics to find unexpected biomarkers for diseases like Alzheimer’s.  And he had a long to-do list of ways he wanted to push his fellow physicians to become more data-driven.But lo and behold, later in 2019 Dudley was lured away from Mount Sinai by Eric Lefkofsky, the billionaire co-founder of Groupon. Lefkosky had started a new company called Tempus, with the goal of creating an advanced genomic testing platform to help oncologists and other physicians make faster, better treatment decisions for their patients. Lefkofsky showed Dudley what the company was doing to document the specific gene variants present in each cancer patient, in order to match them up with the right drugs or clinical trials. And it didn’t take him long to talk Dudley into joining as chief scientific officer.  In our interview, I got Joel to say more about why joining Tempus was an opportunity he couldn’t resist.One cool piece of news that came out right after we talked is that Tempus isn’t just a provider of testing and genomic analysis—it’s now a hardware company too. This year the company plans to release a portable, voice-driven gadget called Tempus One that will allow doctors to interact with Tempus’s genomic reports through natural language inquiries. It’s like Siri or Alexa, but specialized for oncology. I’ll have to get Joel to come back to tell us more about that. But for now, here’s our conversation from early January.Harry Glorikian: Joel, welcome back to the show.Joel Dudley: Thanks for having me back.Harry Glorikian: So, you know, as we were just talking before I hit the record button. It feels like when we last did this, it was almost a lifetime ago. Especially the last few years, it  feels like, every day feels like a month, almost, trying to keep track of everything. But, you know, you were doing something very different the last time we talked to you. You were at Mount Sinai and and now you're, you know, at Tempus. And so let's start there. Like, why the switch and. What are you doing?Joel Dudley: Yeah, I think, like many people, I didn't expect to be at Tempus. I've been here about a little over a year and a half now at Tempus, and I was approached by Eric Lefkofsky, the founder of Tempus, when I was at Mount Sinai. And things were going great at Mount Sinai. I was fully tenured. I had tons of grant funding, cool projects, even startups spinning out of the lab. So I definitely wasn't looking for a job at all. And and I hadn't really heard of Tempus at the time. And I just knew they were kind of out there. And I somewhat heard of him and he approached me about a job. And I'm like, yeah, I'm not looking, you know, and I know Guardent. I know people at all the sort of big precision, Freenome, and precision medicine companies. I mean, I thought, well, if I was going to go, why would go to Tempus. You know, and like, I just, I know everybody else in these other companies. So he's like, just come to Chicago, you know, talk to me and see what's going on.Joel Dudley: And then I looked at the website and I'm like, how the heck is this company worth three billion dollars, you know. $8 billion valuation now. And I'm like, I was being, to be honest, a bit arrogant because I'm thinking I know everybody in this field and I don't know what these guys are doing. Which is a little arrogant, to say that. But it's like sort of like, how could a precision medicine company get to $3 billion without me knowing about it. So at that point, it was almost curiosity at that point that brought me into their headquarters, obviously back when we could fly and travel. And I went I went in there. I'm like, well, I've got some collaborators at Northwestern anyway I've got to meet with. And yeah, I'll just go I'll go see what this tech dude wants. And I was even telling my wife before I left, I'm like, all these tech guys, they, always have the worst health care ideas, like, they have the worst health care ideas. Joel Dudley: So so I'm like I'm like, you know, but that being said, I went and visited Eric at headquarters, Tempus headquarters. I was completely blown away, completely blown away. It was a company like nothing I had ever seen before. And I can get into some specifics on why Tempus was different. But at a high level, it was really the first time. So my background, I'm very much a systems guy. Right. I like to understand everything from multiple systems perspective. Right. And in the molecular world, that means I'm a systems biology guy. I want proteomics. I want genomics. I want the whole thing. So when I look at other companies that were doing targeted DNA panels, I'm like, well, what fun is that? You know? And I know there's a good reason why people do that because of reimbursement and and all that kind of stuff. But it's like, what am I going to learn from DNA? You know, nothing. So that was my bias. And Tempus was the first precision medicine company operating at scale I saw that was totally committed to a multi-scale multimodal data philosophy, which I had never seen before, and was totally committed to this concept that I think you and I get excited about, which is a diagnostics company that was first and foremost a data company, first and foremost. Now, there's a lot of diagnostic companies that paid lip service to being data companies. But when it came down to it, there were all about volumes and margins of their tests. Right. Tempus was the first one that was authentically and seriously and in a big way committed to being a data company first.Joel Dudley: So I was totally blown away and and at first, you know, said there's no way I'm leaving my great job here in Mount Sinai. And I kept thinking about it and I kept thinking about it and I thought, holy cow, these guys are successful. This is going to be massive. I mean, this is going to be bigger than anything I could do at any single academic institution. This is going to be world changing. So anyway, that was a lengthy explanation of why I joined Tempus. It just wouldn't get out of my brain.Harry Glorikian: Well, it's interesting because I remember when you told me, I was like, what? Huh? Like, I was adding up what you were adding up, like all the different things you're doing. And I'm like, he went there? I'm like, I almost was thinking, can I buy stock? If he's going there, I should buy stock. So you know, Eric, before he did, you know, Tempus, obviously, did Groupon and, you know, he's financially successful, I could probably say. But what was his motivation?Joel Dudley: Yeah, he the origin story of Tempus is that Eric's wife had gotten breast cancer and someone of great means, of course, was able to get, have her seen by all the best, literally all the top the top 10 cancer, breast cancer doctors in the country. And what he noticed, being, if you get to know him, he's a very rational, logical guy know, very data driven guy. He noticed very quickly that, you know, first of all, none of the doctors agreed. That data wasn't informing her care, you know, and got a real personal look at sort of the dysfunction, I guess, or let's say missed opportunities to use data in health care that we see we, you and I see. And he decided to do something about it. There's a lot of really admirable things about his personal involvement in Tempus that drew me there. One is he's all in. I mean, he's all in, all in. A thousand percent of his attention is focused on the company. He's got a venture capital firm. He's got Groupon still is in existence and is in, and he is in in a huge way. He's you know, I think every time I've been to that office, I think he's the first one there in the morning. You know, it's just like, in some ways he's sort of like the general that rides the first horse in the battle on this thing. And not only did he not only was in a big way financially, he put a huge amount of his own money into into the endeavor, but his personal investment is, he's fanatical about Tempus.Harry Glorikian: Well, I'm convinced that when you want to change the world, if you're not fanatical, then it's not going to happen. You have to believe it more than anybody else believes it to make it come true.Harry Glorikian: Yeah. One of my favorite stories. I'll just share a quick note and I'll switch was I remember one time we were having a discussion. I can't remember what it was about. A flow cell, after I joined. A flow cell failing or something like that on the sequencer, and Eric I think had asked for which flow cells failed and I had walked by his office attempts and the bitmap images of the flow cells were up on his computer and he was staring at them intently. I have no idea if he even knew what he was looking at. I mean, he does now for sure. But the point was, the point was it was just shocking to me because I'm like, here's the CEO, billionaire CEO of this company, and he's looking at the pixel by pixel at these flow cell images, trying to figure out why they failed. And I thought that was unbelievable. You know, no, no detail is too small.Harry Glorikian: No, you know, I think, you know, you have to be passionate, get involved and want them, you know, I mean, at some point you're at scale and you have to sort of start trusting the people around you. But in the beginning, you know, I think you have to fully be committed. And everybody has to be going with you. Yeah. So and I totally agree on the whole data driven part. I mean, I have given so many talks, especially with a good friend of mine, Jennifer Carter, who was the former CEO of N of 1, where, you know, there's a bunch of doctors where the genomic data is saying one thing and they decide to do another, which boggles my mind why you would do that, because most of the time it doesn't work. But so you guys are at the forefront of genomic data. And I'm sort of imparting words of saying, you're trying to get faster, real time patient care decisions and help physicians make better decisions. Is that, am I summarizing the business?Joel Dudley: Yeah, yeah, that's it. In at a high level, it's obviously to deploy precision medicine at scale. So one of the things we say we're doing a Tempus is building all the boring, boring plumbing that nobody wants to build to actually deliver precision medicine at scale, which includes....So we ingest clinical records for the patients, because we contextualize the reports of the clinical data that we get from the individual patient. So but we work with everything from community, rural community hospitals to sophisticated academic medical centers. So we have this, part of our machine is, we have this interface that can take everything from a direct pull from a Cerner cloud instance all the way to literally people shipping paper to Tempus. But but, you know, basically we've built we built that data abstraction API, if you will, that can take eithr paper or cloud. And it was expensive. It required a lot of people and it cleans up the data. But somebody had to do that, like someone had to build that, the boring plumbing to do that. And and we did it.Harry Glorikian: Well, Flatiron I think, you know, what I've heard is Flatiron has a bunch of people in the back end, like putting things in context right, yesterday versus tomorrow versus, you know, trying to get context, which NLP not very good at. And I got to imagine that Foundation might be doing some of the same sort of stuff. No, not as much?Joel Dudley: Not as much on the clinical data. They're very much focused on the molecular data. The difference, though, between Flatiron and Tempus, though, is that Flatiron bought the EHR which the data was being collected. And so they own that. We take everything, like I said from manila folders to Cerner, to Epic to... Like that was the challenge, that's what makes TEmpus totally different in that we didn't own that that EHR. So it was a bigger challenge. But we also have humans that check all the data because as you mentioned, NLP is imperfect. But the real business, though, if I could make a point, though, is is developing smart diagnostics. Because, the principle being, you know, we all want to bring AI, let's say, to health care. One way to do that is to bring AI into the EHR, which doesn't seem like it's going to happen anytime soon. Like we have a hard time. You know, we barely can get logistic regression to run inside Epic. I don't know. I don't think we're going to, I shouldn't pick on Epic alone. But, you know, it doesn't seem like very sophisticated AI is coming to the EHR anytime soon. Plus, there's sort of a small number of players you have to deal with, you know, to have control over that environment. So that's challenging. You could try to bring the doctors to AI, which doesn't work very well. A lot of companies have failed because they say, oh, we have this beautiful AI machine, this beautiful interface that the doctors would just leave their, you know, standard workflows and just come over to our obviously better system. That feels like 99 percent of the time, right, because doctors don't want to change, physicians don't want to change their workflows. So the idea behind Tempus was more, physicians interact with lab tests all day long. So one step at bringing AI or a Trojan Horse, if you will, is to make the lab test themselves smarter. So a real simple example is, our cancer testing is, e because we pull the clinical data on that patient and the sequencing data, here's a real simple example of something that Tempus can do with a smart test that other people can't, which is if they have a DNA mutation that suggests the patient should go on a certain drug, but we know from their actual clinical records that they tried that drug and failed it, we will dynamically change the report to not put them, not suggest that drug or gray it out or whatever, depending on the version of the report. That's like a brain dead simple example, but most companies can't do that because they're not able to rapidly pull in and structure the patient's clinical data and contextualize the molecular data or the test result with that specific patient's information. So that's the Tempus approach there.Harry Glorikian: Well, not not to not to digress, but I've always said in my talks, I believe that if anything breaks or will break health care, it's the EMR systems being completely, you know, I mean, they're just they're just not where they need to be considering how fast where we want to go to the next level of health care. Right. If we were a tech company, it would have been rewritten, you know, 15 times by now to get us to where we need to go.Joel Dudley: Totally, totally.Harry Glorikian: But you're looking at DNA, you're looking at RNA, you're looking and you're looking at a whole host of 'omics to help drive a positive outcome. I mean, are there concrete examples that you might give in how this is being used and why, you know, why Tempus is compared to everybody else where it is, I would say?Joel Dudley: Yeah, absolutely. So you know what? One of the things that we think about when we get a sample in the door is how much sort of multi-scale data can we generate on the sample without going completely, without being totally insane. Right. So it's like I mean I mean, still being sustainable, let's say. So I'll give you. So what happens today when let's say, by the way, we're expanding outside of cancer, but focusing on cancer for the meantime, when a tumor section comes in to our current lab. So not only do we get sort of the the deep targeted DNA sequencing, we also get normal blood as part of that so we can do tumor normal. A lot of companies don't even do tumor normal. But then, and this is one of the things that really caught my attention, was, we generate full transcriptome on every patient that comes in the door. I mean, that's nuts. I mean, that was nuts that they just decided to as a default on every patient. That's like that's like $800 in extra cost that's not going to be reimbursed. And and even clinicians can barely wrap their heads around RNA today. I mean, it's a super hard time with RNA. I mean, do they like DNA because like the variant's there, or it's not, and the drug gets prescribed or not. But RNA is this analog probabilistic sort of dynamic measure. It gives you all kinds of different types of interpretation that's difficult. But the fact that they committed to that from day one was nuts.Joel Dudley: So then we also have our own pathology lab. So we actually digitize the section and stain and digitize all the tumor sections. We have high quality imaging. And then we pull in the structured clinical data, of course. And then we have an organoid lab actually inside Tempus. So we try to build a patient specific organoid from every every patient we can and bank that for future screen. So we have a huge number of organoids where we have not only the organoid stored and the ability to really expand that but then the patient's actual, you know, in vivo clinical data, molecular data. And you could start to do things like, hey, where you know, if we if we see this pathway in the organoid, it means we're going to see this pathway in the real patient and all that kind of stuff.Joel Dudley: So another interesting thing about Tempus is, we have this new business unit called Algos. And this is something that sounds really obvious when you pointed out and you wonder why nobody else did it. But we go to market with the broadest possible assay. So in a traditional, like, biomarker discovery, you would say, I want to try to find a biomarker of people who respond well to radiotherapy or something like that, prostate radiotherapy or something like that. So I'm going to start with the, people would start with their full transcriptome and then maybe, let's say you find a 10 gene signature that predicts who's going to respond well to radiation therapy. Then the the typical diagnostic company would say, OK, now let's shrink, let's take this 10 signature, let's implement it at Nanostring or PCR or some kind of care platform and and then go to market with that. And Tempus says, well, screw it. Let's go to market with the full transcriptome as our default assay, because then that allows us to digitally layer signatures on top of it. And by default, everybody. So we measure transcriptome now. And maybe five years from now, we find a new signature for drug response. We don't have to remeasure everybody. We just run it digitally, you know, on top of the signature.Harry Glorikian: You know, that was one of the I remember when we were talking about this years ago, I was like, that's what you would want to do. That's why you'd want the data. Right. So you want all of this data so that as time goes on, you don't have to go back and get it again. You've got it. And you just look at it. It's almost like I think about it like topology. I mean, at some point you take the first scan and you start layering things on top to get a better idea of what what is there over time, because, hell, the technology, you know, your insight becomes better over time. Some new piece of information comes in, and you go, oh, let me go back and look at this again. So you guys do that. And then the recommendation is a targeted therapy. I mean, I haven't seen any of the reports, so I'm sort of guessing along here.Joel Dudley: Yeah, we've got we've got a great report that summarizes the patient's clinical history and all the stuff you sort of expect. And then it offers various recommendations also about, of course, clinical trials. So the other thing we have is a huge clinical trial network, which I haven't mentioned yet. A national clinical trial network where we can spin up trials and match patients to trials. That's owned and operated by Tempus. But we can, so it takes the DNA information and RNA information and synthesizes recommendations. And it's going to be up to the doctor. Of course, you know, some doctors like to look at the DNA. Some people like to see where does the DNA and the RNA corroborate each other? You know, is there a PI3 kinase mutation plus activation or deactivations of a PI3 kinase pathway or something like that, and so we present all that information and a pretty, pretty digestible way.Harry Glorikian: So, two questions. A, does the patient ever get something to look at? And B, have you done any stats on success, right, of recommendations and so forth?Joel Dudley: Yeah, we've publishd some papers. We had a paper in Nature Biotech and a couple of, a couple of others that sort of show the value of this additional information and continue to publish, you know, papers. But we've been primarily on the cancer side, primarily physician facing. And, you know, physicians can, of course, give their reports to the patient's physician facing in other disease areas like neuropsych, which we've gotten into. We do have a patient facing digital app that is being tested right now to go more directly to patients, but not yet, and COVID as well. We have a patient facing up. So but that actually will be a bigger part of all the disease areas.Harry Glorikian: You have agreements with tons of institutions coming in. I mean, you and I were at one point sort of throwing this idea of having enough data where you're at that escape velocity of, it sort of stops making sense to go someplace else because the Encyclopedia Britannica is in one place. So where are you guys on that journey?Joel Dudley: Yeah, I think we're, you know, it depends. You could argue it, but I think we're basically approaching escape velocity at this point, where if you look at the trajectory of our data and I don't have the exact numbers handy, but it's a, it's a steep it's a steep line in terms of the number of samples we sequence. I think it's close to 200,000 samples last year or something like that. But but but our RNA, for example, our RNA database alone, I mean, the Cancer Genome Atlas looks like a little baby toy dataset compared to the Tempus's internal dataset. And that's, of course, a massive, I don't know if it's a multibillion dollar, but it's a massive Internet effort among academics. It's a great effort by the way, I'm not knocking the Cancer Genome Atlas, but but by comparison Tempus is able to eclipse that, you know, like you wouldn't believe. And then also have very much richer clinical data associated with those samples and have continuous updates of that data where something like the Cancer Genome Atlas is like this frozen thing that gets updated by an academic consortia every year. So even when we look at the cancer Genome Atlas, which again, I think was a worthwhile investment, and remains a worthwhile investment. But if you just compare those, the growth trajectories and the density and quality of that data side by side, Tempus is just a rocket ship compared to that data sets like that, which used to be like, you know, even Big Pharma would rely on the Cancer Genome Atlas is their sort of discovery data set. But now you'd be kind of insane not to use Tempus, it's just so much bigger.Harry Glorikian: So so that brings me to that next question. Right. So we've got we've got these patient samples. We've got clinical data. You make a recommendation, you can actually recommend a clinical trial. But now the next step comes to me and says, well, but if I have all all those pieces of information, shouldn't I be also looking at drug discovery?Joel Dudley: Yeah. So quick on the trial site. It's worth it. I'd like to point out 'cause we're really proud of this. So we have this thing called the Time Trial Network. It's a national network of I think it's 2,000 oncologists around the country on a common rate sheet, a common IRB. And the whole idea was when we match a patient, instead of a drug company going to, say, an AMC like Dana Farber or something, which, of course is a great institution, and saying, hey, we want to run our X, Y, Z drug trial with you, and all the patients will have to either fly here or drive here every couple of months, if you don't have all the patients here locally, we created this national network. And the idea was rapid site activation of trials. So if a pharma is looking for a certain type of pancreatic cancer patient subset and we match that patient in Tulsa, Oklahoma, or nearby or something like that, just picking a random city, that instead of that person driving into the AMC, an academic medical center that has the trial, or CRO, we spent a trial as close as possible to where that patient lives at one of our partners, whether it's a community hospital or something like that. At the end of the year, don't quote me on this, I think we had, we went from like a patient match to first dose in patient and something like less than 10 days or something like that, because we rapidly activate a single patient trial site.Harry Glorikian: Wow, that's cool.Joel Dudley: It's pretty cool. So it's sort of like a whole ecosystem. Right. So it's not only are we sequencing the patient and finding who are eligible, we can we also have the trial site integrated into our platform.Harry Glorikian: So it it's interesting, you always wonder, like how much how aware our patients that some of these things are. Out there when they need it, right, as opposed to the way that you and I both know the way the system runs, which is, oh, come here so that we can make the dollars as opposed to what what's really going to be the best for the patient?Joel Dudley: Yeah, yeah, absolutely. And you had asked me a second question that I totally forgot now because I distracted.Harry Glorikian: The drug discovery side of it, making that connection at some point of...Joel Dudley: Yes, it's super valuable data for drug discovery. And that is part of the value proposition of Tempus, of course, to our pharma partners who want to develop therapeutics. So part of Tempus's business is to partner with pharmaceutical companies and assist them in their discovery or biomarker efforts through Tempus's data and platforms. And we have some backend platform technologies for investment targeting our data. We have a platform called Lens for interrogating our data that is produced. Pretty interesting. And then, you know, we have a business called Alpha, which is about spinning out joint ventures around therapeutic discovery from from Tempus's data.Harry Glorikian: Ok, so that's how you if you identify something, you're willing to sort of spin it out at that point and see it come to life.Joel Dudley: Yeah. Yeah. So it's partnering with pharma or partnering with, you know, a joint venture that we're involved in around the data, but per se we don't do the drug discovery internally on the data.Harry Glorikian: You and I love the data and love the AI and machine learning. What gets you super excited? Where do you see the biggest applications of the A.I. and machine learning? Where do you see the biggest opportunities?Joel Dudley: And in no particular order, so a lot of interesting things can be done with machine learning when you have not necessarily orthogonal but multiskale data on the same samples. Right. So I'll give you a concrete example is, we have we have a large histo genomics, we call it program that our AI data science team is working on, where, of course, if we have rich RNA sequencing and rich DNA sequencing plus digital pathology on slides and samples, we can start doing things like calling PDL1 status directly from an H&E stain via deep learning instead of actually sequencing a patient. Because sequencing is great. But but imagine if you could call it the critical markers for a trial via an H&D stain and deep learning, you know, in rural Louisiana, or something like that, where people don't want to pay for sequencing or you just want to be much more capital efficient. So once we once we start collecting all these different dimensions of data, we can start predicting, you know, across all these different dimensions. Right. So what in the rich sequencing data can we predict from images, for example, which is really interesting, because then that cost, you know, nothing practically. But the key up front, you have to collect those those cohesive, coherent data sets of multiple dimensions to train. Once you've trained, it's super valuable.Harry Glorikian: It's interesting because I was having a conversation earlier today about spatial resolution of single cell, but but actually looking at the genomics inside the cell, the expression patterns and looking at that based on geography, let's call it that, for so everybody understands it, but very cool how you could see individual cells lighting up versus, you know, the other cells around them, which would give you an indication of what's being activated, how it's influencing the cells around it, et cetera.Joel Dudley: Yeah, absolutely. And that's an area we're exploring within Tempus, of course, is related to the histo-genomics I mentioned is if we start with a single cell and spatial transcriptomics on tumor cells plus rich imaging, at some point we're going to build up a data set that will give us deep molecular insights from the images alone, once we've built up the single cell and spatial transcriptomics that accompany those those images. So that's one, it's a really useful practical application of AI. Another one that's interesting for us is just getting additional insights out of existing data, which is something I've always enjoyed. But a concrete examples is, we have a big partnership with Geisinger where we've developed a deep learning model that runs on ECG traces. ECG traces are collected for elective surgeries, for physicals. And we're not the only ones necessarily exploring this, but a lot of people are using deep learning models to see if the, because an ECG trace, you could consider an image, basically. Right. And so people are using it episodically to see, like, is there something, that subtle pattern that's not being detected in the episode of care, but we're actually trying to predict things that will happen in the future. And we published some papers on this. But so we're taking a single ECG trace and we're saying, are there hidden signals basically in this ECG trace that will predict if someone is going to get future a-fib, future stroke future, you know, coronary syndrome? And we have a very large data set with Geisinger that we've done in partnership. And we've it's just amazing, like the one year, three year future events you can predict from a single snapshot of an ECG. There you go. Myocardia.Harry Glorikian: Yeah, I like I have my little monitor here, and I, I, I tend to do it every day just just to get some longitudinal data.Joel Dudley: Yeah. Yeah. Alivecor is a great is a great device. Yeah. So a couple of really interesting applications of that. One is, you know, from a population health standpoint, just going through all of the ECGs that have been collected and you can triage people into high risk low risk groups and manage them. But it's also interesting for clinical trials, because if you can predict things in the future from an ECG trace, say, for, like an anticoagulation trial, you can enrich that trial population for events and things like that from a fairly cheap standard device. So I'm interested in, you know, the ability of ML and AI to get additional, squeeze, additional information and utility out of these sort of everyday things that are measured routinely.Harry Glorikian: Yeah, and I think that, I mean, you know, whenever I've seen it, we've always gone from a complicated measurement to figuring out easier modalities to sort of identify that information from. We just didn't have the, maybe the power per se to get it in the first place. So, okay, you guys are in oncology now, you're moving out to cardiology and I think infectious disease and do I dare say neurology, depression and things like that. So why? Like, why wouldn't you just go deep and, you know, crush the space in that one area? Why?Joel Dudley: Yeah, it's interesting. I feel like we are doing fairly well in oncology. But this goes back to why I joined Tempus, which is, I always joke that this is like four different companies. And, you know, it's like it's like Flatiron plus Foundation plus, you know, we don't like to compare ourselves these companies, but like this is early on when I was, because we're actually not like those companies, which I'll explain in a second, but I was like, on the outside, it sounds sort of crazy to say, well, we're like six companies in one. But the difference was, it was built that way from the ground up in an integrated platform, a vertically integrated platform. And that's what makes it powerful. It requires a lot of capital to do that up front. But the vision was pretty interesting. So they built this sort of vertically integrated, very powerful machine to tackle cancer in this like multi-modal, comprehensive way. But they were smart in that they built it in a fairly abstract way so that it could be repurposed for for other diseases. And from day one, that was always the intention. And to me, that was amazing because I'm thinking, well, geez, a company that just tackles cancer alone with this approach is a massive company, you know,, putting on my venture adviser hat. You know, it's like, well, jeez, this is huge because this is like this company plus that company, plus that company all wrapped into one nice, seamless package. That's huge. And then I thought, well, if they replicate this success they're having clearly going to have in cancer in just one other major disease area that is an unprecedented precision medicine company in history. You know, no company would have done what Tempus has done in cancer and a whole other disease area in terms of ushering in this like very large scale multimodal approach, with clinical tests in the market and things like that. So I was like this, I got to join this. This is nuts.Harry Glorikian: Well, it's interesting that you say that, right? I keep trying to explain to people and I guess one of the examples that I've been using lately is something like Ant Financial, right. Where how they started in one area and were able to broaden, based on some very simple capabilities. And now it's 10,000 people managing 1.2 Billion customers. Yeah, you don't do that because of a personal touch. You have to have automation to tackle that. And and I know that you guys have like your robotic systems for sequencing. And I have to believe that that thing doesn't, I always tell people it doesn't care what it ingests. Right. Analytics on the back end may need to be adjusted accordingly. But, you know, that's the power of this data approach as opposed to the way we've done it historically.Joel Dudley: Absolutely. And the way I would describe it, I'm not sure everybody loves this analogy, but I think it's a very accurate analogy, which is, what I saw, and we're doing this, so we built this very sophisticated, vertically integrated infrastructure that connects sequencers to clinical and back, plus data abstraction and clinical data structuring. And so we built that machine and sort of dogfooded it ourselves on cancer and and other things that we continue to sort of dogfood it and use it our use ourselves. But eventually the goal of Tempus is to open this platform up to other people, so the way I what I saw early on was that while Tempus has the chance to become the AWS of precision medicine, basically. We're building all this boring plumbing or connecting hospitals. We're building this, like I mentioned, this API of data abstraction that can connect everything from cloud based EHRs to paper, you know, and everything in between. So at some point we want to open, and we are actually beginning some partnerships where we're opening up Tempus's platform, because if we've invested a billion dollars in that plumbing, then the beauty is, you know, you should is a startup. You don't have to do that now, just like AWS. You know, it's like now three guys in a in a garage to get out their credit card and start Stripe or Shopify or whatever the next big company is. And that was always been the aspiration of Tempus, not only to build this for ourselves, but to build it as an enabling platform for other people who would want to deploy precision medicine at scale, which is, we're actually executing on that vision in a serious way. It was more of an aspiration, I think, when I joined. But now we're full on executing.Harry Glorikian: It's interesting. I mean, I remember you saying that to me, I want to say, last JPMorgan, when we were actually able to travel and sit down with each other. I mean, I talk to other people and I mention Tempus and some people go, who? And other people are who are very knowledgeable are like, well, I don't see what the big deal is. And so it almost seems like. Do you think people know what's there that they can take advantage of?Joel Dudley: I don't think people fully appreciate it. And of course, there's a bunch of things I can't even talk about that are even more exciting that are being cooked up. But you'll be hearing about them soon. I think we'll make a few JP Morgan announcements, but it's sort of the M.O. Actually, one of the things that attracted me to Tempus was our CEO is very much a show don't tell kind of guy, to the point where even some people get frustrated because.. Nobody gets frustrated. But it's like, hey, we're doing all these amazing things and nobody knows about them yet. But but he's 100 percent right in that people will know when we're actually doing, once we're doing the stuff, right. You know, and and that was impressive to me because we're obviously in an area that's overhyped, you know, precision medicine, AI in medicine. And there's a gazillion companies out there doing proof by press release, you know, on all their vaporware. And Tempus is doing real, real stuff that's saving patients lives. And, you know, and they're being very disciplined about it and not overhyping it and just putting in the work. And then in the long run, people will know. I think it's going to be all one of those things, like who's Temples? To, like, Oh, my God, I had no idea, where did this come from.Harry Glorikian: Yeah, and I think your biggest challenge is going to be the last mile, right? I mean, it's like Internet connectivity, right? Well, it's on the street, but how do you get it into the house? And the biggest complaint I always hear from everybody is getting this implemented at an institution is not trivial.Harry Glorikian: I would argue that's what Tempus is mainly solving is that last mile problem. In fact, you know, I don't know how many institutions are connected inti Tempus, but it's well over 100 for sure. And that's a KPI that we're tracking. How much how many institutions we have last mile connectivity into. And that's been just growing up. That was a huge KPI for us the last last year. And it continues to be. But I would argue that's the problem solving, is that last mile, because we are in clinic, in EHRs, have bidirectional data feeds and decision support and a large number of institutions, it's just people don't realize it.Harry Glorikian: Let me ask you to I don't even know if you're still doing this. You were part of the Institute for Next Generation Health Care. I don't know if you're still.Joel Dudley: No, no, no. Not anymore. Harry Glorikian: OK, well, so I'm trying to get you to put your next generation hat on here for a second. And if you're looking at everything that's going on and where this is going, like where do you see the next big leaps coming? Where do you see the next changes coming in how we're going to make a difference for patients and hopefully bring down cost? And how is the technology that you guys are working on where you see it going sort of driving that next level of outcome for patients?Joel Dudley: What I always like we always like to say at Tempus is we don't know, because it's actually it's a very Tempus-y thing, to be humble that way, because we don't know. Like. Well, we all we know is that, you know, we have to build this data set and we need to build these pipes and we need to, like because that will enable whatever the thing is that hits is the next big thing, I mean, clearly, like in cancer and other areas, we've got some clear value propositions and starting in cardio and neuropsych. But I'm convinced if Eric was on this podcast, the first thing he would say is, I don't know. We don't know. We do know that it's going to require huge amounts of data and we're going to, so we're going to collect that data and then hope we figure it out or someone we work with figures out what the next big thing is. But if I put on my my personal hat, I guess I've always been interested in prevention. It's not an area we work in at Tempus a lot, we work with a lot of late stage disease, obviously when you start in cancer, you're starting in some pretty heavy disease area, right. And life and death. But we are getting into cardiology and we're looking at endocrinology, diabetes. We have a big diabetes effort that will be announced soon. And so I think when the stuff we're doing in cancer or when the approaches we're building at Tempus can start to be applied to prevention, I think will be really interesting in terms of moving the needle. And then, you know, in post COVID, we'll see what happens with telemedicine. But right now, we primarily interface with the, and again, I'm speaking personally. I'm not divulging any any strategic roadmap or anything here. But I would imagine at some point if telemedicine continues to go the way it's going, there's no reason a purely virtual telemedicine company could plug into temper's in the same way an academic medical center does. Right. So which I think would would be enabling.Harry Glorikian: Well, I would I would hope that that would be, I mean, if you think about the CVS-Aetna deal, I know that CVS, last year, you guys announced a deal with CVS, if I remember correctly.Joel Dudley: Correct.Joel Dudley: And so I think now that telemedicine has become much more. You know the way to do things, wy would you want somebody going to the ivory tower when you could plug them in through the system and interact with them there? And I mean, there's a huge cost savings. And and from a I mean, time standpoint, it's just more efficient.Joel Dudley: Yeah, yeah, and we spoke with a institution which I don't think I can name at this point, but they had mentioned that during covid they had even spun up a tele-oncology practice, which was surprising to me because oncology is just one of the things where you think what's so complicated, you know, you can't spin up a tele-oncology service. But in fact, they had and and they did extremely well over COVD. And then when you start to think about oncology, well, it's like, OK, I mean, you've got to see your doctor. But then they're saying, well, go get your labs at Quest. Go get your infusion at the infusion clinic, you know. You know, it's not it's not like you have to stay in the doctor's office. And I started thinking about it. I'm like, OK, tele-oncology can work. So, you know, whether we'll see broad, you know, expansion of tele-oncology probably after people see the profits AMC made, or AMC but another health system. But so so yeah. So it could be even in oncology, we see totally virtual services, you know, plugging into something like Tempus.Harry Glorikian: That would be interesting. I always think, like, I'm getting older. So the faster that we move into this new world, the happier that will be. I'll have a better experience, right?Joel Dudley: Absolutely.Harry Glorikian: So knowing the two of us, we could probably talk about this for hours. Right? Especially on the data side. You know, I think I think you're right. There's an under appreciation for where, once you have the data, what the different things you can do with it over time. It's more looked at from the science as opposed to the data side of things.Joel Dudley: Yeah, yeah. And I think a lot of people who practice data science and machine learning know this, that it's just, huge amounts of data of high quality data just trump any, you know, sophisticated machine learning methods. What I mean is like choosing between like the latest greatest deep learning or whatever method, versus just having a simpler method with huge amounts of high quality, the high quality part being important, data -- I would take huge amounts of high quality data any day because that's way more enabling than whatever sexy machine learning method is. And it's usually the case that once you have vast amounts of high quality dfairly straightforward statistical modeling methods will yield just amazing insights that come as a virtue of the scale and the quality of that data. And I think that's the lesson I learned at Tempus is that data just trumps all from that perspective. Then I think it's important to point out, because there's a lot of tool-only companies in the field like, "oh, I got, trust me, this deep learning methd is better than that deep learning method. Or It's got this little extra thing. Or this topological method is better than deep learning." I's like, who cares when once you have the volume of data that we have?Harry Glorikian: Yeah. The only place where I would not differ, but say, I think when you've got multiple high quality data sets, then you need a little bit of help making sense of it all, because the human brain was not designed to look at multiple pieces of data coming together and see patterns that it might not normally be able to sort of visualize.Joel Dudley: No, that's absolutely true. And that's the and probably being oversimplifying that, because that's my career, has been multi scale data. It's like machine learning and stuff like that. So I feel like I should, yeah, that's a good point. But huge amounts of high quality data and this multimodal, you know, we always say multimodal, the multimodal aspect is really important because we want different high dimensional measures on the same sample or same individual, if you will. And obviously, longitudinal as a dimension is a very powerful dimension as well.Harry Glorikian: Yep. Yep. No, well, this is something like, you know, I, I talk to people about and Joel, not to sort of build you up, but I mean, there's not many people that have the biological and the data background in one. We haven't I don't I don't believe we've graduated enough of them yet. We're moving in that direction, but not not enough of them yet. So it was great to have you on the show. I'm hoping that we'll actually get together sooner physically rather than later. But I have a feeling we're in this for another four or five more months. Before this thing starts dying down.Joel Dudley: Yeah, probably, when we'll travel back, but it's wild. I was thinking, like I said, I maybe mentioned this last time. I've been at Tempus only like a year and a half and we've added five dollars billion of valuation in that time. But what's really cool about that is not that we're worth $8 billion in valuation because valuations are, you know, whatever, but is that there's a sense within Tempus that we are still a small, scrappy startup just getting started. So like that that's my favorite part about that number, is not that, because I think a lot of companies, if they had an $8 billion valuation they'd be like, "We made we made it. This is great." But Tempus is like, "just completely ignore that. We are just getting started." It doesn't matter to anything we do day to day.Harry Glorikian: Well, I remember when when I was at Applied Biosystems, you know, the valuation was going off the chart because we were doing the genome. Couldn't install machines fast enough. And I remember talking to some of the senior people and saying, okay, well, what are we going to do next? And I remember the gentleman who was taller, way taller than me looking down at me and said, have you seen our stock price like we are? We're killing it. We're performing admirably. And I remember going home and telling my wife, like, I think it's time to sell some stock. Because that is not the right mindset for success.Joel Dudley: Not the right mindset, no. Yeah, it's it's it's very refreshing, you know, that it's that attitude is just, you know, across the board at Tempus, everybody is like, we're just getting started. We're just getting started, heads down, keep cranking. And we really, you know, obviously comes from leadership, but we really block out any distraction that would come from from that type of valuation or whatever, you know. So it's really fantastic leadership on the part of Tempus.Harry Glorikian: Well, one of these days, I hope to to meet Eric, he sounds like an interesting character. But you know, stay stay safe, stay healthy, and, you know, obviously, you and I will constantly continue the conversation in the background, but is great to have you back on the show. And you know what, honestly, huge change from Mount Sinai, I never thought you would leave that place, considering.Joel Dudley: I never thought either. But I enjoy it. It's been, like I said, as I've been recruiting people, I said, you've got to, like I don't care how good your job is now. You've got to get out now. There's like there's this wave where, everybody's going to be riding in the next decade, when I talk to someone like me. You're so well positioned to do it. And you're going to, if you don't get out and just try, you're going to kick yourself in five to 10 years and say, I saw this coming. I saw this big thing coming and I didn't get out.Harry Glorikian: Well, I've been saying, you know, since we since we were doing the genome. I remember telling all my friends, I'm like, "Biology, man biology and where the data is going is where it's going to be." And people were like, "Well, tell me specifically where to put my money." I'm like, look, I'm not, I can't tell you right now specifically. I'm just telling you that that whole area is going to explode. And I think it's just going to, I mean, now we're at a point where it's, the curve is ridiculous. Gene editing stocks. What's happening in the space. I mean. COVID has pulled stuff forward in a way that I could never have imagined.Joel Dudley: Yeah, me either. Yeah. Yeah, it's a huge catalyst. I agree, though. It's amazing. Good good time to to be in the field for sure.Harry Glorikian: Oh, best job in the world. I always tell people.Joel Dudley: Yeah, yeah. Science fiction is a cool business.Harry Glorikian: Oh yeah, yeah, yeah, yeah. You got to have a little bit of both. Otherwise it gets boring.Joel Dudley: Yeah, exactly. Awesome man.Harry Glorikian: All right. Good to talk and we'll stay in touch.Joel Dudley: All right. Sounds good. Take care man. Good to see you.Harry Glorikian: All right.Harry Glorikian: That’s it for this week’s show.  We’ve made more than 50 episodes of MoneyBall Medicine, and you can find all of them at glorikian dot com forward-slash podcast. You can follow me on Twitter at hglorikian. If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.  Thanks, and we’ll be back soon with our next interview.

Aging and chronic stress can obtain activation of CNS-resident microglia and astrocytes, that produce type 1 interferons (T1 IFNs) which signal through the heterodimeric IFN-α/β receptor (IFNAR) where receptor binding of T1 IFNs activates the JAK/STAT thus inducing IFN-stimulated genes (ISGs) which mediate both pro- and anti-inflammatory functions depending upon the cellular micro-environment. Now consider how aging is linked to elevated & activated leukocyte counts and it becomes clear that this is a patho-biochemical phenocopy to T cell acute lymphoblastc leukaemia (T-ALL) where signaling through Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK are shared. IL7-induced glucocorticoid resistance is diagnostic of certain subtypes of T-ALL and this is also associated with the senescence associated secretory phenotype of aging-linked morbidity and mortality. Finally, consider that chronic CNS stress leads to increased glucocorticoid production leading to a suppression of cell adhesion protein thus corrupting synaptic plasticity, memory re-formation, and cognitive acuity while promoting sarcopenia by stimulating proteasomal removal of contractile proteins and inhibiting the PI3-kinase/Akt pathway. Glucocorticoids also prevent IL-2 synthesis and secretion thus causing immune suppression by blocking T cell activation. J Neuroinflammation. 2019; 16: 236. Cytokine & Growth Factor Reviews, 22 Apr 2017, 35:85-96 --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

During the European School of Haematology (ESH)'s 2nd How to Diagnose & Treat Lymphoma conference, the Lymphoma Hub spoke to Nathan Fowler, MD Anderson Cancer Center, Houston, US, who discussed the non-chemotherapy approaches to treating follicular lymphoma.Treatment for follicular lymphoma has been improving over recent years. The addition of rituximab, an anti-CD20 antibody, to the clinician's arsenal has been a real game changer in the field. Nathan Fowler describes its mode of action and the role it plays in modern treatment strategies.Fowler discusses the different courses the disease can take and how therapy can be tailored to suit an individual's needs. The current treatment standards and the response rates achieved with these agents are examined. Lenalidomide, an immunomodulatory drug, in combination with rituximab was investigated in comparison to three different chemotherapy regimes in the RELEVANCE trial, and Fowler details the outcomes of this study. The differing adverse events experienced by patients following these therapies are listed. He goes on to say how this result has influenced his clinical practice and how the presence of high-risk factors impacts treatment decision making.Nathan Fowler rounds off his talk by introducing other non-chemotherapy options, such as obinutuzumab, Pi3 kinase inhibitors, tazemetostat, and chimeric antigen receptor (CAR) T cells. Hosted on Acast. See acast.com/privacy for more information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.09.374355v1?rss=1 Authors: Pearl, L. H., Pal, M., Munoz-Hernandez, H., Bjorklund, D., Zhou, L., Degliesposti, G., Skehel, J. M., Hesketh, E. L., Thompson, R. F., Llorca, O., Prodromou, C. Abstract: The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with HSP90, functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, snRNPs and PI3 kinase-like kinases (PIKK) such as TOR and SMG1. PIKK stabilisation depends on an additional complex of TELO2, TTI1 and TTI2 (TTT), whose structure and function are poorly understood. We have now determined the cryo-EM structure of the human R2TP-TTT complex that together with biochemical experiments reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system. Copy rights belong to original authors. Visit the link for more info

A roundtable discussion with Drs Carla Casulo and John P Leonard on recent developments in the treatment of follicular lymphomas, including the following topics: Current management of newly diagnosed follicular lymphoma (FL); choice of observation versus rituximab monotherapy (00:00) Association between vitamin D insufficiency and outcomes for patients with FL   5m41s Efficacy and tolerability of obinutuzumab/bendamustine for patients with newly diagnosed FL (9:44) Activity of lenalidomide/rituximab (R2) in patients with FL (15:56) Biology of FL; criteria for initiating therapy after diagnosis (20:55) Results of the Phase III GALLIUM study of obinutuzumab or rituximab, each in combination with chemotherapy, followed by maintenance obinutuzumab or rituximab for patients with untreated, advanced FL (31:02) Phase III RELEVANCE trial evaluating R2 versus rituximab/chemotherapy, each followed by maintenance rituximab, as first-line therapy for advanced FL (34:58) Selection and sequencing of therapies for relapsed/refractory FL; management of early progression of disease (41:07) Biologic predictors of early relapse; role of transplant for patients with FL (47:20) Activity and tolerability of CAR (chimeric antigen receptor) T-cell therapies for FL (54:39) Response to the PI3 kinase inhibitor umbralisib in combination with obinutuzumab for relapsed FL (58:02) Outcomes for patients with early relapse of FL in the National LymphoCare Study (1:04:35) Integration of the PI3 kinase inhibitors idelalisib, copanlisib and duvelisib into the management of FL (1:12:18) Mechanism of action, efficacy and tolerability of the recently approved EZH2 inhibitor tazemetostat for relapsed/refractory FL (1:22:01) Results of the Phase II ZUMA-5 study of axicabtagene ciloleucel for patients with relapsed/refractory indolent non-Hodgkin lymphoma (1:26:32) Biologic rationale for the use of the novel bispecific antibody mosunetuzumab for relapsed/refractory FL (1:30:40) Novel agents and approaches under investigation for patients with FL (1:34:58) CME information and select publications

Crikey! Nick Marentes is at it again! Earlier this year he released Gun Stah, and followed that up with Rally-SG, you'd think he'd be busy counting all his money and watching his Swiss bank accounts, but no, he's at it again with yet another new game for the Coco and we'll see the world premier of his current project in progress! That along with all the other usual boring stuff, Games, News, old guys, blah, blah, blah.   General segments with time stamps you can quick link to: 00:02:49 Panel Introductions 00:09:19 Simon Jonassen - Demo 00:36:01 Nightmare Highway song 00:40:34 Rick Adams - Bomb Threat talk 01:03:35 CoCo Thoughts 01:05:23 GameON! challenge results 01:34:04 Next week's game announcment - Sea Dragon 01:41:23 Nick Marentes - New game annoucement 01:02:15 GameON! news 02:43:38 News from around the world 03:32:05 Project updates and acquisitions 03:54:52 CoCo Caboose - after show & wrap-up discussion News stories for Episode #173, August 15, 2020 show: 1) Boisy has released The Coco Collector Part 4   https://youtu.be/cU4vOGXS3eE   2) Keith (ChibiAkumas) on YouTube has another Dragon/Coco assembly language tutorial episode   https://youtu.be/QlnXqshkTyw   3) Jim Gerrie has a video up for the Lissajous program from Creative Computing in 1979   https://youtu.be/IGFFXY_si7U   4) Glen Dahlgren has put up an image of the dust jacket for the hardcover version of his novel coming out on August 16th: https://tinyurl.com/y6nf5tr7   5) Ralph Klein has released the CocoPI update - MAME 0.223 on both the Pi3 and the Pi4: (I will only show one link on the show) https://tinyurl.com/y6ppt3l3 https://tinyurl.com/y28lph34   6) Boysontech has posted a picture of a new version of the design of a little satellite board that will allow a Sound/Speech pack to run at .895, 1.78 and 2.86 MHz. https://tinyurl.com/y22qozdr   7) Guillaume Major has released an update to the "complete Coco SDC image", which now has 600+ new disk images of applications, games, demos, educational, etc. compared to the previous version. https://tinyurl.com/y6ntwlyw   8) Curtis F. Kaylor showed some output from his TP-10 simulator program (TP-10 was the small thermal printed that Tandy sold): https://tinyurl.com/y5jc8xjh   9) James Tamer has uploaded Virtual MC-10 version 0.73i, which includes some bug fixes. https://tinyurl.com/yxcp4fea   10) Another very young fella did a Coco 2 restoration on YouTube (channel: Jackson's_antiqueAdventures) retrobrighting it: https://youtu.be/5S3A3RLfnaY   11) TJBChris has a new video on tricks you can do with the LOADM command: https://youtu.be/MzO7t87baTo   12) A YouTube channel called hirudov2d did multiple videos of different Coco's (and a Dragon-64) https://www.youtube.com/c/hirudov2d/videos   13) Glenside has their latest newsletter out https://tinyurl.com/y4ja8qdx   Game On news: 1) Marlin Lee has a video up showing New Burt, a Q-Bert clone from Mike Ro Productions: https://youtu.be/UlB4IwL-16c   2) Jim Gerrie has a video showing an update to Pitman https://youtu.be/IGFFXY_si7U He also has a port to the MC-10 from an old Dragon 32 game from the book "More Programs for your Dragon 32" from 1984, called Joust https://youtu.be/LVv4x_7pz5g Also a game called Civil War, from Creative Computing: https://youtu.be/KbUntsdxPeE Time Bomb https://youtu.be/XnN0TNNLNuI   3) Paul Shoemaker shows some possible palettes that he is considering for a Wizardry clone that he is calling Sorcery, https://tinyurl.com/y2ubh875   4) Jerry Stratton has a text version of Hunt the Wumpus https://tinyurl.com/yyzxfpot   5) Erico Monteiro has two new blogs up about his semi-graphics fighting game: Part 2: https://tinyurl.com/y693oque Part 3: https://tinyurl.com/y29ttaxy   6) Erico  playing Cashman on screens 40+ https://youtu.be/UAUHVGMlSMI?t=236   7) Stevie did a live stream demo of Rally-SG and the Digger III https://youtu.be/BIfepYk8wYE   8) Simonwgb did a 3 hour stream on Twitch playing about half a dozen Dragon 32 games: https://youtu.be/eWaJi82Dmgo?t=114 9) Adam Haase has released a complete map and tips breakdowns of the huge Coco 3 RPG game, The Seventh Link. https://tinyurl.com/y52jjxbo   Email any suggestions you have for the show to cocotalk@cocotalk.live Visit us on the web at http://cocotalk.live Join us for daily conversations on Discord: http://discord.cocotalk.live To find out more about the Color Computer visit http://imacoconut.com Custom artwork designed by Instagram artist Joel M. Adams:   https://www.instagram.com/artistjoelmadams/ Custom CoCoTALK! and retro merchandise is available at: http://8bit256.com Consider becoming a patron of the show: https://patreon.com/ogsteviestrow Live interactive video streams: https://www.youtube.com/c/Ogsteviestrow/live https://www.facebook.com/cocotalklive https://www.periscope.tv/CoCoTALKlive/ https://twitter.com/CoCoTALKlive  

Crikey! Nick Marentes is at it again! Earlier this year he released Gun Stah, and followed that up with Rally-SG, you'd think he'd be busy counting all his money and watching his Swiss bank accounts, but no, he's at it again with yet another new game for the Coco and we'll see the world premier of his current project in progress! That along with all the other usual boring stuff, Games, News, old guys, blah, blah, blah.   General segments with time stamps you can quick link to: 00:02:39 Panel Introductions 00:09:09 Simon Jonassen - Demo 00:35:50 Nightmare Highway song 00:40:24 Rick Adams - Bomb Threat talk 01:03:25 CoCo Thoughts 01:05:13 GameON! challenge results 01:33:50 Next week's game announcment - Sea Dragon 01:41:13 Nick Marentes - New game annoucement 01:02:05 GameON! news 02:43:28 News from around the world 03:31:55 Project updates and acquisitions 03:54:42 CoCo Caboose - after show & wrap-up discussion News stories for Episode #173, August 15, 2020 show: 1) Boisy has released The Coco Collector Part 4   https://youtu.be/cU4vOGXS3eE   2) Keith (ChibiAkumas) on YouTube has another Dragon/Coco assembly language tutorial episode   https://youtu.be/QlnXqshkTyw   3) Jim Gerrie has a video up for the Lissajous program from Creative Computing in 1979   https://youtu.be/IGFFXY_si7U   4) Glen Dahlgren has put up an image of the dust jacket for the hardcover version of his novel coming out on August 16th: https://tinyurl.com/y6nf5tr7   5) Ralph Klein has released the CocoPI update - MAME 0.223 on both the Pi3 and the Pi4: (I will only show one link on the show) https://tinyurl.com/y6ppt3l3 https://tinyurl.com/y28lph34   6) Boysontech has posted a picture of a new version of the design of a little satellite board that will allow a Sound/Speech pack to run at .895, 1.78 and 2.86 MHz. https://tinyurl.com/y22qozdr   7) Guillaume Major has released an update to the "complete Coco SDC image", which now has 600+ new disk images of applications, games, demos, educational, etc. compared to the previous version. https://tinyurl.com/y6ntwlyw   8) Curtis F. Kaylor showed some output from his TP-10 simulator program (TP-10 was the small thermal printed that Tandy sold): https://tinyurl.com/y5jc8xjh   9) James Tamer has uploaded Virtual MC-10 version 0.73i, which includes some bug fixes. https://tinyurl.com/yxcp4fea   10) Another very young fella did a Coco 2 restoration on YouTube (channel: Jackson's_antiqueAdventures) retrobrighting it: https://youtu.be/5S3A3RLfnaY   11) TJBChris has a new video on tricks you can do with the LOADM command: https://youtu.be/MzO7t87baTo   12) A YouTube channel called hirudov2d did multiple videos of different Coco's (and a Dragon-64) https://www.youtube.com/c/hirudov2d/videos   13) Glenside has their latest newsletter out https://tinyurl.com/y4ja8qdx   Game On news: 1) Marlin Lee has a video up showing New Burt, a Q-Bert clone from Mike Ro Productions: https://youtu.be/UlB4IwL-16c   2) Jim Gerrie has a video showing an update to Pitman https://youtu.be/IGFFXY_si7U He also has a port to the MC-10 from an old Dragon 32 game from the book "More Programs for your Dragon 32" from 1984, called Joust https://youtu.be/LVv4x_7pz5g Also a game called Civil War, from Creative Computing: https://youtu.be/KbUntsdxPeE Time Bomb https://youtu.be/XnN0TNNLNuI   3) Paul Shoemaker shows some possible palettes that he is considering for a Wizardry clone that he is calling Sorcery, https://tinyurl.com/y2ubh875   4) Jerry Stratton has a text version of Hunt the Wumpus https://tinyurl.com/yyzxfpot   5) Erico Monteiro has two new blogs up about his semi-graphics fighting game: Part 2: https://tinyurl.com/y693oque Part 3: https://tinyurl.com/y29ttaxy   6) Erico  playing Cashman on screens 40+ https://youtu.be/UAUHVGMlSMI?t=236   7) Stevie did a live stream demo of Rally-SG and the Digger III https://youtu.be/BIfepYk8wYE   8) Simonwgb did a 3 hour stream on Twitch playing about half a dozen Dragon 32 games: https://youtu.be/eWaJi82Dmgo?t=114 9) Adam Haase has released a complete map and tips breakdowns of the huge Coco 3 RPG game, The Seventh Link. https://tinyurl.com/y52jjxbo     Email any suggestions you have for the show to cocotalk@cocotalk.live Visit us on the web at http://cocotalk.live Join us for daily conversations on Discord: http://discord.cocotalk.live To find out more about the Color Computer visit http://imacoconut.com Custom artwork designed by Instagram artist Joel M. Adams:   https://www.instagram.com/artistjoelmadams/ Custom CoCoTALK! and retro merchandise is available at: http://8bit256.com Consider becoming a patron of the show: https://patreon.com/ogsteviestrow Live interactive video streams: https://www.youtube.com/c/Ogsteviestrow/live https://www.facebook.com/cocotalklive https://www.periscope.tv/CoCoTALKlive/ https://twitter.com/CoCoTALKlive  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.25.170266v1?rss=1 Authors: Ichwan, M., Walker, T., Nicola, Z., Ludwig-Mueller, J., Boettcher, C., Overall, R. W., Adusumilli, V., Bulut, M., Lugo-Hernandez, E. A., Ramirez-Rodriguez, G., Kempermann, G. Abstract: As mammals evolved exposed to particular diets, naturally abundant compounds may have become part of the set of environmental co-determinants that shaped brain structure and function. Here we investigated whether bioactive factors found in apples directly affect hippocampal neural stem cells and promote neurogenesis in the adult mouse. Whereas the consumption of apple juice per se neither altered adult hippocampal neurogenesis nor improved learning and memory, we did find specific direct effects of apple-derived factors on neural stem cell survival and differentiation. Our results revealed that quercetin, the most abundant flavanol in apple peel, was anti-proliferative at high concentrations but acted pro-neurogenically at low concentrations. This was confirmed in vivo, with intraperitoneally-delivered quercetin promoting survival and neuronal differentiation, without affecting proliferation, likely via the PI3 kinase-Akt and Nrf2-Keap1 pathways, respectively. Using a bio-assay-guided fractionation approach with high-resolution collision induced dissociation mass spectroscopy, we also identified additional pro-neurogenic compounds in apple flesh that were not related to flavonoids. In particular, we found that 3,5-dihydroxybenzoic acid, a weak agonist to the lactate receptor, significantly increased both in vitro and in vivo neural precursor cell proliferation and neurogenesis. Altogether, this work shows that both flavonoids and 3,5-dihydroxybenzoic acid are pro-neurogenic, not only by activating precursor cell proliferation but also through promoting cell cycle exit, cellular survival, and neuronal differentiation. Copy rights belong to original authors. Visit the link for more info

Proceedings from a CME webinar focused on COVID-19 and chronic lymphocytic leukemia. Featuring perspectives from Drs Matthew S Davids, Anthony R Mato and Jeff Sharman. Changes in chronic lymphocytic leukemia (CLL) institutional processes and procedures brought on by the COVID-19 pandemic (00:00) Case: A woman in her late 50s with a history of breast cancer requires treatment for CLL during the pandemic (9:03) Recommendations regarding the management of CLL in the COVID-19 environment (14:37) Rationale for the use of Bruton tyrosine kinase inhibitors for patients with cancer and COVID-19 (18:29) Current approach for patients with CLL requiring treatment with venetoclax/obinutuzumab (20:49) Case: A woman in her early 60s with CLL in remission after treatment with an obinutuzumab-based therapy on a clinical trial receives results of a prescribed study-related CT scan that are suspicious for COVID-19 infection (28:16) Limitations of COVID-19 testing techniques and platforms (drive-through testing, false-negative rates, et cetera) (34:31) Case: A man in his early 70s with relapsed/refractory CLL is hospitalized with COVID-19; potential role of noncancer therapeutic interventions (eg, remdesivir, anticoagulants) (39:44) Perspectives on continuing versus stopping therapy both before and during the current pandemic (47:18) Case: A man in his early 70s who is receiving PI3 kinase inhibitor therapy for relapsed/refractory CLL begins to experience symptoms of COVID-19 after his wife tests positive for the novel coronavirus (53:03) CME information and select publications

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.18.158709v1?rss=1 Authors: Schechter, M., Atias, M., Abd Elhadi, S., Davidi, D., Gitler, D., Sharon, R. Abstract: alpha-Synuclein (a-Syn) is a protein implicated in the pathogenesis of Parkinson s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for a-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of a-Syn in these mechanisms is currently unclear. Here we have investigated the role of a-Syn in membrane trafficking through its association with acidic phosphoinositides (PIPs), such as phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that a-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor AP2 at clathrin-coated pits. Using endocytosis of transferrin, an indicator of clathrin mediated endocytosis (CME), we find that a-Syn involvement in endocytosis is specifically mediated through PI4,5P2 levels. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by a-Syn mutations. In accord with their effects on PI4,5P2 levels at the plasma membrane, the PD associated E46K and A53T mutations further enhance SV endocytosis. However, neither A30P mutation, nor Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of a-Syn, that interfere with phospholipid binding, affect SV endocytosis. This study provides evidence for a critical involvement of PIPs in a-Syn-mediated membrane trafficking. Copy rights belong to original authors. Visit the link for more info

Dr. Neelima Denduluri, a medical oncologist at Virginia Cancer Specialists and Associate Chair of the Breast Cancer Research for the US Oncology Network, discusses key abstracts in the breast cancer field that were featured at the ASCO20 Virtual Scientific Program.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Neelima Denduluri, a medical oncologist at Virginia Cancer Specialists and Associate Chair of Breast Cancer Research for the US Oncology Network. Dr. Denduluri serves on the editorial board of the ASCO Daily News, and will highlight key abstracts that were featured at the ASCO20 Virtual Scientific Program.   Dr. Denduluri has received institutional research funding from Amgen, Novartis, Genentech, Eli Lilly, Pfizer, Daiichi Sankyo, Seattle Genetics and Immunomedics. Full disclosures relating to all Daily News podcasts can be found on our episode pages. Dr. Denduluri, it's great to have you on the podcast today.   Dr. Neelima Denduluri: Thank you, Geraldine, for asking me to participate on the podcast.   ASCO Daily News: Let's start with advanced breast cancer. Can you tell us about the key abstracts that address this patient population?   Dr. Neelima Denduluri: Absolutely. So this year's ASCO was filled with many rich advancements across the therapeutic, diagnostic, and symptom management spectrum, which is always wonderful when we're trying to treat our patients adequately. In advanced breast cancer, one abstract that generated significant interest is whether surgery improves outcomes in patients that present with advanced breast cancer.   Generally, the paradigm in advanced breast cancer is to give systemic therapy. We've always wondered, does taking out the local site of disease or the primary tumor, in terms of the breast tumor and lymph nodes, and possibly giving radiation, does that improve outcomes in advanced breast cancer? Well, the late-breaking abstract 2 (LBA2), presented by Dr. Khan, looked at women or men who presented with stage IV de novo breast cancer. And these patients obviously started their appropriate systemic therapy based on the subtype of breast cancer.   And these patients, after three to six months, were randomized to continue the systemic therapy or stop their systemic therapy for local management before resuming their systemic therapy. And what the study showed is that those patients that did receive local therapy did not have an improvement in survival compared with those patients that did not receive local therapy to their breasts and/or lymph nodes. So I think that was an excellent lesson for all of us. And how it guides our management is to say that the vast majority of our patients with advanced breast cancer do not need to undergo surgery to improve outcomes. Now, having said that, about 25% of patients that did not have any local therapy did have some progression. And so for those patients, despite no improvement in long-term quality of life, it is something that we should consider and talk about with them. Especially if that is the only site of disease that is progressing, should we go ahead and give them some palliation in terms of symptoms in the short term.   The most common subtype of advanced breast cancer that we treat is hormone receptor positive, HER2 negative breast cancer. There are data that have been previously presented that show that fulvestrant, which is an injectable selective estrogen receptor downgrader, is possibly superior to aromatase inhibitors. So one trial evaluated this concept, but in the face of CDK4/6 inhibition. CDK4/6 inhibitors have become the mainstay of therapy in advanced hormone receptor positive, HER2 negative breast cancer. What abstract 1007, or the PARSIFAL trial, looked at was is fulvestrant and a CDK4/6 inhibitor superior to an aromatase inhibitor and CDK4/6 inhibitor. And what they showed is that, in advanced breast cancer, fulvestrant was not superior to an aromatase inhibitor when given in combination with CDK4/6 inhibition. And this is something that I think was reassuring to patients, especially if they have to come in to the clinic to receive an injection.   What will be interesting going forward is how do selective estrogen receptor downgraders that are oral come into play, and how do they compare with fulvestrant or how do they compare with aromatase inhibitors. So that was something that was quite reassuring, that we can give aromatase inhibitors with CDK4/6 inhibitors without compromising efficacy in patients with advanced breast cancer.   Another trial that generated some excitement for our patients and therapeutic options is the BYLieve trial, or abstract 1006. As I stated earlier, the mainstay of therapy for those patients with advanced breast cancer that's hormone receptor positive and HER2 negative is some type of endocrine partner, whether it be tamoxifen, fulvestrant, or an aromatase inhibitor and a CDK4/6 inhibitor. Mainly, it's an aromatase inhibitor and a CDK4/6 inhibitor. So for those patients that progress on that regimen, what do we do next is something that comes up.   We know that up to 40% of patients with advanced breast cancer that's hormone receptor positive and HER2 negative have PI3-kinase mutations, and alpha-specific PI3-kinase inhibitor that has shown to improve outcomes in patients with advanced breast cancer that have PI3-kinase mutations. What the BYLieve trial looked at was how about after CDK4/6 inhibition.   And what it showed is that patients that received CDK4/6 inhibition and fulvestrant and alpelisib did have about a 50% chance of not progressing at six months. And there was about a seven-month progression-free survival benefit in these patients. The toxicities that we know of with alpelisib include rash, diarrhea, and hypoglycemia. And those side effects were reported less than in the SOLAR-1 trial.   So we know that, in this group of patients, we really do need to monitor their blood sugars, give them prophylactic antihistamines, and also counsel them on adequate anti-diarrheal management. So the BYLieve trial helped us with two concepts. One is, after CDK4/6 inhibition, in those patients with PI3-kinase mutations, yes, there is a role for alpelisib. And the second thing is that we're doing a better job, while we can't do cross-trial comparisons, of improving the quality of life and symptoms that arise from alpelisib, including the rash, the diarrhea, and the hypoglycemia.   Another trial that was very exciting, shifting gears, is the HER2CLIMB trial. And that was abstract 1005. We knew from December that tucatinib improves outcomes when added to trastuzumab and capecitabine in patients with advanced HER2 positive breast cancer. We also knew that it does improve survival irrespective of brain metastases, and brain metastases that might have been progressing.   What this analysis of the HER2CLIMB showed was that the patients that received tucatinib did have an improved survival benefit compared with trastuzumab and capecitabine of six months. Additionally, the response rate solely in the central nervous system was 41% on the tucatinib arm versus 23% on the arm that received capecitabine and trastuzumab alone. So these were really exciting data because we do know that about 50% of patients with advanced stage IV breast cancer that's HER2 positive do eventually develop brain metastases.   So while we know that tucatinib, in addition to trastuzumab and capecitabine, does improve survival irrespective of brain metastases, we know now that those patients with progressing brain metastases do have an improved outcome when tucatinib is added. The side effects that we have to monitor for are diarrhea and liver function abnormalities, of course.   Shifting gears a little bit more is the immunotherapy trial in triple-negative breast cancer. And that is abstract 1000. So over the past 12 to 18 months, we've seen data from the IMpassion130 trial, which showed that patients who had PD-L1 positivity in their immune cells did derive benefit when atezolizumab was added to nab-paclitaxel, and it did improve outcomes.   Now, this trial, the KEYNOTE-355 trial, looked at patients that were untreated for their advanced breast cancer. And these patients were randomized to paclitaxel, nab-paclitaxel, or gemcitabine and carboplatin chemotherapy with pembrolizumab or without pembrolizumab. And what was noted is those patients that had a combined positive score of PD-L1 greater than or equal to 10 derived about a four-month progression-free survival benefit if they received pembrolizumab.   Now, we have two trials, the IMpassion trial and the KEYNOTE trial, that show that patients with some element of PD-L1 expression, whether it's the immune cells, as evidenced by the IMpassion trial, or the combined positive score of PD-L1, as was evaluated in the KEYNOTE trial, did have significantly better outcomes if immunotherapy was incorporated as first-line treatment for their triple-negative breast cancer.   There are questions, though, that we have to answer, in what is the optimal measurement to predict response to immunotherapy in the triple-negative breast cancer setting, and also what is the optimal cut point that we should use to say whether we should employ immunotherapy. However, it was another advancement for an unmet need, which is triple-negative breast cancer.   One thing we know in advanced breast cancer, whether it's because of PI3-kinase mutations, whether it's measuring PD-L1, that we need to do testing beyond estrogen receptor, progesterone receptor, and HER2. We're increasingly utilizing genomic and germline testing to see if we can give more personalized therapy to our patients. 1002 looked at the effectiveness of patients with BRCA mutations that were somatic, as well as patients with germline mutations, including PALB2, and they found that olaparib did improve outcomes in patients with somatic BRCA mutations, as well as those patients that harbored PALB2 mutations. So I think that this is another reason for us to make sure that we are sending our patients for germline testing in the advanced breast cancer setting, as well as to make sure that we're looking for somatic mutations that we can target.   ASCO Daily News: What are your key takeaways from the studies on early breast cancer?   Dr. Neelima Denduluri: Thanks for asking that question. As I said earlier, there are many advancements, but one that I want to highlight is abstract 501. We know that anthracyclines have improved survival in breast cancer over the last several decades. However, we also know that HER2-targeted therapy using trastuzumab, pertuzumab, and now TDM1 has significantly improved outcomes in early breast cancer. So we've never known whether we truly need to give anthracyclines in the face of effective HER2-targeted therapy.   The TRAIN-2 trial, which is abstract 501, evaluated whether anthracyclines improve outcomes when there is optimal HER2-targeted therapy. And the answer is no, it did not. So I think that's very promising. And potentially, what we'll be able to do is to decrease cardiotoxicity, as well as treatment-related leukemias and myelodysplasia, possibly, in terms of reducing the risk of those by omitting anthracyclines in the early HER2 breast cancer setting.   Another abstract that I want to highlight is 507, which was looking at the role of adjuvant capecitabine in a metronomic fashion, meaning lower doses and giving it for a longer period of time, in those patients with triple-negative breast cancer. Just to give a quick historical background, we know from the CREATE-X trial that those patients that received preoperative therapy with third-generation chemotherapy and had residual disease at the time of surgery, those patients did benefit from the addition of capecitabine as part of their adjuvant treatment, compared with no adjuvant treatment.   So these are further data that we have further elucidating the role of capecitabine, primarily in the triple-negative breast cancer setting. And we did see that there was an improved outcome in terms of disease-free survival in these patients with anatomic stage I to III triple-negative breast cancer, and they did benefit from the addition of capecitabine.   Also, two side effects that we worry about with capecitabine are diarrhea and hand-foot syndrome. And they seem to be more manageable with this lower dose of capecitabine compared with the traditional 2,500 mgs per meter squared twice a day that was approved initially with capecitabine or that was used in CREATE-X.   ASCO Daily News: Dr. Denduluri, are there any new advancements in supportive care and symptom management?   Dr. Neelima Denduluri: So Geraldine, we know that a geriatric assessment is very important when we treat our patients that are elderly. Abstract 12009 performed a geriatric assessment on patients that had stage III or IV cancer and were aged 70 or older. And once they performed that geriatric assessment, they sent the treating oncologist the geriatric assessment and guided recommendations to improve their tolerance to therapy, potentially. And what they found is that it reduced clinically graded grade III to V toxicities significantly by providing this geriatric assessment. And also, it didn't lower survival.   So I thought that this was really nice prospective data that shows that we should be performing a geriatric assessment, and what we find, we should make sure to support our patients better based on the findings. And this improves our patients' tolerability to therapy, and it does not decrease their survival. So I thought that that was a very uplifting trial. We have a lot of programs around the country that are saying how best do we support our geriatric population, and this was a good step in the right direction.   ASCO Daily News: Absolutely. Is there anything else you'd like to add today? Any other abstracts that we should know about?   Dr. Neelima Denduluri: A couple of other things that we talk about quite a bit in our clinic is disparities. And abstract 1080 found that those patients with triple-negative breast cancer were continuing to receive non-guideline-adherent care when it was compared to their Caucasian population compared with the black population. So I think that this underscores that we really need to make sure that we address the disparities in cancer care.   Cancer survivorship is very important. One thing that patients complain about is insomnia. Abstract 12005 showed that yoga, cognitive behavioral therapy, and survivorship health education really improved insomnia in cancer survivors. So again, when we look at taking care of patients, we really need to look at the whole spectrum. And while we have excellent drugs and drug development that is improving outcomes, we also need to make sure that disparities, financial toxicity, survivorship are addressed. And therefore, I thought that this ASCO did a great job of looking at those issues, as well as drug development.   ASCO Daily News: Absolutely. Well, thank you, Dr. Denduluri, for sharing your insights with us today on these promising new developments in the breast cancer field.   Dr. Neelima Denduluri: Thank you, Geraldine.   ASCO Daily News: And thanks to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us on Apple 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Lauren Davis, and joining me today is Dr. Megan Cruz, a medical oncologist at the Cleveland Clinic who treats patients with breast cancer. ASCO Daily News: Today we're talking about a new therapeutic option for patients with metastatic breast cancer who carry the PIC3CA mutation. Dr. Cruz, welcome to the podcast. Dr. Megan Cruz: Good morning. Thank you for having me. ASCO Daily News: We're glad you're here. ASCO Daily News: So the PIK3CA is a commonly mutated gene in HR positive and HER2 negative advanced breast cancer. What kind of tests are used to detect this mutation? Dr. Megan Cruz: Yes, so that's correct. The PI3 kinase mutation is found in about 40% of hormone receptor positive HER2 negative advanced breast cancer cases. And this mutation can actually be detected by a variety of tests, many of which are convenient for our patients. Dr. Megan Cruz: Most commonly, we use tissue-based testing. And that can be samples of tissue that have been archived from either a patient's initial breast cancer diagnosis or a newer biopsy from a metastatic site. If neither of those places can be accessed or that tissue sample is no longer available, patients can have testing run on a blood-based sample. And this is often very helpful for patients who potentially have bone-only metastatic disease. ASCO Daily News: Are new agents are available to treat this form of cancer? Dr. Megan Cruz: Yes. So earlier this year, we had FDA approval of a new medication called alpelisib, which is used in combination with endocrine-based therapy in the form of fulvestrant in order to treat patients with the PI3 kinase mutated breast cancer. ASCO Daily News: And how effective is this treatment in terms of survival or overall survival? Dr. Megan Cruz: So this treatment was studied in the SOLAR-1 trial. And in that trial, it was found that there was a progression-free survival advantage for patients who received the combination of alpelisib and fulvestrant compared to placebo and fulvestrant. And that difference at 20 months was approximately from 11 months with alpelisib and fulvestrant from 5.7 months for the placebo fulvestrant combination. ASCO Daily News: And what do clinicians need to know about side effects? Dr. Megan Cruz: So there are some unique side effects with this medication, alpelisib, that clinicians will need to pay attention to. The most common ones are hypoglycemia and rash, which are generally pretty easily managed, but we have to be aware of them. Dr. Megan Cruz: When starting a patient on this medication, they need to have fasting blood sugar testing as well as hemoglobin A1C testing done prior to starting as a baseline. And then shortly after initiation of the medication, we recheck these labs to make sure that they're staying stable. Dr. Megan Cruz: If the blood sugar is rising, it's recommended to do more frequent monitoring and consideration of starting a medication like metformin to help control the blood sugars. In terms of the rash, that can actually be dealt with in a preventative way, where patients can be started on prophylactic antihistamine medications along with the start of alpelisib. And then if the rash does happen once they're on the medication, we often use either topical steroids or oral steroids to help control it. Dr. Megan Cruz: The last toxicity that I think that the clinicians should be aware of his diarrhea, which is one that we're more familiar with managing from other chemotherapies and targeted agents. So typically, use of our common anti-diarrheal medications will help to control that. ASCO Daily News: What do you think's on the horizon for metastatic breast cancer treatment? Dr. Megan Cruz: I think that we will continue to see medications like this that are targeted for specific mutations that we find in a patient's breast cancer. And then along with that, I think we'll be combining these targeted medications potentially with immunotherapy moving forward. I think those are the new horizons for metastatic breast cancer treatment. ASCO Daily News: Again, today my guest has been Dr. Megan Cruz. It's been a pleasure speaking with you. Thank you for being on our podcast. Dr. Megan Cruz: Absolutely. Thanks for having me. ASCO Daily News: And to our listeners, thank you for tuning into the ASCO Daily News Podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

  Keto diets have been extremely popular lately, but how does being in ketosis impact our training and performance? The expert on these topics is Dr. Dominic D’Agostino. Dr. Dominic is a Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida, and Research Scientist at the Institute for Human and Machine Cognition (IHMC). He is well-respected in the science world as well as the performance industry having been featured on Tim Ferriss' podcast as well as having his research supported by the Department of Defense, the Navy SEALs, etc. 35. Keto Diets, Training and Performance with Dr. Dominic D’Agostino In today's episode, we dig into Dr. D'Agostino's research plus his own personal experience and experimentation with keto diets and bodybuilding, including how he achieved his personal best deadlift while fasting! We also discuss what it means to be "fat adapted" and why our bodies can run on both ketones and glucose at the same time. Dr. D’Agostino says the idea is to adapt our bodies over time by training while we're fasting periodically; if we are training in a state of nutritional ketosis and occasionally consuming carbohydrates then our body recognizes carbs and as ketones both as fuel sources. One strategy to do this could be to eat a carbohydrate-based diet that is low enough to maintain optimal insulin sensitivity while including ketogenic nutrition, such as MCT oils or ketone supplements. But it's important to also do this without necessarily restricting carbohydrates to the point of entering ketosis. And we finish up with a chat about when it's beneficial to be on a keto diet as well as how often to follow a ketogenic protocol to get the full benefit. Dr. D'Agostino suggests we can achieve many of the metabolic benefits and anti-cancer benefits by going keto for just three to five days per month either through fasting or by going down to 500 calories per day. You’ll hear him explain the science behind these approaches plus much more on this fascinating and enriching conversation on today’s edition of the Awesome Health Podcast! Resources for this Episode Dr. Dominic's Website Dr. Dominic on Instagram Dr. Dominic on Facebook Read the Episode Transcript : Wade Lightheart: Good afternoon, good morning and good evening. It's Wade T Lightheart here today with co-founder Matt Gallant. And a super special guest, Dr Dominic D'Agostino. I have been, you know, hoping for this interview for a long time. For those who don't know who Dominic D'Agostino is, he is one of the preeminent experts on ketogenic diets and ketosis. He works with the Navy seals and in a variety of projects that he's done, they're heavily research oriented and the benefits that this potential dietary practice can have both in performance applications as well as physical health issues, you know, related to cancer, things like that. Cognitive function, a bunch of different things. Dom is a professor at the department of molecular pharmacology and physiology at the university of South Florida and a research scientist at the Institute for human and machine cognition. His laboratory develops and tests metabolically based strategies for neurological disorders, cancer and for enhancing the safety and resilience of military personnel in extreme environments. His research is supported by the office of Naval research, department of defense, private organizations and foundations. He just recently came back from a trip from Australia where he was speaking literally in what, five cities in 11 days. And he was gracious enough to take the time to join us on the Awesome Health Podcast. So delighted to have you here. Dom, welcome to the show. Dominic D'Agostino: Great to be here. Thanks for having me Matt and Wade. Matt Gallant: As much as Wade is excited, I'm, I'm even more excited. You know, I've been a fan of your work since. I think I first heard you probably I think on the Tim Ferriss podcast which, which was very enlightening and I've been a longtime keto user and dieter for over 26 years on and off nonstop now for four and a half. And a BiOptimizers, you know, we have these, this three sided triangle of, you know, aesthetics, how we look, the performance and the health side. And I think you're one of the top guys in the world to talk about the performance side and the health side of keto. Cause most people talk more about the aesthetics, the fat loss and that, that component. But today I really like to dive into maybe we could start with some of your background and what you've been doing research wise and then we can get really into all of their current stuff you're doing in a run performance and help. So maybe give us a little bit of background as far as what you've been up to the last five, 10 years. First Quito and kettle research. Dominic D'Agostino: Yeah. for 10 years, well, this quickly, going back to 25 years ago, I was always interested in nutrition and I majored actually in as an undergrad in nutrition scientists and dietetics. And as I navigated my, you know, college career, I realized that there wasn't a whole lot of jobs in nutrition. So I kind of moved to majoring in biology too. And then I did my PhD actually in neuroscience and, and when I finished my pHD I was funded by the office of Navy research for my fellowship, a postdoctoral fellowship. And that was really to understand oxygen toxicity seizures as it pertains to the Navy seal dieter that's using a closed circuit rebreather that they use or operational conditions. There's a stealth component to this equipment. There's no bubbles when you dive underwater. A disadvantage would be that you're breathing high oxygen 100%, actually with a certain type of breather and it just did the be the seawater. Dominic D'Agostino: You can have a seizure and within 10 minutes some people you know can have that and there's really no way to predict or prevent them. So the first area of my research was developing different technologies that would allow us to understand sort of how the brain is working under these conditions. And if you understand the problem, then you can come up with a solution. But we didn't fundamentally understand the problem. So we developed things like microscopes and electrophysiology equipment and telemetry equipment and we adapted that for use inside a hyperbaric chamber. And then over, you know, five or six years, I started to realize that targeting brain energy metabolism and the neuropharmacology of the brain are two strategies to protect the brain under these extreme conditions. And I was sort of interested in antioxidants, loading up animals with antioxidants really did not seem to work much, although in theory it should have. Dominic D’Agostino: But then I started moving towards like coaxing our own bodies to be more resilient. And there was some studies that we've done with fasting rats for 24 to 36 hours and that actually had a remarkable effect at preventing the seizures and it was actually greater neuroprotection than the antiseizure drugs. So I began sort of became interested in how fast and could mitigate and be a mitigation strategy or counter measure against these types of seizures. And then discovered the ketogenic diet, which I thought of, sort of thought I knew, but I really didn't know the whole history of the ketogenic diet, you know, growing up you hear about low carb diets, Atkins diets and you know, I had interested in the ozone diet at one point and a little carb a little bit and I did it kind of on and off for different years. Dominic D’Agostino: But when I delved into the history of the ketogenic diet and met with the practitioners at major universities, like especially Johns Hopkins group I realized that this could potentially be, I could incorporate nutrition back into my research program and do sort of like a nutritional neuroscience project. I would just have to convince my program officer at the department of defense or Navy that, you know, this was a good strategy and the science was actually there like on PubMed, you know, I mean it was good peer reviewed studies sharing that independent of the etiology independent of the cause of the seizures. The ketogenic diet seemed to help across the board. So, and oxygen toxicity seizures are powerful. Tonic clonic seizures we think are being generated in the hippocampus, which was an area that I was studying and published on. And also maybe influencing the neuro control of autonomic regulation and actually did my PhD on respiratory neurobiology brain set. Dominic D’Agostino: So I had a sort of an understanding of, of sort of what was happening and, and a new understanding and appreciation for nutrition as a metabolic therapy. And and I was never taught anything about the ketogenic diet through my four years of training and two, two semesters actually, the advanced nutrition and graduate nutrition. I never even heard about the ketogenic diet being used, and it was like the standard of care for drug refractory epilepsy. So long story short the dietary approach wasn't, it didn't really grab the attention of the program officers. They wanted to see a ketogenic diet sort of in a drug. So I went down the path personally from a research perspective of just studying ketones and different formulations or ketones. But I also started doing the ketogenic diet myself to understand it from the implementation perspective. And, and, and not people weren't doing the ketogenic diet, the clinical ketogenic diet back when I started and maybe 2008, seven or eight. Dominic D’Agostino: But as I followed it, I realized after I got through the initial adaptation, I felt really good. And I I, prior to this, my, my meal frequency was five or six meals a day and I transitioned actually to eating less often and to the point where I adapted to doing intermittent fasting occasionally, once in awhile. And, and then as we developed ketone various ketone technologies, including ketone esters and ketone electrolyte preparations mixed with a MCT and started studying it, we realized that these are very powerful neuroprotective compounds that have a wide range of applications, not just oxygen toxicity seizures, but different metabolic disorders are highly responsive to nutritional ketosis. Some are the standard of care are the ketogenic diet, I should say, is the standard of care for things like metabolic disorders, like glucose transporter deficiency, other deficiency complex. We studied Kabuki syndrome, which is a genetic disease. Dominic D’Agostino: And we look at the role of ketone bodies as an epigenetic regulator activating some genes and silencing others that can impart their therapeutic effects. So, and then cancer too is another area. I've had three PhD students graduate under me training under me that actually focused on looking at the ketogenic diet to impact the growth and proliferation of cancer, metastatic cancer. We we're looking at cancer parts, which is muscle wasting associated with cancer. We're also looking at drugs like Metformin and other metabolic drugs that sort of target different pathways that overlap with the ketogenic diet. So, so I started studying it for something that was relatively esoteric to most people. Oxygen toxicity seizures are now, we now are studying, I would say probably close to a dozen different things including glucose regulation, you know, everything from ALS to angelman syndrome to Alzheimer's disease, Kabuki syndrome, glucose transporter syndrome a number of other kind of even more rare things that you may not have heard of. Dominic D’Agostino: And, and we're also, you know, developing forms of ketogenic compounds, diets, and also supplements that would allow the war fighter and potentially even the astronaut to implement some form of ketogenic nutrition to enhance performance and resilience in extreme environments. You know, so going back to the, the Navy project, I've continued to be funded by them, you know, for like almost 12 to 13 years now. And I continue to have projects and we've developed the animal work and now we're actually doing studies in humans. And, and now we've actually moved on to working with NASA where we, eh, we do experiments where we live in an undersea environment for an extended period of time in what's called saturation. And when you're in saturation, it takes a long time to decompress and to come up. So your body is an extreme environment, not just pressure, but higher ATA of oxygen, higher partial pressure of carbon dioxide too, which has an effect. Dominic D’Agostino: So we have projects where I look at the gut microbiome, psychological testing, body composition. We look at a number of other factors, you know that are influenced, you know, in these extreme environments, a lot of like psychological, what we call team-building or cognitive team cognition. So how the group works together and that can be impacted by our energy state, our metabolism, and our pharmacology. So we're looking at a whole suite of parameters of people in these environments. So we figure out where the detriment is. And then once we understand that, then we develop a sort of a lifestyle, which is micro focuses, nutrition and supplementation to basically enhance, you know, resilience in that environment. And that would be physiological resilience and psychological resilience. So that's, we're putting a lot of time and effort into that project now. Wade Lightheart: That's pretty exciting stuff. Yeah, no I just wanted to comment on that. And one of the things I think from a practical standpoint that I think people can relate to. And I'm curious about this one because I think as listening to you on Tim Ferris, you had gone an extended period time of fasting and were able to like do a ridiculous deadlifts set. Do you want to talk about that just, just briefly, cause I'm just, this is a curiosity component of I heard about it. I want to be confirmed that I heard it correctly. So I'll let you speak from the hearts because what it seems that you've been able to do is something that almost no one would believe possible. Dominic D’Agostino: Well, I, I don't, I don't think fasting or being in it, and I don't think the ketogenic diet has, some people didn't accuse diet will dramatically impair your strength and performance and once you're adapted, and I don't see that as being necessarily a problem if you have protein a equate for protein and total calories. So fasting is sort of like another thing, but also kind of similar in a fasting state. It after about the second or third day it gets hard around that time, but once your body adapts you actually feel better. Your energy level starts to get a little bit low. Towards day five or day seven in me. I haven't went beyond a seven day fast. And I realized that, you know, I wouldn't want to do a high volume workout during that time, but I realized that my, my overall strength just by how I felt really was not impaired much in a, I just wanted to, you know, kind of feel how the weight spell on my body and actually my inflammation was gone. Dominic D’Agostino: Like, I mean, I felt good in so many ways that I just kept adding weight. One 35 to 25, three 15 four or five, four or five easier than I expected. So I was like, okay, let me try five plates. And I did five and I was thinking maybe I should stop there and my body's sort of in a low energy state and I just kept going. I normally can do more, but I, I felt that the 10, I don't even think I got sore the next day. But yesterday actually I just, I got back from traveling in Australia and I picked up a stomach bug on the last day as I really didn't eat for about two or three days. And yesterday I just posted it on Instagram, Facebook, I deadlifted five plates for 15. And my body weight was really low to one 98. Dominic D'Agostino That's extremely low for me. I'd be, haven't been that low since I was a teenager and I was kind of in a backseat state again. And again, I don't for exercises, like if for things pressing movements, if I lose weight, my, my strength goes way down. But for things like deadlift, I always kind of feel strong in a semi fasted state. And I think I've mentioned this to Tim's brand and Tim friend told Tim and then he unexpectedly added it to that podcast and it's like, I don't, I don't, don't, it's like, no, no, I think it's, you've got to start off. That's how you engage people. So I requested it not, you know, I mentioned that, but he mentioned it and it's like, then I had to live up to it, then I had to actually go and do it. Wade Lightheart: That's a fascinating, it's the next fascinating segue cause it's a pattern interrupt for most people who think three or four hours without eating, they're going to die. Especially bodybuilding six times a day probably. Yeah, exactly. So it's a point of interest. I think that kind of, you know, creates another level of curiosity for people to find out, well, well how is that possible? What is this guy doing? You know? And, and it, I think it just adds a a level of verification about the efficacy of what you're doing and what you're promoting and, and, and how you're going about doing it. It also opens a door, I think, which Matt's going to dive into here about asking some very specific questions because as is, he'll reveal he's, he's been deep down the ketogenic adventure for as long as anybody I know. Matt Gallant: So, so I want to get into I guess some nerdy stuff and you know, one of the things I believe in, I'm curious what your thoughts on this phone is that if we look at health as a spectrum on one side you got, you know, sickness and then your death and that in the middle what people call normal. Wade Lightheart: And then at the very end of the other side you have peak performance, peak health. So what I've seemed to notice is that all the things that might fix health issues, you know, for that get us from no sickness to normal will typically also get us from normal to a peak state. And you know, I want to get into the neuro cognitive enhancements that happened with the ketogenic side and you really want to understand what's happening exactly, again on a brain level and on a nervous system level that is producing enhancements. Like why, why is ketones enhancing the cognitive side? Dominic D'Agostino: Yeah, that's a subject of intense research and numerous labs right now. We have garnered sort of a lot of information over the years. Well personally doing it myself and actually measuring my neurotransmitters and, and other blood markers of metabolic health and inflammatory health and neuroinflammation. Matt Gallant: So can I ask you, like what have you seen on a neurotransmitter level? Wade Lightheart: Yeah. And what tests are you running. Dominic D'Agostino I Oh, have different kits here in my drawers. I was going to say that for neurotransmitters, it's not a great test, but one of them that I did, and I did a couple ZRT labs has a urine neurotransmitter test. And I think when I did it down inside the habitat for the NASA emo mission, a couple of them for some reason didn't come out. But the things that came out and made a lot of sense you know, I've, I've done repeated measurements and my GABA to glutamate ratio is very high. It's on the order of two to three times outside the range of normal. So I tend to, at least in a ketogenic state, you make the neurotransmitter gamma-Aminobutyric acid GABA you make, it's a brain stabilizing your transmitter. You actually make that from an excited Tori neurotransmitter called glutamate through the an enzyme called glutamic acid decarboxylase and being in a state of nutritional ketosis with the diet and now we know with supplementation activates the GAD enzyme to convert more glutamate to GABA. Dominic D’Agostino: So you go from a a state of the brain that's hyperactive in the context of what we study. There's excitotoxicity, glutamate, excitotoxicity and it, I think it's in part therapeutic because you are reducing in neurotransmitter that's causing a neuronal hyperexcitability and making GABA, which I don't want to get too down in the weeds, but it mediates, it does chloride mediated post-synaptic inhibition, which it opens up an ion channel that hyperpolarizes the membrane potential of the cell. And when a membrane potential is hyperpolarized, it doesn't fire action potentials as fast. It's more, it's very stabilized. And if there's lots of glutamate excitatory, that will deep polarize the membrane potential and it comes closer to its threshold for firing. So it starts firing action potentials very fast. And if all your neurons are doing that, then you're like dumping glutamate, you're dumping potassium, you're dumping calcium potentially. And this can create a scenario where you have excited toxicity. So in a nutshell, what being in nutritional ketosis does is it changes the neuropharmacology of your brain to prevent you from entering that hyperexcitable state. And so that's one of about a dozen things. And I could go down that sort of list of that on a dozen different things. Another thing that we can, Matt Gallant: No, but that's, that's, that's fascinating. Cause I've done some tests and I'm on the slightly deficient side of, of GABA. So it's probably one of the reasons why I love keto in general and, and why I respond well in that I did not know it what you just reveal. That's fascinating. Dominic D’Agostino: Yeah, we've published that too actually in well it's been published in Humans. But we, we did it in a model of Angelman syndrome and we actually have an Angelman syndrome clinical trial at Vanderbilt right now because of, you know, some of this, the work that we did in preclinical models. Matt Gallant: So a question. I mean when obviously common belief is that the brain runs on glucose, what's your answer to people that go with that? Dominic D’Agostino: Well, you know, that's what I was taught, that that was part of my training in nutrition. You know, you never go below a 60 grams of glucose because that's what the brain's obligate requirement. But then because I got interested in fasting, I was thinking, well, like what does happen when you fast? And I was thinking you know, well, how can people, how can people fast and not go hypoglycemic? And then I started reading a work of Dr. George F Cahill from Harvard medical school where he facet subjects for 40 days. You know, towards the end of that, he injected them with insulin to push their glucose down farther. And it revealed that they were asymptomatic for hypoglycemia because they're the fact that their bodies are adipose was releasing for energy to be used by skeletal muscle and the heart, the brain really doesn't use these large fat molecules for fuel because of the blood brain barrier. Dominic D’Agostino: So the liver converts them to small water-soluble fat molecules. We call ketone bodies or fat derived molecules. And then the ketone bodies can largely replace glucose as an energy source. Although we still our blood glucose levels, they're very powerful homeostatic mechanisms that maintain our blood glucose levels. So glucose really doesn't change all that much. It'll go down to like maybe three millimole or something like that at the glycerol backbone of triglycerides. We'll make continue to make glucose. And then you have gluconeogenic amino acids, especially Alanine that gets released from muscle tissues and that becomes can become glucose. But the primary fuel for brain energy metabolism can switch to from glucose to ketone bodies. And I say that I say primary fuel because more than 50% of brain energy metabolism, it's kind of universally agreed that after prolonged fasting that we are using primarily ketones. And the same thing can happen with a, a strict clinical ketogenic diet. You're primarily running the brain off a ketone bodies. Matt Gallant: So, just to recap, your body has a lot of different ways to internally produce glucose, which is kind of a fascinating cause I've noticed that too, that even when you know, zero carbs, carb or fasting, that, you know, my blood glucose might drop as, you know, high seventies, but it's, it's, it's hard for me to go lower than that even if I'm zero carb and fasting and what not. So, yeah. Have you noticed too that the longer, and I've seen some interesting research recently on this that if you're, it'd been on keto for a long time. That seems to be another level of adoptation where even while you're exercising, the glucose is staying in the muscle. Like the body's actually not even touching some of the glucose, cause I've noticed that even in the last like year or so that I, I just seem to be holding onto more glycogen in the muscle than I used to, even when I'm doing all the same things. Dominic D’Agostino: Yeah. That'll be dependent to some extent on calories. So if calories are if you're, you caloric and you're not at a calorie deficit actually, well I'll come to that later. But if you are, if you do become at a calorie deficit and you're carb dependent, you lose glycogen really fast. If you do become calorie deficit and you're adapted to a ketogenic diet, you, you, you lose glycogen much slower because you are using fat for energy or more fat. The ratio is higher than the ratio of glucose you're using. So, but yes, I think Jeff Bullock has published on these two and athletes is that skeletal muscle glycogen, not liver glycogen, but skeletal muscle glycogen does not change that much. And athletes that are extremely carbohydrate restrictive with their diets, which is difficult for some people to believe. But once you understand metabolic physiology and that we've had adapted the skeletal muscle, the primary engine, you know, that's, that's burning and a substrate to using fatty acids for fuel that actually has a glucose sparing effect and the glucose sparing effect because you're using more fats as opposed to glucose will preserve muscle glycogen. Dominic D'Agostino: Over time there becomes a tipping point. And I think everybody's a little bit different. But I think the point is that, you know, athletes that are, that are adapted to nutritional ketosis really do have a remarkable ability to retain also glycogen. Matt Gallant: So one of the big concerns that some people have and Wade has this concern as well is the loss in kind of, let's just call it the, the last 10% like that peak, especially if you're more of a power athlete. What's your opinion on that? Is that something that if you're fat adapted for long enough that you can regain? What have you seen as far as peak performance, again from a sprinting, weight lifting, those types of athletic endeavors? Dominic D’Agostino: Yeah, these are really good questions. You know, I do believe I've seen enough data to suggest that if you are on a very carbohydrate restricted ketogenic diet and you push an athlete to two dates, extreme short bursts of, of output, total power output may be compromised would likely be compromised to some degree. If someone's on a very restrictive ketogenic diet if you don't add carbohydrates in. So I think, you know, there, there's a lot of nuances here but, but I think that if you take the average athlete who's carbohydrate adapted and adapt them to a low carbohydrate diet forcing their body to sort of burn preferentially more fat for fuel, they can get 80 to 90% of the benefits of low carb without compromising their glycolytic capacity. And you can do this simply by titrating in the carbohydrates back into the diet. Dominic D’Agostino: A tip, you know, low glycemic index carbohydrates, small amounts of carbohydrates will keep glycolytic pathway sort of open various enzyme systems like every big dehydrogenase complex. So that enzyme, the people who favor high carb diets will say, well, your pre-rebate dehydrogenate complex will be suppressed. You won't make as much protein and that the enzyme itself won't be as active. I think one way to keep that, that energetic path open is to periodically add some carbohydrates in, maybe in around your training. And that could be beneficial too. And also if you are, if you are a low carb athlete, when you fuel up intro workout, the type of workouts I do, I don't, I don't really have a fuel up if I, I work my workouts are like 15, 20 minutes or something. But for athletes that work out for like hours at a time to then introduce a sort of a, you know, a carb and a bat sort of supplement at the same time like MCT oil or maybe even mixed with some long chain fats but also a slower burning carbohydrate source after a certain point because you do get carbohydrate, you know it does become a limiting substrate under some conditions and I think each person is a unique metabolic entity. Dominic D’Agostino: I need to experiment, but like the take home messages that if you go on a super strict diet, your low end maybe knocked down a little bit. But if you learn how to use carbohydrates as a performance enhancing substance and you use it sparingly, then I think you can get the best of both worlds. From, from my perspective. Matt Gallant: Yeah, I've seen, I know some guys that have tested their, their, their ketones by doing some cyclical carb re feeds, intro workout, and you know, they've gone as high as like 80 grams on a leg day and had no changes. So they've been able to just maintain ketosis. And because obviously in a squat day, you know, the big deadlift day, you're just going to be burning that glucose in real time. Dominic D’Agostino: The keto community may like cringe at this, but I, I really believe that carbohydrates are a powerful performance enhancing sort of substrate. If you strip strategically and if you deliver a certain types of carbs. I mean, it could be any kind of carb. I mean, when I experiment, I'll use chocolate. I mean, I'll, she's like stuff like that. So it doesn't really have to be a particular kind of carbohydrates, but if you add also lots of water and sodium too, while you're delivering the carbohydrates your blood volume will go up. I mean, you'll notice things in the gym, you know the energy that you feel may just be due to the hyperhydration you get and it doesn't take much. So that's the key. You don't have to throw in like three, 400 grams of carbs and it can be as little as 30 or 40 grams of carbs. If you're a really big guy doing a long workout. Yeah, you might want to titrate, you know, 80 grams of carbs over that duration and maybe a little bit with a refeed. But it certainly doesn't take a lot of carbs to when you're talking about someone who's fat adapted and the, I think 30 grams of carbs for the typical, you know, one, one and a half hour workout, however long people work out these days. Matt Gallant: So you really open up a topic that I had in mindful on time, which is the idea of dual fuel, right? So the idea that you can both run on glucose and ketones simultaneously. I mean, I've done it personally many times. Can you, first of all, can we start with the physiology? Like, how, how is that happening? How is the body burning both glucose and ketones at the same time? Dominic D’Agostino: Yeah, there doesn't seem to be like, it's a strange question for me, like someone who studies physiology because I mean it's just, that's what the body does. But I know there's two camps out there who just kind of believed that, you know, we fuel off carbohydrates or refuel off ketones and fat. But your body has in your brain. We now know, has amazing metabolic flexibility. So if we adapt our bodies over time, and the best way to adapt is to train under specific metabolic conditions. So training while you're fasting periodically, I mean, some people cringe at that, but I think doing it occasionally is a good idea. Training in a state of nutritional ketosis occasionally throwing carbohydrates in so your body recognizes that fuel and to do that periodically. So I mean, I'm coming at a, at a neuroscience perspective because I, I believe a lot of our digital output and our brains are wired to our muscles. Dominic D’Agostino: So if our central nervous system is energized and we have good fuel flow to it, it's going to buy our muscles and can attract more muscle fibers so we can actually get stronger contractions and maintain that over longer periods of time. If we give, our brain has metabolic flexibility and we'll use whatever fuel is available. So glucose and, and ketone bodies we know it can use lactate to a little bit amino acids, but usually, you know, glucose or ketones. So it will use whatever's available and whatever's in the blood. So one strategy could be to do a carbohydrate-based diet that you know, low enough that you maintain optimal insulin sensitivity and then throw in ketogenic nutrition, which could be MCT oils or on supplements without necessarily restricting carbohydrates to the point where you are in ketosis. A MCQ oils can achieve that. Dominic D’Agostino: And also ketone supplements on the market can also achieve that. This is a new idea. But we do know that independent of a carbohydrate restriction, if you administer a ketogenic agent, whether it's a ketone salts, even MCTs or ketone esters, the body will use what's available. So if you elevate that substrate, interestingly, if your ketones are elevated, it seems to facilitate a glucose disposal into the tissue to although it, it kind of appears that because your blood glucose goes down when you administer acutely a ketogenic agent, some individuals, some labs believe that that's an increase in insulin sensitivity that's facilitating glucose disposal that could be happening. But I think when you orally administer a ketogenic compound through counter-regulatory mechanisms, we don't quite understand. There's a decrease in hepatic gluconeogenesis and thereby a paddock glucose output is reduced. We have not done a liver metabolics to figure out what's going on, but it kind of makes sense that it delivers, you know, seeing a high concentration of ketone bodies, it's going to want to spare glucose. Dominic D’Agostino: The glucose you have in your blood now is not like it's the glucose that your liver regulates. So your liver is the master regulator of the glucose that your peripheral tissues seats. So the glucose that's in your blood now, it might be from a couple of days ago, the glycogen that's stored in the liver a couple of days ago. So your liver is like the master regulator. It's why it's important to keep the liver healthy. And when the literacy is ketones, I think that it's a decreasing glucose output. This is important therapeutically for like type two diabetes and also, but it's also kind of important too from a fuel, a dual fuel perspective, which was the question I think people will ask, well what will happen if you throw ketones on top of glucose? You know, then you're just, you're creating this artificial scenario, which could be dangerous. But I believe that, well, we now have experimental data to show that the liver does a pretty good job at recognizing it. Dominic D’Agostino: You know, the, the level of ketones that you have and, and utilizing those fuels and people maybe look at exogenous ketones as an artificial fuel, but it's really just another energy source. I mean you could say that it's creatine, right? I mean, we take or we make creatine, we store it a little bit and when we drink it, we're getting super physiological levels. And from the literature all we can tell it's doing positive things. And I think ketones are kind of like it's good to make them through our own physiology because that forces adaptations and adaptations are necessary for the ketogenic process, that ketone transporter process going across biological membranes. And also with cell C ketones, you're also up regulating keto lit enzymes which allow cells to derive energy and ATP from the ketone molecules. And I think that happens faster when you do it naturally with the ketogenic diet or fasting. And then if you throw ketone supplements on, you know, sparingly. I don't, I don't use em today. I don't use them every day, but I think you can kind of gain, you can kind of gain the system a little bit and gain an advantage. I mean, what our research shows. Wade Lightheart: I can, I would echo that from just a clinical conspiracy, my own stuff. Matt, of course, has been on the ketogenic diet. I'm a, I'm a plant based guy and, but I have an extraordinary blood insulin response, you know, whether it's genetics or whatever. I, you know, when I measure myself, I'm often in a ketogenic state almost when we do our typical fasting on a HomeAway or that sort of stuff. But when I've added ketones, exogenous ketones that Matt's provided for me I, I noticed an instant cognitive performance benefit. Like it's like, okay, I'm a little sharper, everything's a little, little, little crisper and the endurance factor seems amplified for sure. So I, I would echo that just, and that's not very scientific, but it's certainly experimental. And I, and I'm curious, do you kind of do these experiments on your own and then start doing the data and kind of like hitting your bio feedback and then go, I didn't, let's dive into this and see if this is true. I'm just projecting. Or is it you come up with a theory you do in the lab and then you go the other way? I'm kind of curious which way you like to go. Dominic D'Agostino: Well that's a good question. It goes both ways sometimes. And when I got interested in fasting and I read the Cahill studies, then I was like, okay, I gotta do this myself. You know, I gotta, you know, I'm not going to do 40 days, but I'll do a week and see what happens and do the blood work and things like that. And basically all my health markers improved, kind of as you guys would expect. And you know, and as we develop things in the lab, like synthetic ketogenic agents, you know, we'll use them experimentally and sometimes I, you know, take a little myself through the years and, and so some of the things that we use are not, you know, they are experimental compounds right now, but they are tracked towards a clinical use. And once you tinker with these things, then you start to realize some of their potential, right? Their therapeutic potential because some of them like you can actually feel you know, quite remarkably with a acute administration and it's not acting like stimulant. It's not, you know, you're not mixing with caffeine, you're just, you're just elevating the level of available fuel that your brain sees and that has, that has an effect. Matt Gallant: I have a question on that. Cause I usually a twice a year we, we go and do some really extensive hardcore difficult brain training. It's about six hours a day of pushing your brain to its absolute limit, be the equivalent of probably running a couple of marathons a day. And I D I did the first couple of times without ketones and then we started adding like, you know, 30 to 60 grams of esters a day and that allowed us to just continue training cause usually your brain crashing by day three, day four, you know, Wade and I've gone through that. But with the, with the, with the testers, there was no crash. Like day four, day five, day six. I mean you're, you're kind of getting tired, but that's more of a nervous system, you know, but at the same time we were able to continue the training, but the thing that really blew my mind, and I don't understand the, what's going on was the recovery. Like yeah, it gave me a little more energy, but what I really noticed was one, it seemed like I needed almost less sleep taking that many ketones and that I just felt relatively fresh the next day. Again, even despite pushing myself. So from a recovery standpoint, like why, what's going on there? Dominic D’Agostino: Yeah, that's a good, interesting observation too. If you collected data on that, it'd be good to put that together. I, I guess going back to the experience that I can draw off of where I've quantified things to as much as possible would be the NASA extreme environment, mission operations NEMO 22 where a lot of people think I use ketone supplements like every day because we kind of, we're kind of like the people who brought them to market. It mean like Patrick Arnold actually had and you know, years ago and, and different companies or some now. But you know, I don't use ketone supplements every day, but I did during that mission, especially doing the EDAs, the extra vehicular activities and things like that. And for morning multidose and Europe day and and I experimented with in the past. And what I do consistently notice getting back to recovery is that if I'm in a state of deep ketosis I do tend to sleep a little bit less. Dominic D’Agostino: Like lately I've been sleeping like eight hours, sometimes not, but I could sleep about six and a half. And then my amount of deep and REM are the same. So the restorative sleep that I'm getting when my body is in a state of nutritional ketosis seems to be better. So if you have ketones, if your brain has ketones available we now know that the carbon backbone of those ketones are part of the biosynthetic process of making neurotransmitters. Like alpha-ketoglutarate for example, is the precursor to glutamate is the precursor to GABA. And this is called an anaplerotic pathway. So the try-carboxylic acid cycle or the Krebs cycle and the cycle of the NSX make you make the Murray Mallee etc. All these, the, we have demonstrated through metabolomics that these become elevated and you are sort of driving the biosynthesis of neurotransmitters by virtue of increasing TCA cycle intermediates. Dominic D’Agostino: So I believe that this is accelerated a bit because you have the substrate available, you have more precursors can make neuro-transmitters when you sleep. Also, if you're in a state of ketosis, our astrocytes, so we have neurons and we have astrocytes and there's other cells like, like oligodendrocytes and other. But if we just talk about, you know, the two main cells, neurons and astrocytes, the astrocytes tend to store energy in the form of glycogen. When you're on, when you're in a state of ketosis, the ketones will spare just as it does sparing muscle glycogen. The ketones will spare that glycogen in the astrocytes. And part of the restorative process of sleep is to restore the glycogen levels in the astrocytes. So because you're using ketones, you don't have to kind of restore a glycogen levels. So I think that's something. And also there's something called the glymphatic system. Dominic D’Agostino: So your brain has a system that is activated. It's activated all the time, but more so when you sleep and there are things ketones can enhance brain blood flow by 30% with an acute when you acutely elevate ketones with like different ketogenic competence. So I believe that that increase in blood flow and other other factors that are associated with ketosis will increase the glymphatic system performance, if you will. And we'll get a, and this needs to be tested. It's just my, my speculation is that you're enhancing astrocyte glycogen neurotransmitters synthesis and also the glymphatic activity while we sleep. Makes sense. That's a multi-day thing that you're doing. So you're looking at it. So sleep is what would be really important. Matt Gallant: It's critical and we're running dual fuel during that time. So like I'll, I'll, I'll eat a little more carbs. So actually running dual-fuel seems to help. Your thing it seems to help too is like I'll, I'm not a big branch chain amino or amino guy, but adding aminos. So I'm taking 60 grams of ketones, taking like 20 grams of aminos. Plus I'm eating carbs and a lot of good fats as well. And it just seems to help on a lot on all levels. One question that I've had in a, and I haven't seen too much research on this, but experientially I've certainly noticed that. What have you seen in terms of the types of fats and their ketogenic response? Cause for an example, like if I eat animal saturated fats and I measure my ketones, especially like things like pig fat or that it definitely seems to produce more ketones then, you know, monounsaturated, you know, like just different fats seem to produce a different ketone response. What have you seen around that? And, and do you think that's important? Dominic D’Agostino: Yeah, so that's an ongoing question in a ketogenic diet. Well, it should have been ongoing for like 20 years, but only recently are they kind of recognizing that, you know, different fats have different effects. It's not just like macronutrient profiles. And I think it people will have, people have different food sensitivities. So some people who have a dairy a mild dairy allergy, if they take a dairy-based spat it the, the activation of the sympathetic nervous system or various immune factors may actually prevent ketone production. You know, so that's, I found that mildly in myself. But I kind of going back to your observation, I think a fat in the form of butter, you know, a meat fat like pork fat be fat and to some extent maybe chicken fat, these all contribute to very stable, predictable ketone production and meat. And when I tried to sort of mimic that with more of a plant based, I could get my ketones elevated, but it's a little bit less predictable. Dominic D’Agostino: But I think that's primarily because of sort of the plants that I'm getting the fat from. Like nuts, like macadamia nuts and almonds and avocados. You're delivering fiber with it too. So sometimes I can get my ketones elevated to the same extent. And sometimes I think because the natural fibers that are in plants are maybe preventing the release of the fat. And it's going through me. I know if I like a lot of raw homage or something like that, I'm definitely not absorbing all those fats, you know. So if I eat an equivalent amount of fat from raw almond as opposed to pig fat and I acutely do it, I eat the meal and then measure fat. There you're keeping on production will be like proportional to the amount of fat that the liver is seen, dietary fat. So it's kinda hard to quantify that. I guess you could use plant oils and things like that, but Matt Gallant: It seemed that though of course there's the neutrogenomic aspect, there are certain certain genes that obviously seem to indicate better saturated fat breakdown and so on and so forth. So there's probably a pretty strong genetic component to that question. Dominic D'Agostino: Absolutely. And you know, I sh I would like to know more about that and I try to keep up on that as much as possible. I have my own 23andme data and just looking at, you know, putting it on different platforms. I kind of know what works me just through experientially and I know some people have, you know, they have different snips that prevent them from, from metabolizing fatty acids as efficiently as possible. And it may not be an honor off kind of thing, but on a spectrum, right. And some people are just poor oxidizers or metabolizers of fat, so they will if they eat a high fat diet of animal fat, they feel sick, they don't feel good and their triglycerides go up and then does it come down over time. And I would tell that person don't do an animal based. Dominic D'Agostino: You know, and some people feel really good on a, on a plant based diet and all their health markers improve. And you know, I don't know if they give the ketogenic diet enough time, but cause your body does need to adapt to that over time. But I'm not one or the other. But actually I probably eat an enormous amount of plants and I have lots of and I do believe that they should sort of be in the raw form as much as possible. A lot of broccoli, asparagus, cauliflower, things like that and a big salad pretty much every day. And then I add a fatty beef, chicken or a lot of fish and eat a lot of fish in our house to that salad typically. And then maybe add oil on top of that in the form of avocado oil, macadamia nut oil, olive oil. And then I mix MCT oil with the salad dressings too. So I find that the optimal way to get my ketones as high as possible. Matt Gallant: I mean, Wade is the king of the big ass salad. He is, you know, we had introduced me to that know 20 years ago when we were both living in Vancouver and a half to say. And usually I'll try to do at least one big, a solid a week that just like another energy component that I feel from, I don't know if it's a phytonutrients or what's going on exactly. But you know, it, it kicks her, it just kicks something in. So wait, I mean maybe talk about your big ass salad strategy. Dominic D’Agostino: Yeah, I'd like to hear that. I mean, from a, I'll add this real quick if you, cause there's a lot of people are carnivore now and they do one or the other, but if you put your meat, if you eat it with a salad, the fiber from the salad will delay gastric absorption. And also it's aiding your gut microbiome, especially if you have a diverse array of things in the salad. And that's actually enhancing. It's decreasing your glucose and insulin response to the protein. But but I also think it's promoting, you know, healthy digestion, optimal gut microbiome. So I'm just kinda throwing it out there because I dunno, I just posted something recently and someone said, I'm killing myself by eating plants or something because plants are trying to kill you. So it's like, Wade Lightheart: Yeah, that's a pretty extreme position that something Wade Lightheart: We have adapted convenience land. Like wow, I didn't know my salad was so dangerous. Yeah. I've, I've been a big proponent of, you know, there's this certain, you know, when I go, I go to obviously whole foods and things like that to the salad bar, especially when I'm on the road. That's my first stop. And there's something I, there's two things that I think are anecdotally interesting. One is I noticed they're at different times I'll be attracted to different colors. Like I like and, and, and I always indicate to me that there's some sort of mechanism that's letting me know that I need to get more beets today or I need to get more cabbage or whatever it happens to be that. And so I always find it interesting about the colors. The second thing that I've noticed, it was without a doubt, and I'll be going to whole foods right after this call in variably I make these giant sounds like I get the big green bowls at the whole foods that they have them and it's piled up and it's 30 bucks or whatever for my salad. Wade Lightheart: And every single time somebody in the lineup or the cashier will comment that and say, that looks amazing. And I find that's a very interesting response that it's so across the board that there's seems to be some sort of internal recognition that that's good or that's healthy or that's something that I'd like to try. You know, cause it's obviously a ridiculous salad, but I think there was a good point you brought up was the fiber relation to insulin response or the use of fats. And it's, I believe it's one of the reasons why I have such a great insulin response to spite the fact I'm on a plant based diet. I eat a ton of carbs. Yet when you do my testing, it's like, it looks like I'm on a ketogenic diet from a, from an insulin response. Any other comments on your work? Dominic D’Agostino: It doesn't surprise me. I mean, you know, all those vegetables are carbohydrates, right? So as you would expect an increase in glucose, but if you have a steak and then you have that same steak with a big salad you will have a less of a glycaemic response and less of a rise in insulin too because it's the fiber is delaying gastric absorption to some extent and just delaying the breakdown and release of amino acids into the blood. And and I think it's even more pronounced if you add back to that salad. I actually think of in ketogenic diet formulation, the vegetables are a way are a fat delivery vehicle. So you could lightly steam vegetables, saute them, and then add a lot of fat to that or a salad. You can add a significant amount that to that you can add up condos and nuts and olive oil or a mixed oil dressing and then deliver in a relatively small salad, you can deliver 50 or 60 grams of fat. Dominic D’Agostino: So that, that's, that's important clinically. And this, these approaches are now being used and to keep the genic diets that are having better outcomes as far as seizure controls or metabolic management of particular disorders. And it kinda goes against what was traditionally that the carbohydrates need to be below a certain level. You're adding a lot more carbohydrates in the form of these essentially non glycemic fats, but the fiber and the phytonutrients and other factors are greatly helping to actually induce and sustain ketosis. And you're actually probably significantly enhancing the nutritional status of that patient too by not, you know, eliminating plants, which some ketogenic diets do, but actually being very liberal with your plants consumption, which I think as our nutrition evolves, we need to start incorporating more plants into ketogenic diets. Wade Lightheart: Sounds like there might be an actual unification between ketogenic and plant based diet. Yeah, I'm on that. I'm on that train because you know, we're just into optimal. What is the optimal diet for any given person in there, any, any given lifestyle and something they can sustain. So yeah, great, great to hear that you're on the bleeding edge of that. Matt Gallant: Speaking of optimal diets, I mean when one thing I'll share is I optimize my big ass salad using VIUM data. So the VIUM data is, it got tests and you can send them a school sample and it tells you which foods you should eat, a lot of which food you should eat less of. So I decided, you know what, I'm going to build like a super salad kind of just with the foods that it's saying or should eat a lot of. Matt Gallant: So for example, watercress, rucola those came up because I, I guess I have the gut biome that breaks those foods down. So what was really fascinating was despite eating like two pounds of, it almost sounds about two pounds. I would just incinerate it, like almost nothing would come out and like even my weight would go down. It almost like it almost defied science in the sense that it's like, okay, I'm meeting two pounds, almost nothing's coming out and my weight would drop. And, but if we look at it from a gut biome perspective where they're eating all, like I'm feeding all the bacteria that I have and they're just devouring that food, then it does make sense. So I just wanted to share that anecdotal story cause it kind of surprised me so significantly. You know, it is to shift gears here. You know, to talk about a subject that I think is, is near and dear to all of our hearts, which has cancer. I lost one of my best friends and recently an Matt Gallant::Aunt and an uncle and I like Wade to share his story about his experience with this. And then I love to get into what you've seen as far as ketosis, ketones and cancer. But Wade, why don't you share your story? Wade Lightheart: Yeah. So for those who don't know my sister died at the age of 22. She got sick with Hodgkin's disease of formula lymphatic cancer and progressed over four years. When I was young, it had a big impact, got me into kind of physiology and exercise and performance. And I've been graced now to actually serve as an advisor for the American Anti-Cancer Institute. And we help people who are either going through cancer or recovering from cancer to, to, to make better nutritional solo selections and to prevent it in the future or to optimize their diet. So it's something I'm really, really passionate about. And I'm curious what you have kind of revealed, cause I think one of the, one of the things you talk about was the death at cancer. The, the powerful effects of both the ketogenic diet and its relation to the pre cancer prevention or even as an augmentation. What, what, of, what's kind of fueled that and what have you learned and how can people who may be in one of those situations, where would they go and how would they start researching and for the self to kind of create the best survival situation for them? Dominic D’Agostino: Yeah, that's a, well, it's kind of a long story, but I'll make it as short as possible. Some of the, some of the technologies that we developed for the office of Navy research allowed us to look at a variety of cell lines. And one of them was a equal glioblastoma, a cancer cell line. And I made two observations. One was that high pressure oxygen killed the cancer cells faster than normal healthy cells. And that was because cancer cells had a dysregulation in their mitochondrial function. And if you hyper oxygenate them, they divert more molecular oxygen to super oxide anion, which is the precursor free radical that can go on to other radicals that can basically trigger apoptosis and cells. So we observed this acutely and I thought it was interesting and nobody had observed it before because they didn't have a confocal microscope inside a hyperbaric chamber. Dominic D’Agostino: So so this was like, I was curiously interested in that. And also when I grew cancer cells under different substrates, including low glucose or high glucose in particular high ketones, the ketones suppressed the growth and proliferation of the cancer cell lines I was looking at. So I made, I made two observations studying a military project, which is oxygen and how high oxygen high ketones are bad for cancer. So, so a, a PhD student came along and actually this became a PhD. She's now Dr Angela Pop. And throughout her PhD studies in the lab, we observed that a ketogenic diet with hyperbaric oxygen therapy given three times per week suppressed the growth of a cancer in a particularly aggressive form of metastatic cancer, a model of metastatic cancer that we had in the lab. And you know, so it, it kind of begs the question then, how does a high fat ketogenic diet, how does that contribute to suppressing cancer growth? Dominic D’Agostino: And proliferation and it does it through a number of different pathways. One is that we understand now we actually did back, you know, in the 1920s and thirties, that cancer growth is primarily fueled by glucose and cancer cells preferentially use a higher consumption glucose than normal. Healthy cells do. And we can, we can use a fluorodeoxyglucose pet scan oncologists use a pet scan to image the location and aggressiveness of cancer, but they don't really use that information to target the cancer. But we can, we can share through our best imaging techniques that, that there are consumption of glucose a hundred times higher in certain cancers relative to the healthy tissue that's surrounding it. So it's out competing the healthy tissue to get the glucose. So it keeps a genic diet restricts glucose availability to some extent, right? We know baseline glucose doesn't change all that much unless calories are restricted. Dominic D’Agostino: But when you eat a ketogenic diet, there is a very minimal increase in blood glucose and insulin. When you eat at carbohydrate-based diet, there's a relatively high spike in glucose and insulin. Those spikes in glucose and insulin are abolished if not significantly attenuated on a ketogenic diet. So I think that's important. And, and really what's important, it's a suppression of the hormone insulin. That's how actually we make ketones. The ketogenetic diet works by suppressing the hormone insulin, maybe slightly increase in glucagon and that accelerates fatty acid oxidation in the liver. And that continual suppression of the hormone insulin is absolutely necessary for us to stay in a state of ketosis. Cancer cells are there, growth is driven by insulin. IGF1, PI3-kinase, AKT/mTOR pathway and a few other, you know, things related to that. So what the key to dining diet does is suppress insulin and insulin signaling. Dominic D’Agostino: IGF1, PI3-kinase, AKT/mTOR pathway is acutely and continually suppressed if you follow a ketogenic diet. So what that does is it takes the foot off the gas pedal of cancer growth. Most cancers are driven in growth and proliferation by this particular pathway. And that's why pharmaceutical companies are scrambling to develop drugs that target enter PI three kinase IGF one, things like that. So that the ketogenic diet does that naturally as this fasting, but that that can't be sustained. So what you do is create a scenario where you slow down cancer growth. The ketogenic diet is not going to cure cancer. So that's really important. But what you do is you see in some people it has actually, so I should kind of stop and there's anecdotal or it's an even case board, but most importantly it will slow cancer growth and make cancer a more vulnerable target for other modalities. Dominic D’Agostino: And those modalities could be chemotherapy, it could be radiation. We know from clinical data that chemo and radiation can be a lifesaving for many people there are things like advanced brain cancer and metastatic cancer where these things do not offer much of an advantage. But in the context that I keep a general diet, you may sensitize the tumor in a way or make it more vulnerable to make the cancer or the tumor solid tumor more sensitive to these modalities. And also immune based therapies to may work better in the context of the ketogenic diet where you are limiting glucose availability. So essentially what's that's doing? It's suppressing the glycolytic pathway. That's how cancer cells are primarily making energy, glutamine and glucose. When cancer cells do that, it activates a particular pathway called the pentose phosphate pathway. And that pathway develops, it generates reduced glutathione, and that reduced glutathione makes that cell like a super cell. Dominic D’Agostino: It can protect it against a chemo and radiation because it's, it's an endogenous antioxidant. If you inhibit the glycolytic pathway, you could do it with a Cuban drank diet. There are now drugs that inhibit glycolytic pathways. You crippled the cancer cells ability to defend itself by virtue of suppressing reduced glutathione. And so now that cancer cell becomes more vulnerable target, especially to modalities that kill cancer cells through an oxidative stress mechanism. And that could be various chemo drugs and also radiation. So I'm trying to keep it as simple as possible, but I think that the thing is that the, the, the ketogenic diet works through many different ways. I just described a metabolic way, but it also functioned that suppressing inflammation, which is a major driver of cancer. And then the ketone bodies themselves are epigenetic regulators by acting as class one and class two histone deacetylase inhibitors. So that's an intense area of focus now in our lab and other labs as ketones functioning as signaling molecules, even hormones, if you like, in ways that have anticancer effects by activating tumor suppressors and actually turning off or turning down a oncogenic drivers. So that's an area of intense interest right now that ketones functioning independent of metabolism as influencing various anti-inflammatory pathways. NF-Κb, NALP3 inflammasome, but also through epigenetic regulation. Matt Gallant: I'm gonna steal a question from Tim Ferris and see if your answers is different today, which is if you or a loved one had cancer, what would you do? Dominic D’Agostino: Find out what all the options are given the type of cancer if it's an option where, or if it's a type of cancer where the options are very limited in regards to the standard of care not being very efficacious, and if it's minimally efficacious, you have to evaluate the patient, you know, with their doctor, whether it's worth doing that. Right. So I guess the simplest thing to do is to use a what's called a glucose ketone index. So we know if we can normal glucose being five millimolar, say if we could bring our glucose down to say three millimolar and elevate our ketones to three millimolar, that would give us a glucose ketone index of one. So if our glucose stays at four millimolar and we get our ketones only at two millimolar, that would give us a glucose ketone index of two. Dominic D’Agostino: If you could maintain a glucose ketone index of one to two, even one to four, normal American is like 25, right? So if we can bring that down from 25, which is a glucose dominant metabolism to a glucose ketone index between one and four, again, which is glucose over ketones in millimolar concentrations. And in America we use milligrams per deciliter for some reason, but in millimolar concentrations, so get a GKI of one to four and that will slow cancer growth. Right? I think that's incredibly important. Evaluate the potential for drugs like Metformin. Metformin is available. You could jump online and probably get it. Metformin is when we started studying Metformin, there was maybe two or three clinical trials. Now there's about 200 clinical trials looking at the drug, Metformin as a means to enhance other

Chronic Lymphocytic Lymphoma, Issue 2, 2019 — Part 2: Our interview with Dr Woyach highlights the following topics as well as cases from her practice: Recent data and evolution of the front-line treatment paradigm for patients with CLL (00:00) Evaluation of MRD and implications for therapy (03:50) Efficacy and tolerability of first-line regimens for CLL (06:14) Perspective on the role of chemoimmunotherapy for patients with CLL (08:41) Case: A woman in her mid-70s experiences a dramatic response after receiving ibrutinib as first-line therapy for CLL (10:48) Bleeding and arthralgias associated with ibrutinib (12:14) Rates of discontinuation and the role of dose reduction to mitigate side effects in patients receiving ibrutinib (14:45) Incidence and management of opportunistic infections during ibrutinib treatment (18:11) Role of chimeric antigen receptor (CAR) T-cell therapy in CLL; effect of ibrutinib on CAR T-cell generation and efficacy (21:54) Case: A man in his late 60s with CLL receives acalabrutinib on a clinical trial after developing atrial fibrillation on ibrutinib therapy (24:01) Therapeutic approach for patients who develop resistance to BTK inhibitors (27:19) Understanding the C481S mutation as a mechanism of resistance to ibrutinib and acalabrutinib (30:47) Targeting the C481S mutation to overcome resistance to BTK inhibitors (32:06) Case: A woman in her mid-60s with del(17p) CLL and no IGHV mutation receives venetoclax after disease progression on multiple lines of therapy (36:11) Prophylactic measures to prevent venetoclax-associated tumor lysis syndrome (38:25) Emerging data with the combination of ibrutinib and venetoclax for CLL (40:04) Activity and tolerability of PI3 kinase inhibitors for patients with CLL (44:17) Acalabrutinib with obinutuzumab for treatment-naïve and relapsed/refractory CLL (47:51) Incidence and spectrum of second cancers among patients with CLL receiving BTK inhibitors (49:51) Case: A man in his early 70s develops RT to DLBCL after receiving ibrutinib as first-line therapy for CLL (51:00) Prognosis and management of RT (53:38) Role of immune checkpoint inhibitors and CAR T-cell therapy in the management of RT (56:37) Ongoing Phase III EA9161 and Alliance A041702 studies evaluating the addition of venetoclax to ibrutinib with obinutuzumab for patients with CLL (59:21) CME information and select publications  

Meet The Professors: Key Questions and Emerging Research in the Management of Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma — Part 1: A special video supplement to a CME symposium held at the 2019 ASCO Annual Meeting featuring Dr Smith’s comments on the application of emerging research to patient care: Appropriate management of molecular subtypes of diffuse large B-cell lymphoma (DLBCL); challenges in improving outcomes with the addition of novel agents to front-line R-CHOP (0:00) Smart Start study: Final results with a rituximab/lenalidomide/ibrutinib lead-in before the combination with chemotherapy for patients with newly diagnosed DLBCL (3:25) Importance of the interval between diagnosis and treatment for newly diagnosed DLBCL and implications for bias in clinical trials (7:05) Risk of relapse with germinal center versus non-germinal center subtypes of DLBCL (8:19) Activity and tolerability of the recently FDA-approved anti-CD79b antibody-drug conjugate polatuzumab vedotin in combination with bendamustine/rituximab (BR) for relapsed/refractory (R/R) DLBCL (9:45) Activity of single-agent polatuzumab vedotin in patients with R/R DLBCL; integration of polatuzumab vedotin/BR into clinical practice (12:06) Therapeutic options and investigational approaches for R/R DLBCL (14:50) POLARIX: An ongoing Phase III trial comparing polatuzumab vedotin with R-CHP to R-CHOP for patients with previously untreated DLBCL (17:22) Variations in chimeric antigen receptor (CAR) T-cell constructs; activity and tolerability of different CAR T-cell therapy products for R/R DLBCL (19:37) Integration of CAR T-cell therapy into the treatment algorithm for R/R DLBCL (24:12) Neurologic toxicity and cytokine release syndrome associated with CAR T-cell therapy (27:01) Selection and sequencing of therapy for patients with R/R mantle cell lymphoma (MCL) (32:00) Drug activity and tolerability and patient quality of life with ibrutinib compared to acalabrutinib (34:42) Results of the Phase III ECOG-E1912 trial evaluating up-front ibrutinib/rituximab versus FCR (fludarabine/cyclophosphamide/rituximab) for younger patients with chronic lymphocytic leukemia (CLL) (38:05) Alliance A041202 trial: Efficacy and tolerability of ibrutinib alone or in combination with either rituximab or BR for older patients with untreated CLL (42:44) Response rates and duration of minimal residual disease (MRD) negativity with limited-duration nonchemotherapy combination regimens for previously untreated CLL (44:28) Risk assessment, prevention and management of venetoclax-associated tumor lysis syndrome (48:39) Activity and tolerability of acalabrutinib alone or in combination with obinutuzumab for CLL (54:44) Second- and third-line therapy options for patients with CLL (56:54) Perspective on the results of the Phase III RELEVANCE trial: Lenalidomide/rituximab (R2) versus rituximab/chemotherapy, each followed by maintenance rituximab, for patients with newly diagnosed follicular lymphoma (FL) (59:00) Available data with and current clinical role of R2 for patients with R/R FL (1:0m49) Comparison of the activity and side-effect profiles of approved and investigational PI3 kinase inhibitors for R/R FL (1:04:02) Approach to choosing among brentuximab vedotin with doxorubicin/vinblastine/dacarbazine (AVD), standard AVD/bleomycin (ABVD) and response-adapted ABVD as first-line therapy for advanced classical Hodgkin lymphoma (1:06:24) Activity of brentuximab vedotin alone or in combination with nivolumab in patients with R/R Hodgkin lymphoma (1:09:48) CME information and select publications  

In this episode, Keith Flaherty, director of clinical research and targeted cancer therapy at Massachusetts General Hospital, shares his vast wealth of knowledge in cancer starting with the history of treatment from chemotherapy to radiation to surgical therapy and where those methodologies seemed to have leveled off. He also walks us through the timeline of advancements (and lack there of) from when the War on Cancer was declared in the 1970s, through the sequencing of the entire human genome, and all the way to today. Keith dives into the topic of immunotherapy, probably the most exciting recent development in cancer therapy, and also provides us a rundown of his notion of a different approach to cancer that attacks all the essential pillars of cancer growth and survival. Finally, we talk a little bit about liquid biopsies, we discuss the roles of CRISPR and other potentially over-hyped therapies with respect to cancer. We also touch on stem cell therapy a bit, as well as some other common cancer-related questions such as the role of vitamin D and sun exposure in melanoma, and much more. We discuss: Growing up around medicine, and finding a career that you love [7:30]; Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30]; Explaining chemotherapy, radiation, and how a cancer develops [23:45]; Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal  [33:15]; 25 years after the War on Cancer is declared, gene sequencing, and why Keith’s was fascinated by the HIV case study [37:15]; Cancer immunotherapy: History, how it works, and why some cancers respond and others don’t [46:00]; MHC complexes, and cancer cloaking mechanisms [56:00]; Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00]; What we learned from the Cancer Genome Atlas Project [1:07:00]; Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00]; Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45]; Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith’s “aha moment” [1:24:15]; Advice for starting your career as a scientist/clinician [1:37:00]; Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45]; Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00]; Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15]; The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40]; Peter’s clinical framework for thinking about cancer and how Keith might improve it, and how the biotech environment is hampering our ability to put together novel cancer treatments [2:05:00]; How useful is CRISPR in terms of tumor suppressing? [2:16:15]; Liquid biopsies as a therapeutic monitoring tool [2:18:00]; Stem cell therapy: The efficacy and potential risks [2:25:15]; Aging and cancer: Is cancer inevitable? [2:28:45]; Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30]; How and why Keith has straddled the line between science/research and industry/drug companies, and the importance of getting more voices of practitioners at the table [2:42:00]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Discussing the 1st PI3-kinase inhibitor approved for a solid tumor, alpelisib for HR(+), HER2(-) metastatic breast cancer as 2nd line treatment. Worth sharing with her endocrine/DM colleagues...

Myeloproliferative Neoplasms Update — Part 2: Our interview with Dr Gerds highlights the following topics and cases from his practice: Common misconceptions about MPNs (0:00) Alterations of the JAK-STAT signaling pathway in MPNs (1:43) Case: A 61-year-old woman with primary MF and mutations in JAK2, EZH2 and CALR receives ruxolitinib (4:29) Prognostic significance of the JAK2, EZH2 and CALR mutations associated with MF (7:20) Dosing and activity of ruxolitinib for MF (8:53) Management of ruxolitinib-associated cytopenias and effect of ruxolitinib on disease pathogenesis (12:19) Evolution of clinical research with the selective JAK2 inhibitor fedratinib for MF (15:32) Association between fedratinib and thiamine levels; cytopenias associated with fedratinib (17:20) Efficacy of fedratinib as second-line treatment for patients with disease progression on ruxolitinib (18:38) Risks and benefits associated with pacritinib therapy (20:00) Case: A 66-year-old man who presents with anemia is diagnosed with MF and a Type 1 CALR mutation (21:48) Risk of infections associated with ruxolitinib (23:12) Evaluation of ruxolitinib for the treatment of graft-versus-host disease (27:05) Activity of the JAK1/2 inhibitor momelotinib in patients with MF (28:23) Hepcidin suppression and improvement of anemia in patients with MF; effect of novel JAK inhibitors, including fedratinib and momelotinib (30:03) Results of the SIMPLIFY 2 study evaluating momelotinib versus best available therapy for patients with MF previously treated with ruxolitinib (32:28) Use of JAK inhibitors for rheumatoid arthritis (35:29) Novel agents and approaches under investigation for MPNs (36:48) Perspective on the potential role of venetoclax for patients with MPNs (40:30) Case: A 75-year-old woman previously diagnosed with ET and a JAK2 V617F mutation is found to have disease transformation to PV on reassessment 12 years later (43:34) Efficacy and side effects of the MDM2 antagonist idasanutlin in the treatment of PV (47:36) Importance of maintaining hematocrit control in patients with PV (50:15) Role of ruxolitinib for patients with PV (51:55) Case: A 45-year-old woman with persistent headaches is diagnosed with ET and a JAK2 V617F mutation (54:08) Therapeutic options for patients with ET (56:47) Perspective on the need for aspirin for ET (59:17) Role of interferon and PI3-kinase inhibitors in the treatment of MPNs (1:00:37) Select publications

Oncology Today with Dr Neil Love: Breast Cancer Edition — A virtual roundtable discussion with noted investigators Charles Geyer and Sara Tolaney for a review of recent innovations in breast cancer medicine: Design and results of the Phase III KATHERINE study investigating adjuvant T-DM1 versus trastuzumab for patients with residual invasive HER2-positive early breast cancer (0:00) Side effects and tolerability of T-DM1 compared to trastuzumab (3:00) Clinical implications of the KATHERINE trial (7:27) Case (Dr Geyer): A 53-year-old woman with a locally advanced ER/PR-negative, HER2-positive, ulcerated infiltrating ductal carcinoma (IDC) experiences neuropathy after 6 cycles of neoadjuvant TCHP (docetaxel/carboplatin/trastuzumab/pertuzumab) (12:52) Management of the axilla in patients with positive sentinel lymph nodes after neoadjuvant chemotherapy (15:36) Case (Dr Tolaney): A 56-year-old woman with a 3.7-cm ER/PR-negative, HER2-positive IDC receives neoadjuvant THP (paclitaxel/trastuzumab/pertuzumab) and adjuvant AC followed by trastuzumab/pertuzumab (20:01) Selection of (neo)adjuvant treatment for patients with HER2-positive breast cancer (22:14) Optimal treatment for early-stage HER2-positive breast cancer (28:05) Role of the recently FDA-approved subcutaneous formulation of trastuzumab alone or in combination with chemotherapy for patients with HER2-positive BC (32:01) Final results from the OlympiAD trial of olaparib versus standard chemotherapy; results from the EMBRACA trial comparing talazoparib to standard therapy for patients with germline BRCA mutations (34:52) Case (Dr Geyer): A 31-year-old woman with metastatic ER/PR-positive, HER2-negative breast cancer receives ovarian suppression, fulvestrant and abemaciclib (39:45) Use of PARP inhibitors for patients with metastatic breast cancer and BRCA mutations (41:51) Case (Dr Tolaney): A 59-year-old woman with ER/PR-positive, HER2-negative metastatic breast cancer and a BRCA2 mutation receives olaparib as second-line therapy (45:18) Sequencing of PARP inhibitors for patients with metastatic triple-negative breast cancer (TNBC) and BRCA mutations (49:52) Ongoing PARTNER/PARTNERING studies evaluating olaparib with platinum-based neoadjuvant chemotherapy or as a part of novel combination approaches; investigation of neoadjuvant talazoparib for patients with TNBC and a germline BRCA mutation (51:49) Ongoing Phase III OlympiA trial evaluating olaparib as adjuvant treatment for high-risk, HER2-negative breast cancer with a germline BRCA mutation (54:33) Efficacy and safety of atezolizumab with nab paclitaxel for advanced TNBC in the Phase III IMpassion130 trial (56:57) Choice of chemotherapy for patients with metastatic TNBC (59:49) Perspective on overall survival for patients with advanced TNBC and PD-L1-positive tumors treated with atezolizumab and nab paclitaxel (1:4:42) Case (Dr Tolaney): A 52-year-old woman develops pneumonitis while receiving pembrolizumab and eribulin for metastatic TNBC (1:7:09) Endocrine toxicities associated with immune checkpoint inhibitors (1:9:26) Ongoing Phase III NSABP-B-59/GBG-96-GeparDouze trial evaluating neoadjuvant chemotherapy with atezolizumab followed by adjuvant atezolizumab (1:10:34) Ongoing Phase III ALEXANDRA/IMpassion030 study evaluating standard adjuvant chemotherapy with or without atezolizumab for early TNBC (1:13:10) Emerging data with the HER2-selective tyrosine kinase inhibitor tucatinib for advanced HER2-positive metastatic breast cancer (1:14:48) Comparison of the activity and tolerability of tucatinib to that of lapatinib and neratinib (1:19:15) Efficacy and safety of the novel antibody-drug conjugate trastuzumab deruxtecan for HER2-positive breast cancer (1:21:46) Results of the Phase III SOLAR-1 trial evaluating the PI3 kinase inhibitor alpelisib with fulvestrant for ER-positive advanced breast cancer (1:27:4) NEO-ORB: A randomized Phase II study of neoadjuvant letrozole with alpelisib for HR-positive, HER2-negative breast cancer (1:31:47) Select publications  

We begin this episode with a discussion of Dr. Mukherjee's ongoing study combining a ketogenic diet with PI3 kinase inhibition. We continue with a take on a recent reanalysis of COMET-1 and COMET-2, two failed randomized controlled trials of cabozantinib versus prednisone or mitoxantrone-prednisone in metastatic castration-resistant prostate cancer. We end with an interview on instabilities in the health insurance marketplace with Dr. Jane Zhu of OHSU, an expert in the Affordable Care Act. Keto diet + PI3 kinase: https://www.nytimes.com/2018/12/05/magazine/its-time-to-study-whether-eating-particular-diets-can-help-heal-us.html COMET-1: http://doi.org/10.1200/jco.2015.65.5597 COMET-2: https://doi.org/10.1016/j.eururo.2018.11.033 Back us on Patreon! https://www.patreon.com/plenarysession

Localizing mTORC2 activity The mTORC2 complex regulates cell growth and proliferation by phosphorylating the protein kinase Akt, but where in the cell mTORC2 is active, and how growth factors direct its activity towards Akt, remains unclear. Ebner et al. use a novel reporter to show that endogenous mTORC2 activity localizes to plasma membrane, mitochondrial, and endosomal pools with distinct sensitivities to PI3 kinase and growth factor signaling, and that growth factors induce Akt phosphorylation by promoting Akt's recruitment to the plasma membrane. This biosights episode presents the paper by Ebner et al. from the February 6th, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Michael Ebner and Ivan Yudushkin (Max F. Perutz Laboratories and Medical University of Vienna, Vienna, Austria). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

  Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.                                                 The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.                                                 They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.                                                 On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.                                                  In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.                                                 The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.                                                 This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.                                                 All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.                                                 They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.                                                 In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.                                                 In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.                                                 The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.                                                 They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.                                                 Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.                                                 Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.                                                 The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.                                                 The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.                                                 These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.                                                 After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.                                                 These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.                                                 The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.                                                 As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.                                                 The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.                                                 Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.                                                 Those were your highlights. Now, for our featured discussion.                                                 On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.                                                 This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.                                                 Welcome Daniel. Dr. Daniel Singer:             Thank you for having me. Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana. Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here. Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found? Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.                                                 There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.                                                 While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.                                                 What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper. Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation. Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.                                                 Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.                                                 Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.                                                 If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"                                                 We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores. Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static. Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.                                                 We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.                                                 One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation. Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.                                                 Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts? Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.                                                 A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.                                                 I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well. Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.                                                 The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.                                                 We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.                                                 This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.                                                 I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror. Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.                                                 As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.                                                 If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.                                                 In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that? Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.                                                 At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.                                                 We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke. Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.                                                 I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.                                                 One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients. Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.                                                 Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings. Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.                                                 The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.                                                 I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid. Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.  

This episode @bradbor, @urbankiwi & @bulldognz talk Video Game voice actors strike, Hawaiki Cable, Pi3 discounts, Lulzbots, Amazon Prime and Kiwicon

O keramičnih telefonih, Yahooju in čudni glasbi. Povezave Apple splavil Spoken Editions (je mogoče tudi iskati v Overcast, napišeš samo “Spoken edition”) Stvari oznanjene na Google dogodku Pixel telefon Daydream Ruter in home Yahoo! preiskuje vso pošto za ključne besede Mirai botnet https://krebsonsecurity.com/2016/10/source-code-for-iot-botnet-mirai-released http://motherboard.vice.com/read/heres-a-live-map-of-the-mirai-malware-infecting-the-world https://krebsonsecurity.com/2016/10/who-makes-the-iot-things-under-attack/ Applova keramična prihodnost Albums That Never Were Glasba za osciloskop Special Guest: Alan Rener.

Prof John Gribben (Barts Cancer Institute, London, UK) chairs an expert discussion for ecancertv at EHA 2015 with Prof Marivi Mateos (University Hospital of Salamanca, Salamanca, Spain), Prof Umberto Vitolo (Città della Salute e della Scienza, Turin, Italy) and Prof Paolo Ghia (Università Vita-Salute San Raffaele, Milan, Italy). Representing the spectrum of haematological malignancies, this panel consists of experts in mantle cell lymphoma (MCL), multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL). Each expert discusses the most recent highlights of their field, including novel agents such as carfilzomib (MM) and PI3-kinase delta inhibitors such as idelalisib (CLL). The experts discuss the implications of these recent developments in their fields, including the cost and practicality of continuous therapy - and predict future directions of their fields. This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

Prof Workman (Institute of Cancer Research, UK) talks to ecancertv at TAT 2015 about his work on the cancer genome and how this knowledge can be harnessed to help improve drug discovery and hopefully overcome resistance to molecularly targeted therapies. He also discusses his research on developing inhibitors to the heat shock protein (HSP) 90 molecular chaperone and the PI3 kinase family of signalling enzymes.

Blebs lead the way in Dictyostelium chemotaxis Membrane blebs can help the leading edge of migrating cells protrude forwards, but the contribution of blebs to the motility of Dictyostelium cells is unclear. Zatulovskiy et al. reveal that blebs form at the front of chemotaxing Dictyostelium cells, particularly when the cells are faced with a mechanically resistant environment, and that this process is guided by a PI3-kinase-dependent signaling pathway. This biosights episode presents the paper by Zatulovskiy et al. from the March 17, 2014, issue of The Journal of Cell Biology and includes an interview with senior author Robert Kay (MRC Laboratory of Molecular Biology, Cambridge, UK). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

Background: Colorectal cancers carrying the B-Raf V600E-mutation are associated with a poor prognosis. The purpose of this study was to identify B-Raf(V600E)-mediated traits of cancer cells in a genetic in vitro model and to assess the selective sensitization of B-Raf(V600E)-mutant cancer cells towards therapeutic agents. Methods: Somatic cell gene targeting was used to generate subclones of the colorectal cancer cell line RKO containing either wild-type or V600E-mutant B-Raf kinase. Cell-biologic analyses were performed in order to link cancer cell traits to the BRAF-mutant genotype. Subsequently, the corresponding tumor cell clones were characterized pharmacogenetically to identify therapeutic agents exhibiting selective sensitivity in B-Raf(V600E)-mutant cells. Results: Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. Conclusion: Mutant BRAF alleles mediate self-sufficiency of growth signals and serum starvation-induced resistance to apoptosis. Targeting of the BRAF mutation leads to a loss of these hallmarks of cancer. Dabrafenib selectively inhibits cell viability in B-Raf(V600E) mutant cancer cells.

Dr Maurizio Scaltriti talks with ecancer at the 2013 AACR Annual Meeting in Washington DC about hyper activation of the PI3 kinase pathway and its prevalence in breast and head and neck cancer subtypes. Many inhibitors currently inhibit cell activity on many different levels, but recent findings in preclinical and phase I studies reveal that, while they do inhibit this pathway, their affect is limited. Complications predominantly include toxicity and tumours cells overcoming inhibition. The new types of inhibitors have a large therapeutic window, but those that are close to clinical use, such as alpha inhibitors, will be used in combination with other agents rather than as a single agent.

Professor John Gribben from Barts and The London Trust Cancer Centre, UK, is joined by Professor Peter Hillman from St James’s University Hospital, Leeds, UK, and Professor Kanti Rai from Long Island Jewish Medical Center, New York, USA, at ASH 2012 to talk to ecancer.TV about the exciting times being witnessed in CLL and the new data presented at the meeting. Professor Rai points to the “astounding” advances that have been made in CLL over the past 4-5 years based on improved understanding of the molecular biology of the disease, eg, the B-cell receptor and signalling pathways, that have led to the development of the PTK inhibitors and the PI3 kinase inhibitors. These new drug groups have given previously refractory patients new hope although Professor Rai comments on the caution still required concerning durability of response with ibrutinib and GS1101 as single versus combination agents. He also comments on the chemo-free approach to treatment and when this might be an appropriate therapeutic option. Professor Hillman notes the impressive and sustained response rates seen with some of these newer agents, and comments on the hope of cure of CLL in the future. Professor Hillman also notes the promise for the combined use of monoclonal antibodies with newer agents. The experts discuss the importance of educating patients on the expected response to newer agents, eg, on speed of response and lymphocytosis, and note from new data presented at ASH 2012 that many questions remain on the mechanism of action of newer agents. They also comment on promising new data being presented with Bcl-2 inhibitors and the challenge of getting all the new agents into logical clinical trial development programmes to speed effective agents to market as safely and rapidly as possible. Finally, the experts discuss the importance of the variety of patients being treated in clinical trials, eg, elderly, younger fitter patients and previously refractory patients.

Dr Sherene Loi talks to ecancer about the heterogeneity of breast cancer tumours at IMPAKT 2012 in Brussels, May 2012. Technology now allows for the understanding of the cancer genome down to the base pair of certain types of cancer. In small tumour breast cancer, less than 2cm, the tumours have multiple ‘clones’ and these ‘clones’ drive the growth of the tumour. Treatment of one tumour can be the reason for relapses as another tumour can then proliferate. Dr Loi also discusses PI3 kinase, which is essential for cell growth but highly irregular in breast cancer and especially in triple negative breast cancer where no targeted therapies yet exist.

The activation of platelets is a central step during the physiological process of hemostasis and its understanding may lead us to control the pathophysiological process of intra-arterial thrombus formation and vascular occlusion, which can cause acute coronary syndrome and myocardial infarction. One of the important aspects of platelet activation is to understand the dynamic regulation and rearrangement of the cytoskeleton after stimulation. The morphological and functional changes of platelets require a drastic remodeling of the actin cytoskeleton regulated by numerous actin-binding proteins and signaling molecules such as the family of Rho-GTPases. The small GTPase Rho can regulate several aspects of cellular function, predominantly through its downstream effector Rho-kinase. One of the well established Rho-kinase-mediated signaling pathways is the phosphorylation of myosin light chain (MLC) and its counteracting MLC phosphatase. Rho-kinase regulates a second pathway that involves activation of LIM-kinases (LIMKs) and subsequent phosphorylation and inactivation of cofilin, an actin dynamizing protein. Dephosphorylation and activation of cofilin lead to severing and depolymerization of existing actin filaments. The signaling pathway Rho-kinase/LIMKs/cofilin phosphorylation during platelet activation and the question, how the phosphorylation of cofilin affects the actin dynamics underlying platelet activation, has not previously been studied. The physiological agonist thrombin and the pathophysiological relevant agonist lysophosphatidic acid (LPA), which is the main platelet-activating lipid in atherosclerotic plaque, were used as platelet stimuli to address these questions. It was found that the activation of Rho-kinase is important for an increase in F-actin content underlying Ca2+-independent platelet shape change. The activation of Rho-kinase was found to be upstream to secretion and integrin IIbβ3 activation. The rapid activation of Rho-kinase during secretion leads to a further increase in F-actin content as compared to shape change. It was observed that LPA-stimulated dense granule secretion is mainly regulated by Rho-kinase, whereas secretion induced by thrombin was only in part Rho-kinase-dependent. Together, these results show that Rho-kinase regulates the F-actin increase underlying shape change and secretion, but it is not directly involved in aggregation. This study for the first time demonstrates that platelet expresses only LIMK-1 and not LIMK-2. LIMK-1 can be activated by Rho-kinase as well as by p21-activated kinases (PAKs). Our study shows that LIMK-1 activation was mainly Rho-kinase dependent in LPA- and thrombin-stimulated platelets. Although, PAK-1/2 activation was observed during LPA-stimulated platelet shape change, PAKs are unlikely to be involved in LIMK-1 activation in these cells. Like Rho-kinase activation, it was also found that LIMK-1 activation was independent and upstream of integrin IIbβ3 activation. Surprisingly, the activation of LIMK-1 failed to increase cofilin phosphorylation during shape change induced by LPA as well as by thrombin. Inhibition of the Rho-kinase/LIMK-1 pathway unmasked cofilin dephosphorylation suggesting that during shape change the simultaneous activation of a cofilin phosphatase counteracts the effect of LIMK-1 for phosphorylating cofilin. During secretion and aggregation induced by LPA and thrombin, cofilin was rapidly dephosphorylated and subsequently rephosphorylated; the latter phase was due to Rho-kinase/LIMK-1 activation. After stimulation with LPA and thrombin under conditions, where platelet aggregation could not occur, the kinetics of cofilin de- and rephosphorylation were unperturbed indicating their independence of integrin IIbβ3 engagement. Furthermore, the results clearly showed that cofilin dephosphorylation is also independent and upstream of secretion, since the onset of cofilin dephosphorylation was as rapid as secretion in thrombin-stimulated platelets and also occurred in the absence of dense granule secretion in LPA (10 µM)-stimulated platelets. Since the kinetics of cofilin phospho-cycle was similar during secretion and platelet aggregation in LPA- and thrombin-stimulated cells, I propose a general two-step regulatory process for cofilin phospho-cycle underlying primarily secretion, and subsequently platelet aggregation: dephosphorylation by a cofilin phosphatase and then rephosphorylation by the Rho-kinase/LIMK-1 pathway. Our results showing that only dephosphorylated (activated) cofilin binds with F-actin support previous observations that the state of cofilin phosphorylation determines its association with F-actin. The effect of Y-27632 in resting platelets showing a reduction in cofilin phosphorylation, and an increase of F-actin content and cofilin association with F-actin suggested that LIMK-1-mediated cofilin phosphorylation reduces the F-actin content and cofilin association with F-actin in resting platelets. In contrast, during shape change, cofilin that showed no change in its phosphorylation was rapidly associated with the actin cytoskeleton. The maximal cofilin association with actin cytoskeleton occurred before the maximal F-actin increase, suggesting that cofilin association with F-actin might regulate the turnover and actin polymerization during platelet shape change. It is an open question, whether cofilin is locally dephosphorylated before binding to F-actin during shape change. Previous studies in other cells could correlate cofilin dephosphorylation (activation) with the depolymerization of F-actin. However, in our studies cofilin dephosphorylation during the initial phase of thrombin-induced secretion (up to 30 seconds) was associated with a large increase of F-actin and a high amount of cofilin association with F-actin. Cofilin rephosphorylation after 30 seconds did not decrease F-actin content and cofilin association with F-actin. Together, in activated platelets the association of cofilin with F-actin and the F-actin increase do not simply correlate to the cofilin phosphorylation state: it seems to be more complex. It is assumed that the cofilin phosphorylation and actin dynamics are regulated in specific compartments during platelet activation. The rapid cofilin dephosphorylation in platelets was mediated by an okadaic-acid insensitive phosphatase. The activation of the cofilin phosphatase seemed to be regulated at least in part by an increase in intracellular Ca2+ and by PI3-kinase. Cofilin de- and rephosphorylation occurring upstream of secretion and platelet aggregation suggests that the enzymes regulating the cofilin phospho-cycle could be potential targets for the development of anti-thrombotic drugs.

In der vorliegenden Arbeit wurden drei verschiedene Schwerpunkte gesetzt: (a) Phosphonium- und Diphosphanium-Kationen, (b) Phosphor-Bor-Addukte und (c) Phosphorazid-Verbindungen. •= Es konnte gezeigt werden, daß die Phosphortrihalogenide PCl3, PBr3, PI3 und P2I4 wie auch die Phosphor-Chalkogenide P4S3 und P4Se3 aufgrund ihrer schwachen Donoreigenschaft nur sehr schwachgebundene Spezies mit Elektronenacceptoren bilden. So sind die gebildeten Komplexverbindungen X3P⋅BY3 (X = Cl, Br, I; Y = Br, I) und (P4E3)⋅(BX3) (X = Br, I) wie auch die PX4 +- (X = Br, I) und P2I5 +-Salze nur im Festkörper stabil. In Lösung hingegen neigen diese Spezies gewöhnlich zur Dissoziation. Die Donorfähigkeit von Phosphinen hingegen ist aufgrund des positiven induktiven Effekts der Alkyl- oder Arylgruppen deutlich höher. So konnte z.B. gezeigt werden, daß die Verbindungen H2PMe2 +AlCl4 − und n-Pr3P⋅BX3 (X = Cl, Br, I) im Gegensatz zu den oben genannten Komplexen auch in Lösung stabil sind. •= Die 31P-NMR-Resonanzen der PI4 +-Spezies zeigen in Abhängigkeit vom jeweiligen Anion ungewöhnlich starke Hochfeldverschiebungen im Bereich zwischen −295 ppm (PI4 +GaI4 −, ∆ δcoord = −532 ppm, Abb. 61) und −519 ppm (PI4 +AsF6 −, ∆ δcoord = −756 ppm, Abb. 61), welche auf Spinbahn-Effekte zurückzuführen sind. Durch Röntgenstrukturanalyse (PI4 +AlCl4 −, PI4 +AlBr4 −, PI4 +GaI4 −), 31P-MAS-NMR- und Schwingungsspektroskopie konnte gezeigt werden, daß das PI4 +-Kation je nach Eigenschaft des Gegenanions "isoliert" oder polymer vorliegt. Die intermolekularen Kation ⋅⋅⋅ Anion- Wechselwirkungen in den PI4 +-Komplexen nehmen in der Reihenfolge PI4 +GaI4 − ≥ PI4 +AlI4 − > PI4 +GaBr4 − ≥ PI4 +AlBr4 − > PI4 +AlCl4 − > PI4 +SbF6 − ≥ PI4 +AsF6 − ab. Die dadurch steigende P-I-Bindungsordnung (kürzere P-I-Bindungslängen, stärkere P-IKraftkonstanten) im PI4 +-Kation verursacht eine Verschiebung der 31P-Resonanz zu niedrigeren Frequenzen (höherem Feld) bzw. eine Verschiebung der Normalschwingungen zu höheren Wellenzahlen (ν1 (PI4 +) = 150 − 180 cm−1). Dieses Phänomen ist in den PBr4 +-Spezies weniger ausgeprägt ( δ = −72 bis −83 ppm, ν1 (PBr4 +) = 250 − 266 cm−1) (s. 3.1). •= Durch Auftragen der P-I-Bindungslänge gegen die 31P-chemische Verschiebung bzw. gegen die ν1-Streckschwingung des PI4 +-Kations konnte zum ersten Mal der P-I-Abstand in PI4 +AsF6 − abgeschätzt werden (d (P-I) ≈ 2.352(2) Å, s. 3.1). •= Mit den Reaktionssystemen PBr3 / I3 +MF6 − (M = As, Sb) und PBr3 / IBr / EBr3 (E = Al, Ga) gelang es erstmalig, die Existenz der bisher unbekannten gemischt substituierten Bromoiodophosphonium-Kationen PBrnI4−n + (0 ≤ n ≤ 3) durch 31P-MAS-NMRSpektroskopie nachzuweisen. Es konnte sowohl experimentell als auch durch quantenchemische Berechnungen gezeigt werden, daß der Hochfeldshift für PBrnI4−n + aufgrund der anwachsenden Spinbahn-Beiträge entlang PBr4 + < PBr3I+ < PBr2I2 + < PBrI3 + < PI4 + ansteigt (s. 3.1). •= Die Verbindungen P2I5 +EI4 − (E = Al, Ga, In) sind auf zwei unterschiedlichen Synthesewegen darstellbar. Das P2I5 +-Kation wird im Festkörper durch schwache I ⋅⋅⋅ IKontakte mit den EI4 −-Anionen stabilisiert. Die 31P-Resonanz des Phosphoratoms des PI3- Fragments zeigt eine deutliche Hochfeldverschiebung von der Resonanz von P2I4 (∆ δcoord = δ (−PI3 +, P2I5 +) − δ (−PI2, P2I4) = −267 ppm, Abb. 61), welche − wie auch in den PI4 +- Spezies − auf Spinbahn-Beiträge der schweren Iodsubstituenten zurückzuführen sind (s. 3.2). •= Durch Röntgenstrukturanalyse von H2PMe2 +AlCl4 −, welches aus HPMe2, HCl und AlCl3 dargestellt wurde, konnte die strukturelle Aufklärung der Dimethylphosphonium-Kationen HnPMe4−n + (0 ≤ n ≤ 3) vervollständigt werden (s. 3.3). •= Die Umsetzung von PBr3 mit Ph3P führte zu einer definierten Verbindung, welche durch 31P-MAS-NMR-Spektroskopie als Ph2P−PBr2 +Br− identifiziert wurde. Im Gegensatz zu früheren Arbeiten, in denen oft über die Zusammensetzung und Struktur der durch die Umsetzungen von Phosphorhalogeniden mit Alkyl- oder Arylphosphinen erhaltenen Reaktionsprodukte (orange Niederschläge) spekuliert wurde, konnte hier gezeigt werden, daß die Festkörper-Spektroskopie eine geeignete Methode zur Untersuchung derartiger Verbindungen darstellt (s. 3.4). •= Im Zusammenhang mit der Untersuchung des Koordinationsverhalten von Phosphor- Basen (Elektronendonoren) gegenüber Lewis-Säuren (Elektronenacceptoren) wie BX3 (X = Cl, Br, I) konnten zahlreiche Addukt-Verbindungen dargestellt werden (Gleichung 20). Base + BX3      →  Base⋅BX3 (20) für X = Br, I: Base = PCl3, PBr3, PI3, n-Pr3P, P4S3, P4Se3 für X = Cl: Base = n-Pr3P •= Strukturell konnten die zum Teil sehr schwachgebundenen Komplexe Br3P⋅BBr3, I3P⋅BBr3 und n-Pr3P⋅BBr3 durch Röntgenstrukturanalyse am Einkristall bestimmt werden (s. 3.5 − 3.6). •= Aufgrund der 31P-MAS-NMR- und Schwingungsdaten und konnte gezeigt werden, daß die Reaktion von BX3 (X = Br, I) mit P4S3 zu apikalen Addukten, mit P4Se3 jedoch zu basalen Addukten führt. Zusätzlich konnten die Molekülstrukturen von (P4S3)⋅(BBr3) und (P4S3)⋅(BI3) durch Röntgen-Pulverbeugung eindeutig bestimmt werden (s. 3.7). •= In Analogie zu früheren Arbeiten konnte bestätigt werden, daß die Acceptorstärke (Lewis- Acidität) von BX3 (X = Cl, Br, I) in der Reihenfolge BCl3 < BBr3 < BI3 ansteigt. So bildet die schwache Lewis-Säure BCl3 nur noch mit starken Phosphor-Basen wie Alkyl- oder Arylphosphinen stabile Komplexe. Bezüglich der Stabilität der Reaktionsprodukte konnte für die BX3-Addukte (X = Br, I) sowohl theoretisch (quantenchemische Berechnungen) als auch experimentell folgende Reihenfolge beobachtet werden: P4S3 < PCl3 < PBr3 < P4Se3 < PI3 < n-Pr3P (s. 3.5 − 3.7). •= Durch Analyse der Bindungsorbitale (NBO) von X3P⋅BY3 (X = Cl, Br, I, Me) konnte gezeigt werden, daß: (a) die Bindungsordnung entlang der BCl3- < BBr3- < BI3-Addukte zunimmt und (b) der Ladungstransfer in der gleichen Reihenfolge ansteigt. blaue Balken: Koordinationsshift ∆ δcoord = δ (Komplex) − δ (PI3); roter Balken: Koordinationsshift ∆ δcoord = δ (Komplex) − δ (P2I4); grüne Balken: Koordinationsshift ∆ δcoord = δ (Komplex) − δ (PBr3); brauner Balken: Koordinationsshift ∆ δcoord = δ (Komplex) − δ (PCl3); orangefarbene Balken: Koordinationsshift ∆ δcoord = δ (Pap; Komplex) − δ (Pap; P4S3); lila Balken: Koordinationsshift ∆ δcoord = δ (Pbas; Komplex) − δ (Pbas; P4Se3). •= Die bei der Koordination in der Reihe Cl3P⋅BBr3 (∆ δcoord = −110 ppm) < Br3P⋅BBr3 (∆ δcoord = −149 ppm) < I3P⋅BBr3 (∆ δcoord = −268 ppm) < I3P⋅BI3 (∆ δcoord = −278 ppm) ansteigende Hochfeldverschiebung der 31P-Resonanz (Abb. 61) ist ebenfalls (vgl. PI4 +- und P2I5 +-Salze) auf Schweratomeffekte zurückzuführen (s. 3.5). •= Ein entgegengesetzter Trend wurde für die Addukte (P4E3)⋅(BX3) (X = Br, I) und (P4Se3)⋅(NbCl5) gefunden: Der Koordinationsshift der Phosphor-Chalkogenid-Komplexe ist im Gegensatz zu den Komplexen X3P⋅BY3 positiv (Verschiebung zum tieferen Feld) und liegt für die apikalen P4S3-Addukte bei ca. 50 − 60 ppm (Abb. 61). Für die basalen P4Se3-Addukte ist der Tieffeld-Koordinationsshift deutlich größer und steigt in der Reihe NbCl5 (∆ δcoord = +64.2 ppm) < BBr3 (∆ δcoord = +104.1 ppm) < BI3 (∆ δcoord = +177.0 ppm) an (s. 3.7, Abb. 61). •= Durch die Umsetzung von [PhNPCl3]2 und [(C6F5)NPCl3]2 mit TMS-N3 konnten die Phosphorazid-Spezies [PhNP(N3)3]2 und [(C6F5)NP(N3)3]2 dargestellt werden. Durch Kernresonanz- und Schwingungsspektroskopie konnte gezeigt werden, daß [PhNP(N3)3]2 sowohl in Lösung als auch im Festkörper als dimere Verbindung zweier monomerer PhNP(N3)3-Einheiten vorliegt, während das analoge Pentafluorphenylderivat durch die elektronenziehende Wirkung der perfluorierten Phenylgruppen in Lösung überwiegend monomer als (C6F5)NP(N3)3, im Festkörper jedoch als Dimer [(C6F5)NP(N3)3]2 vorliegt (s. 3.8). •= [PhNP(N3)3]2 und [(C6F5)NP(N3)3]2 konnten durch Röntgenbeugung am Einkristall charakterisiert werden (Abb. 62) und sind somit die ersten strukturell charakterisierten Phosphorazid-Spezies, in welchen das Phosphoratom verzerrt trigonal-bipyramidal von drei Azidgruppen umgeben ist. Die Molekülstruktur von [PhNP(N3)3]2 zeigt eine ungewöhnliche Bindungssituation mit vier deutlich unterschiedlichen Phosphor- Stickstoff-Bindungslängen. Sowohl im 14N-NMR-Spektrum als auch in den Schwingungsspektren (Raman, IR) konnte eine Aufspaltung durch die chemisch nicht äquivalenten Azidgruppen (eine axiale, zwei äquatoriale N3-Gruppen) beobachtet werden (s. 3.8). Zusammenfassend sind die in der vorliegenden Arbeit dargestellten Verbindungen und ihre Charakterisierung in Tabelle 58 aufgeführt. Sofern die Verbindungen bereits publiziert wurden sind die Orginalarbeiten als Literaturstelle angegeben. Tabelle 58 Im Rahmen der vorliegenden Arbeit dargestellte Verbindungen Verbindung Schwingungsspektroskopie Kernresonanzspektroskopie Röntgenstrukturanalyse Lit. PBr4 +AsF6 − Raman, IR 31P-MAS-NMR 14 PI4 +AlBr4 − Raman, IR 31P-MAS-NMR Einkristall 14 PI4 +GaBr4 − Raman, IR 31P-MAS-NMR, 71Ga-MAS-NMR 14 PI4 +AlCl4 − Raman, IR 31P-MAS-NMR Einkristall 14 PI4 +GaI4 − Einkristall 6,7,14 P2I5 +AlI4 − a Raman, IR 31P-MAS-NMR 27,31 P2I5 +GaI4 − Raman, IR 31P-MAS-NMR Einkristall 31 P2I5 +InI4 − Raman, IR 31P-MAS-NMR 31 H2PMe2 +AlCl4 − Raman, IR 31P-, 13C-, 1H-NMR Einkristall 45 Ph3P−PBr2 +Br− Raman 31P-MAS-NMR Cl3P⋅BBr3 b Raman, IR 31P-MAS-NMR 54,73 Cl3P⋅BI3 b Raman 54,73 Br3P⋅BBr3 b Raman, IR 31P-MAS-NMR Einkristall 52,73 Br3P⋅BI3 b Raman 54,73 I3P⋅BBr3 b Raman, IR 31P-MAS-NMR Einkristall 56,73,74 I3P⋅BI3 b Raman, IR 31P-MAS-NMR 57,73 n-Pr3P⋅BCl3 Raman, IR 31P-, 11B-, 13C- ,1H-NMR n-Pr3P⋅BBr3 Raman, IR 31P-, 11B-, 13C-, 1H-NMR Einkristall 74 n-Pr3P⋅BI3 Raman, IR 31P-, 11B-, 13C-, 1H-NMR (P4S3)⋅(BBr3) Raman, IR 31P-MAS-NMR Pulver 119 (P4S3)⋅(BI3) Raman, IR 31P-MAS-NMR Pulver 119,120 (P4Se3)⋅(NbCl5)a Raman, IR 31P-MAS-NMR 112,119 (P4Se3)⋅(BBr3) Raman, IR 31P-MAS-NMR 119 (P4Se3)⋅(BI3) Raman, IR 31P-MAS-NMR 113,119 [PhNP(N3)3]2 Raman, IR 31P-, 14N-, 13C-, 1H-NMR Einkristall 142 [(C6F5)NP(N3)3]2 Raman, IR 31P-, 14N-, 13C-{19F}-, 19F- NMR Einkristall 143 a Verbindung bekannt, bisher nur durch Röntgenstrukturanalyse charakterisiert; b Verbindung bereits bekannt, wurde aber in der Literatur nur schlecht charakterisiert. Durch die vorliegende Dissertationsschrift konnten neue Aspekte und Einblicke über die vielfältigen chemischen Eigenschaften und Bindungsverhältnisse binärer und ternärer kationischer Phosphor-Spezies sowie Phosphor-Bor-Addukt-Komplexe und Phosphorazide gewonnen werden. Insbesondere gibt diese Arbeit einen Überblick über den Einfluß und das Ausmaß relativistischer Effekte am Phosphor in Gegenwart schweren Halogensubstituenten, denn: "Aufgabe der Naturwissenschaft ist es nicht nur, die Erfahrung stets zu erweitern, sondern in diese Erfahrung eine Ordnung zu bringen." Niels Bohr (1885 − 1962), dänischer Physiker, Nobelpreis für Physik (1922).