Podcasts about schrodinger

Editor's note: CuspAI raised a $100m Series A in September and is rumored to have reached a unicorn valuation. They have all-star advisors from Geoff Hinton to Yann Lecun and team of deep domain experts to tackle this next frontier in AI applications.In this episode, Max Welling traces the thread connecting quantum gravity, equivariant neural networks, diffusion models, and climate-focused materials discovery (yes, there is one!!!).We begin with a provocative framing: experiments as computation. Welling describes the idea of a “physics processing unit”—a world in which digital models and physical experiments work together, with nature itself acting as a kind of processor. It's a grounded but ambitious vision of AI for science: not replacing chemists, but accelerating them.Along the way, we discuss:* Why symmetry and equivariance matter in deep learning* The tradeoff between scale and inductive bias* The deep mathematical links between diffusion models and stochastic thermodynamics* Why materials—not software—may be the real bottleneck for AI and the energy transition* What it actually takes to build an AI-driven materials platformMax reflects on moving from curiosity-driven theoretical physics (including work with Gerard ‘t Hooft) toward impact-driven research in climate and energy. The result is a conversation about convergence: physics and machine learning, digital models and laboratory experiments, long-term ambition and incremental progress.Full Video EpisodeTimestamps* 00:00:00 – The Physics Processing Unit (PPU): Nature as the Ultimate Computer* Max introduces the idea of a Physics Processing Unit — using real-world experiments as computation.* 00:00:44 – From Quantum Gravity to AI for Materials* Brandon frames Max's career arc: VAE pioneer → equivariant GNNs → materials startup founder.* 00:01:34 – Curiosity vs Impact: How His Motivation Evolved* Max explains the shift from pure theoretical curiosity to climate-driven impact.* 00:02:43 – Why CaspAI Exists: Technology as Climate Strategy* Politics struggles; technology scales. Why materials innovation became the focus.* 00:03:39 – The Thread: Physics → Symmetry → Machine Learning* How gauge symmetry, group theory, and relativity informed equivariant neural networks.* 00:06:52 – AI for Science Is Exploding (Not Emerging)* The funding surge and why AI-for-Science feels like a new industrial era.* 00:07:53 – Why Now? The Two Catalysts Behind AI for Science* Protein folding, ML force fields, and the tipping point moment.* 00:10:12 – How Engineers Can Enter AI for Science* Practical pathways: curriculum, workshops, cross-disciplinary training.* 00:11:28 – Why Materials Matter More Than Software* The argument that everything—LLMs included—rests on materials innovation.* 00:13:02 – Materials as a Search Engine* The vision: automated exploration of chemical space like querying Google.* 01:14:48 – Inside CuspAI: The Platform Architecture* Generative models + multi-scale digital twin + experiment loop.* 00:21:17 – Automating Chemistry: Human-in-the-Loop First* Start manual → modular tools → agents → increasing autonomy.* 00:25:04 – Moonshots vs Incremental Wins* Balancing lighthouse materials with paid partnerships.* 00:26:22 – Why Breakthroughs Will Still Require Humans* Automation is vertical-specific and iterative.* 00:29:01 – What Is Equivariance (In Plain English)?* Symmetry in neural networks explained with the bottle example.* 00:30:01 – Why Not Just Use Data Augmentation?* The optimization trade-off between inductive bias and data scale.* 00:31:55 – Generative AI Meets Stochastic Thermodynamics* His upcoming book and the unification of diffusion models and physics.* 00:33:44 – When the Book Drops (ICLR?)TranscriptMax: I want to think of it as what I would call a physics processing unit, like a PPU, right? Which is you have digital processing units and then you have physics processing units. So it's basically nature doing computations for you. It's the fastest computer known, as possible even. It's a bit hard to program because you have to do all these experiments. Those are quite bulky, it's like a very large thing you have to do. But in a way it is a computation and that's the way I want to see it. You can do computations in a data center and then you can ask nature to do some computations. Your interface with nature is a bit more complicated. But then these things will have to seamlessly work together to get to a new material that you're interested in.[01:00:44:14 - 01:01:34:08]Brandon: Yeah, it's a pleasure to have Max Woehling as a guest today. Max has done so much over his career that I've been so excited about. If you're in the deep learning community, you probably know Max for his work on variational autocoders, which has literally stood the test of prime or officially stood the test of prime. If you are a scientist, you probably know him for his like, binary work on graph neural networks on equivariance. And if you're a material science, you probably know him about his new startup, CASPAI. Max has a long history doing lots of cool problems. You started in quantum gravity, which is I think very different than all of these other things you worked on. The first question for AI engineers and for scientists, what is the thread in how you think about problems? What is the thread in the type of things which excite you? And how do you decide what is the next big thing you want to work on?[01:01:34:08 - 01:02:41:13]Max: So it has actually evolved a lot. In my young days, let's breathe, I would just follow what I would find super interesting. I have kind of this sensor. I think many people have, but maybe not really sort of use very much, which is like, you get this feeling about getting very excited about some problem. Like it could be, what's inside of a black hole or what's at the boundary of the universe or what are quantum mechanics actually all about. And so I follow that basically throughout my career. But I have to say that as you get older, this changes a little bit in the sense that there's a new dimension coming to it and there's this impact. Going in two-dimensional quantum gravity, you pretty much guaranteed there's going to be no impact on what you do relative, maybe a few papers, but not in this world, this energy scale. As I get closer to retirement, which is fortunately still 10 years away or so, I do want to kind of make a positive impact in the world. And I got pretty worried about climate change.[01:02:43:15 - 01:03:19:11]Max: I think politics seems to have a hard time solving it, especially these days. And so I thought better work on it from the technology side. And that's why we started CaspAI. But there's also a lot of really interesting science problems in material science. And so it's kind of combining both the impact you can make with it as well as the interesting science. So it's sort of these two dimensions, like working on things which you feel there's like, well, there's something very deep going on here. And on the other hand, trying to build tools that can actually make a real impact in the world.[01:03:19:11 - 01:03:39:23]RJ: So the thread that when I look back, look at the different things that you worked out, some of them seem pretty connected, like the physics to equivariance and, yeah, and, uh, gravitational networks, maybe. And that seems to be somewhat related to Casp. Do you have a thread through there?[01:03:39:23 - 01:06:52:16]Max: Yeah. So physics is the thread. So having done, you know, spent a lot of time in theoretical physics, I think there is first very fundamental and exciting questions, like things that haven't actually been figured out in quantum gravity. So that is really the frontier. There's also a lot of mathematical tools that you can use, right? In, for instance, in particle physics, but also in general relativity, sort of symmetry space to play an enormously important role. And this goes all the way to gauge symmetries as well. And so applying these kinds of symmetries to, uh, machine learning was actually, you know, I thought of it as a very deep and interesting mathematical problem. I did this with Taco Cohen and Taco was the main driver behind this, went all the way from just simple, like rotational symmetries all the way to gauge symmetries on spheres and stuff like that. So, and, uh, Maurice Weiler, who's also here, um, when he was a PhD student, he was a very good student with me, you know, he wrote an entire book, which I can really recommend about the role of symmetries in AI and machine learning. So I find this a very deep and interesting problem. So more recently, so I've taken a sort of different path, which is the relationship between diffusion models and that field called stochastic thermodynamics. This is basically the thermodynamics, which is a theory of equilibrium. So but then formulated for out of equilibrium systems. And it turns out that the mathematics that we use for diffusion models, but even for reinforcement learning for Schrodinger bridges for MCMC sampling has the same mathematics as this theoretical, this physical theory of non-equilibrium systems. And that got me very excited. And actually, uh, when I taught a course in, um, Mauschenberg, uh, it is South Africa, close to Cape Town at the African Institute for Mathematical Sciences Ames. And I turned that into a book site. Two years later, the book was finished. I've sent it to the publisher. And this is about the deep relationship between free energy, diffusion models, basically generative AI and stochastic thermodynamics. So it's always some kind of, I don't know, I find physics very deep. I also think a lot about quantum mechanics and it's, it's, it's a completely weird theory that actually nobody really understands. And there's a very interesting story, which is maybe good to tell to connect sort of my PZ back to where I'm now. So I did my PZ with a Nobel Laureate, Gerard the toft. He says the most brilliant man I've ever met. He was never wrong about anything as long as I've seen him. And now he says quantum mechanics is wrong and he has a new theory of quantum mechanics. Nobody understands what he's saying, even though what he's writing down is not mathematically very complex, but he's trying to address this understandability, let's say of quantum mechanics head on. And I find it very courageous and I'm completely fascinated by it. So I'm also trying to think about, okay, can I actually understand quantum mechanics in a more mundane way? So that, you know, without all the weird multiverses and collapses and stuff like that. So the physics is always been the threat and I'm trying to apply the physics to the machine learning to build better algorithms.[01:06:52:16 - 01:07:05:15]Brandon: You are still very involved in understanding and understanding physics and the worlds. Yeah. And just like applications to machine learning or introducing no formalisms. That's really cool.[01:07:05:15 - 01:07:18:02]Max: Yes, I would say I'm not contributing much to physics, but I'm contributing to the interface between physics and science. And that's called AI for science or science or AI is kind of a super, it's actually a new discipline that's emerging.[01:07:18:02 - 01:07:18:19]Speaker 5: Yeah.[01:07:18:19 - 01:07:45:14]Max: And it's not just emerging, it's exploding, I would say. That's the better term because I know you go from investments into like in the hundreds of millions now in the billions. So there's now actually a startup by Jeff Bezos that is at 6.2 billion sheep round. Right. Insane. I guess it's the largest startup ever, I think. And that's in this field, AI for science. It tells you something that we are creating a new bubble here.[01:07:46:15 - 01:07:53:28]Brandon: So why do you think it is? What has changed that has motivated people to start working on AI for science type problems?[01:07:53:28 - 01:08:49:17]Max: So there's two reasons actually. One is that people have been applying sort of the new tools from AI to the sciences, which is quite natural. And there's of course, I think there's two big examples, protein folding is a big one. And the other one is machine learning forest fields or something called machine learning inter-atomic potentials. Both of them have been actually very successful. Both also had something to do with symmetries, which is a little cool. And sort of people in the AI sciences saw an opportunity to apply the tools that they had developed beyond advertised placement, right, or multimedia applications into something that could actually make a very positive impact in society like health, drug development, materials for the energy transition, carbon capture. These are all really cool, impactful applications.[01:08:50:19 - 01:09:42:14]Max: Despite that, the science and the kind of the is also very interesting. I would say the fact that these sort of these two fields are coming together and that we're now at the point that we can actually model these things effectively and move the needle on some of these sort of science sort of methodologies is also a very unique moment, I would say. People recognize that, okay, now we're at the cusp of something new, where it results whether the company is called after. We're at the cusp of something new. And of course that always creates a lot of energy. It's like, okay, there's something, it's like sort of virgin field. It's like nobody's green field. Nobody's been there. I can rush in and I can sort of start harvesting there, right? And I think that's also what's causing a lot of sort of enthusiasm in the fields.[01:09:42:14 - 01:10:12:18]RJ: If you're an AI engineer, basically if the people that listen to this podcast will be in the field, then you maybe don't have a strong science background. How does, but are excited. Most I would say most AI practitioners, BM engineers or scientists would consider themselves scientists and they have some background, a little bit of physics, a little bit of industry college, maybe even graduate school that have been working or are starting out. How does somebody who is not a scientist on a day-to-day basis, how do they get involved?[01:10:12:18 - 01:10:14:28]Max: Well, they can read my book once it's out.[01:10:16:07 - 01:11:05:24]Max: This is basically saying that there is more, we should create curricula that are on this interface. So I'm not sure there is, also we already have some universities actual courses you can take, maybe online courses you can take. These workshops where we are now are actually very good as well. And we should probably have more tutorials before the workshop starts. Actually we've, I've kind of proposed this at some point. It's like maybe first have an hour of a tutorial so that people can get new into the field. There's a lot out there. Most of it is of course inaccessible, but I would say we will create much more books and other contents that is more accessible, including this podcast I would say. So I think it will come. And these days you can watch videos and things. There's a huge amount of content you can go and see.[01:11:05:24 - 01:11:28:28]Brandon: So maybe a follow-up to that. How do people learn and get involved? But why should they get involved? I mean, we have a lot of people who are of our audience will be interested in AI engineering, but they may be looking for bigger impacts in the world. What opportunities does AI for science provide them to make an impact to change the world? That working in this the world of pure bits would not.[01:11:28:28 - 01:11:40:06]Max: So my view is that underlying almost everything is immaterial. So we are focusing a lot on LLMs now, which is kind of the software layer.[01:11:41:06 - 01:11:56:05]Max: I would say if you think very hard, underlying everything is immaterial. So underlying an LLM is a GPU, and underlying a GPU is a wafer on which we will have to deposit materials. Do we want to wait a little bit?[01:12:02:25 - 01:12:11:06]Max: Underlying everything is immaterial. So I was saying, you know, there's the LLM underlying the LLM is a GPU on which it runs. In order to make that GPU,[01:12:12:08 - 01:12:43:20]Max: you have to put materials down on a wafer and sort of shine on it with sort of EUV light in order to etch kind of the structures in. But that's now an actual material problem, because more or less we've reached the limits of scaling things down. And now we are trying to improve further by new materials. So that's a fundamental materials problem. We need to get through the energy transition fast if we don't want to kind of mess up this world. And so there is, for instance, batteries. That's a complete materials problem. There's fuel cells.[01:12:44:23 - 01:13:01:16]Max: There is solar panels. So that they can now make solar panels with new perovskite layers on top of the silicon layers that can capture, you know, theoretically up to 50% of the light, where now we're at, I don't know, maybe 22 or something. So these are huge changes all by material innovation.[01:13:02:21 - 01:13:47:15]Max: And yeah, I think wherever you go, you know, I can probably dig deep enough and then tell you, well, actually, the very foundation of what you're doing is a material problem. And so I think it's just very nice to work on this very, very foundation. And also because I think this is maybe also something that's happening now is we can start to search through this material space. This has never been the case, right? It's like scientists, the normal way of working is you read papers and then you come up with no hypothesis. You do an experiment and you learn, et cetera. So that's a very slow process. Now we can treat this as a search engine. Like we search the internet, we now search the space of all possible molecules, not just the ones that people have made or that they're in the universe, but all of them.[01:13:48:21 - 01:14:42:01]Max: And we can make this kind of fully automated. That's the hope, right? We can just type, it becomes a tool where you type what you want and something starts spinning and some experiments get going. And then, you know, outcome list of materials and then you look at it and say, maybe not. And then you refine your query a little bit. And you kind of do research with this search engine where a huge amount of computation and experimentation is happening, you know, somewhere far away in some lab or some data center or something like this. I find this a very, very promising view of how we can sort of build a much better sort of materials layer underneath almost everything. And also more sustainable materials. Our plastics are polluting the planet. If you come up with a plastic that kind of destroys itself, you know, after, I don't a few weeks, right? And actually becomes a fertilizer. These are things that are not impossible at all. These things can be done, right? And we should do it.[01:14:42:01 - 01:14:47:23]RJ: Can you tell us a little bit just generally about CUSBI and then I have a ton of questions.[01:14:47:23 - 01:14:48:15]Speaker 5: Yeah.[01:14:48:15 - 01:17:49:10]Max: So CUSBI started about 20 months ago and it was because I was worried about I'm still worried about climate change. And so I realized that in order to get, you know, to stay within two degrees, let's say, we would not only have to reduce our emissions to zero by 2050, but then, you know, another half century or even a century of removing carbon dioxide from the atmosphere, not by reducing your emissions, but actually removing it at a rate that's about half the rate that we now emit it. And that is a unsolved problem. But if we don't solve it, two degrees is not going to happen, right? It's going to be much more. And I don't think people quite understand how bad that can be, like four degrees, like very bad. So this technology needs to be developed. And so this was my and my co-founder, Chet Edwards, motivation to start this startup. And also because, you know, we saw the technology was ready, which is also very good. So if you're, you know, the time is right to do it. And yeah, so we now in the meanwhile, we've grown to about 40 people. We've kind of collected 130 million investment into the company, which is for a European company is quite a lot. I would say it's interesting that right after that, you know, other startups got even more. So that's kind of tells you how fast this is growing. But yeah, we are we are now at the we've built the platform, of course, but it's for a series of material classes and it needs to be constantly expanded to new material classes. And it can be more automated because, you know, we know putting LLMs in as the whole thing gets more and more automated. And now we're moving to sort of high throughput experimentation. So connecting the actual platform, which is computational, to the experiments so that you can get also get fast feedback from experiments. And I kind of think of experiments as something you do at the end, although that's what we've been doing so far. I want to think of it as what I would call a sort of a physics processing unit, like a PPU, right, which is you have digital processing units and then you have physics processing units. So it's basically nature doing computations for you. It's the fastest computer known as possible, even. It's a bit hard to program because you have to do all these experiments. Those are quite, quite bulky. It's like a very large thing you have to do. But in a way, it is a computation. And that's the way I want to see it. So I want to you can do computations in a data center and then you can ask nature to do some computations. Your interface with nature is a bit more complicated. But then these things will have to seamlessly work together to get to a new material that you're interested in. And that's the vision we have. We don't say super intelligence because I don't quite know what it means and I don't want to oversell it. But I do want to automate this process and give a very powerful tool in the hands of the chemists and the material scientists.[01:17:49:10 - 01:18:01:02]Brandon: That actually brings up a question I wanted to ask you. First of all, can you talk about your platform to like whatever degree, like explain kind of how it works and like what you your thought processes was in developing it?[01:18:01:02 - 01:20:47:22]Max: Yeah, I think it's been surprisingly, it's not rocket science, I would say. It's not rocket science in the sense of the design and basically the design that, you know, I wrote down at the very beginning. It's still more or less the design, although you add things like I wasn't thinking very much about multi-scale models and as the common are rated that actually multi-scale is very important. And the beginning, I wasn't thinking very much about self-driving labs. But now I think, you know, we are now at the stage we should be adding that. And so there is sort of bits and details that we're adding. But more or less, it's what you see in the slide decks here as well, which is there is a generative component that you have to train to generate candidates. And then there is a digital twin, multi-scale, multi-fidelity digital twin, which you walk through the steps of the ladder, you know, they do the cheap things first, you weed out everything that's obviously unuseful, and then you go to more and more expensive things later. And so you narrow things down to a small number. Those go into an experiment, you know, do the experiment, get feedback, etc. Now, things that also have been more recently added is sort of more agentic sort of parts. You know, we have agents that search the literature and come up with, you know, actually the chemical literature and come up with, you know, chemical suggestions for doing experiments. We have agents which sort of autonomously orchestrate all of the computations and the experiments that need to be done. You know, they're in various stages of maturity and they can be continuously improved, I would say. And so that's basically I don't think that part. There's rocket science, but, you know, the design of that thing is not like surprising. What is it's surprising hard to actually build it. Right. So that's that's the thing that is where the moat is in the data that you can get your hands on and the and actually building the platform. And I would say there's two people in particular I want to call out, which is Felix Hunker, who is actually, you know, building the scientific part of the platform and Sandra de Maria, who is building the sort of the skate that is kind of this the MLOps part of the platform. Yeah. And so and recently we also added sort of Aaron Walsh to our team, who is a very accomplished scientist from Imperial College. We're very happy about that. He's going to be a chief science officer. And we also have a partnerships team that sort of seeks out all the customers because I think this is one thing I find very important. In print, it's so complex to do to actually bring a material to the real world that you must do this, you know, in collaboration with sort of the domain experts, which are the companies typically. So we always we only start to invest in the direction if we find a good industrial partner to go on that journey with us.[01:20:47:22 - 01:20:55:12]Brandon: Makes a lot of sense. Over the evolution of the platform, did you find that you that human intervention, human,[01:20:56:18 - 01:21:17:01]Brandon: I guess you could start out with a pure, you could imagine two directions when you start up making everything purely automatic, automated, agentic, so on. And then later on, you like find that you need to have more human input and feedback different steps. Or maybe did you start out with having human feedback? You have lots of steps and then like kind of, yeah, figure out ways to remove, you know,[01:21:17:01 - 01:22:39:18]Max: that is the second one. So you build tools for you. So it's much more modular than you think. But it's like, we need these tools for this application. We need these tools. So you build all these tools, and then you go through a workflow actually in the beginning just manually. So you put them in a first this tool, then run this to them or this with sithery. So you put them in a workflow and then you figure out, oh, actually, you know, this this porous material that we are trying to make actually collapses if you shake it a bit. Okay, then you add a new tool that says test for stability. Right. Yeah. And so there's more and more tools. And then you build the agent, which could be a Bayesian optimizer, or it could be an actual other them, you know, maybe trained to be a good chemist that will then start to use all these tools in the right way in the right order. Yeah. Right. But in the beginning, it's like you as a chemist are putting the workflow together. And then you think about, okay, how am I going to automate this? Right. For one very easy question you can ask yourself is, you know, every time somebody who is not a super expert in DFT, yeah, and he wants to do a calculation has to go to somebody who knows DFT. And so could you start to automate that away, which is like, okay, make it so user friendly, so that you actually do the right DFT for the right problem and for the right length of time, and you can actually assess whether it's a good outcome, etc. So you start to automate smaller small pieces and bigger pieces, etc. And in the end, the whole thing is automated.[01:22:39:18 - 01:22:53:25]Brandon: So your philosophy is you want to provide a set of specific tools that make it so that the scientists making decisions are better informed and less so trying to create an automated process.[01:22:53:25 - 01:23:22:01]Max: I think it's this is sort of the same where you're saying because, yes, we want to automate, yeah, but we don't see something very soon where the chemists and the domain expert is out of the loop. Yeah, but it but it's a retreat, right? It's like, okay, so first, you need an expert to tell you precisely how to set the parameters of the DFT calculation. Okay, maybe we can take that out. We can maybe automate that, right? And so increasingly, more of these things are going to be removed.[01:23:22:01 - 01:23:22:19]Speaker 5: Yeah.[01:23:22:19 - 01:24:33:25]Max: In the end, the vision is it will be a search engine where you where somebody, a chemist will type things and we'll get candidates, but the chemist will still decide what is a good material and what is not a good material out of that list, right? And so the vision of a completely dark lab, where you can close the door and you just say, just, you know, find something interesting and then it will it will just figure out what's interesting and we'll figure out, you know, it's like, oh, I found this new material to blah, blah, blah, blah, right? That's not the vision I have. He's not for, you know, a long time. So for me, it's really empowering the domain experts that are sitting in the companies and in universities to be much faster in developing their materials. And I should say, it's also good to be a little humble at times, because it is very complicated, you know, to bring it to make it and to bring it into the real world. And there are people that are doing this for the entire lives. Yeah. Right. And it's like, I wonder if they scratch their head and say, well, you know, how are you going to completely automate that away, like in the next five years? I don't think that's going to happen at all.[01:24:35:01 - 01:24:39:24]Max: Yeah. So to me, it's an increasingly powerful tool in the hands of the chemists.[01:24:39:24 - 01:25:04:02]RJ: I have a question. You've talked before about getting people interested based on having, you know, sort of a big breakthrough in materials, incremental change. I'm curious what you think about the platform you have now in are sort of stepping towards and how are you chasing the big change or is this like incremental or is there they're not mutually exclusive, obviously, but what do you think about that?[01:25:04:02 - 01:26:04:27]Max: We follow a mixed strategy. So we are definitely going after a big material. Again, we do this with a partner. I'm not going to disclose precisely what it is, but we have our own kind of long term goal. You could call it lighthouse or, you know, sort of moonshot or whatever, but it is going to be a really impactful material that we want to develop as a proof point that it can be done and that it will make it into the into the real world and that AI was essential in actually making it happen. At the same time, we also are quite happy to work with companies that have more modest goals. Like I would say one is a very deep partnership where you go on a journey with a company and that's a long term commitment together. And the other one is like somebody says, I knew I need a force field. Can you help me train this force field and then maybe analyze this particular problem for me? And I'll pay you a bunch of money for that. And then maybe after that we'll see. And that's fine too. Right. But we prefer, you know, the deep partnerships where we can really change something for the good.[01:26:04:27 - 01:26:22:02]RJ: Yeah. And do you feel like from a platform standpoint you're ready for that or what are the things that and again, not asking you to disclose proprietary secret sauce, but what are the things generally speaking that need to happen from where we are to where to get those big breakthroughs?[01:26:22:02 - 01:28:40:01]Max: What I find interesting about this field is that every time you build something, it's actually immediately useful. Right. And so unlike quantum computing, which or nuclear fusion, so you work for 20, 30, 40 years and nothing, nothing, nothing, nothing. And then it has to happen. Right. And when it happens, it's huge. So it's quite different here because every time you introduce, so you go to a customer and you say, so what do you need? Right. So we work, let's say, on a problem like a water filtration. We want to remove PFAS from water. Right. So we do this with a company, Camira. So they are a deep partner for us. Right. So we on a journey together. I think that the breakthrough will happen with a lot of human in the loop because there is the chemists who have a whole lot more knowledge of their field and it's us who will help them with training, having a new message. And in that kind of interface, these interactions, something beautiful will happen and that will have to happen first before this field will really take off, I think. And so in the sense that it's not a bubble, let's put it that way. So that's people see that as actual real what's happening. So in the beginning, it will be very, you know, with a lot of humans in the loop, I would say, and I would I would hope we will have this new sort of breakthrough material before, you know, everything is completely automated because that will take a while. And also it is very vertical specific. So it's like completely automating something for problem A, you know, you can probably achieve it, but then you'll sort of have to start over again for problem B because, you know, your experimental setup looks very different in the machines that you characterize your materials look very different. Even the models in your platform will have to be retrained and fine tuned to the new class. So every time, you know, you have a lot of learnings to transfer, but also, you know, the problems are actually different. And so, yes, I would want that breakthrough material before it's completely automated, which I think is kind of a long term vision. And I would say every time you move to something new, you'll have to start retraining and humans will have to come in again and say, okay, so what does this problem look like? And now sort of, you know, point the the machine again, you know, in the new direction and then and then use it again.[01:28:40:01 - 01:28:47:17]RJ: For the non-scientists among us, me included a bit of a scientist. There's a lot of terminology. You mentioned DFT,[01:28:49:00 - 01:29:01:11]RJ: you equivariance we've talked about. Can you sort of explain in engineering terms or the level of sophistication and engineering? Well, how what is equivariance?[01:29:01:11 - 01:29:55:01]Max: So equivariance is the infusion of symmetry in neural networks. So if I build a neural network, let's say that needs to recognize this bottle, right, and then I rotate the bottle, it will then actually have to completely start again because it has no idea that the rotated bottle. Well, actually, the input that represents a rotated bottle is actually rotated bottle. It just doesn't understand that. Right. If you build equivariance in basically once you've trained it in one orientation, it will understand it in any other orientation. So that means you need a lot less data to train these models. And these are constraints on the weights of the model. So so basically you have to constrain the way such data to understand it. And you can build it in, you can hard code it in. And yeah, this the symmetry groups can be, you know, translations, rotations, but also permutations. I can graph neural network, their permutations and then physics, of course, as many more of these groups.[01:29:55:01 - 01:30:01:08]RJ: To pray devil's advocate, why not just use data augmentation by your bottle is in all the different orientations?[01:30:01:08 - 01:30:58:23]Max: As an option, it's just not exact. It's like, why would you go through the work of doing all that? Where you would really need an infinite number of augmentations to get it completely right. Where you can also hard code it in. Now, I have to say sometimes actually data augmentation works even better than hard coding the equivariance in. And this is something to do with the fact that if you constrain the optimization, the weights before the optimization starts, the optimization surface or objective becomes more complicated. And so it's harder to find good minima. So there is also a complicated interplay, I think, between the optimization process and these constraints you put in your network. And so, yeah, you'll hear kind of contradicting claims in this field. Like some people and for certain applications, it works just better than not doing it. And sometimes you hear other people, if you have a lot of data and you can do data augmentation, then actually it's easier to optimize them and it actually works better than putting the equivariance in.[01:30:58:23 - 01:31:07:16]Brandon: Do you think there's kind of a bitter lesson for mathematically founded models and strategies for doing deep learning?[01:31:07:16 - 01:31:46:06]Max: Yeah, ultimately it's a trade-off between data and inductive bias. So if your inductive bias is not perfectly correct, you have to be careful because you put a ceiling to what you can do. But if you know the symmetry is there, it's hard to imagine there isn't a way to actually leverage it. But yeah, so there is a bitter lesson. And one of the bitter lessons is you should always make sure your architecture is scale, unless you have a tiny data set, in which case it doesn't matter. But if you, you know, the same bitter lessons or lessons that you can draw in LLM space are eventually going to be true in this space as well, I think.[01:31:47:10 - 01:31:55:01]RJ: Can you talk a little bit about your upcoming book and tell the listeners, like, what's exciting about it? Yeah, I should read it.[01:31:55:01 - 01:33:42:20]Max: So this book is about, it's called Generative AI and Stochastic Thermodynamics. It basically lays bare the fact that the mathematics that goes into both generative AI, which is the technology to generate images and videos, and this field of non-equilibrium statistical mechanics, which are systems of molecules that are just moving around and relaxing to the ground state, or that you can control to have certain, you know, be in a certain state, the mathematics of these two is actually identical. And so that's fascinating. And in fact, what's interesting is that Jeff Hinton and Radford Neal already wrote down the variational free energy for machine learning a long time ago. And there's also Carl Friston's work on free energy principle and active entrance. But now we've related it to this very new field in physics, which is called stochastic thermodynamics or non-equilibrium thermodynamics, which has its own very interesting theorems, like fluctuation theorems, which we don't typically talk about, but we can learn a lot from. And I think it's just it can sort of now start to cross fertilize. When we see that these things are actually the same, we can, like we did for symmetries, we can now look at this new theory that's out there, developed by these very smart physicists, and say, okay, what can we take from here that will make our algorithms better? At the same time, we can use our models to now help the scientists do better science. And so it becomes a beautiful cross-fertilization between these two fields. The book is rather technical, I would say. And it takes all sorts of things that have been done as stochastic thermodynamics, and all sorts of models that have been done in the machine learning literature, and it basically equates them to each other. And I think hopefully that sense of unification will be revealing to people.[01:33:42:20 - 01:33:44:05]RJ: Wait, and when is it out?[01:33:44:05 - 01:33:56:09]Max: Well, it depends on the publisher now. But I hope in April, I'm going to give a keynote at ICLR. And it would be very nice if they have this book in my hand. But you know, it's hard to control these kind of timelines.[01:33:56:09 - 01:33:58:19]RJ: Yeah, I'm looking forward to it. Great.[01:33:58:19 - 01:33:59:25]Max: Thank you very much. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.latent.space/subscribe

Do mércores 11 ao venres 13 de febreiro de 2026 terá lugar a segunda edición do festival “Coruña Comunica Ciencia”. Polo coruñés Teatro Colón desfilarán divulgadores como Eduardo Sáenz de Cabezón, Eva Cabanelas, Rocio Vidal (La Gata de Schrodinger), Patricia Barciela, Dosi Veiga, o cirurxián Diego González Rivas... Tamén se representará o espectáculo “Elemental”, haberá unha charla-concerto de música e matemáticas con Laura Farré, musica e IA con Sofía Oriana e gravación con público de Efervesciencia. Conversamos co organizador do festival, David Basllesteros de Ceo Aberto, que ofrece aos oíntes 100 entradas de balde. Para conseguir un código de desconto tes que escoitar a entrevista a Ballesteros ou tamén o podes atopar na nosa canle de Telegram, https://t.me/efervescentes https://coruñacomunicaciencia.es/

This week the Buddies discuss what they think they're experts in (but really aren't), good band names, the idea of personhood and bad art being key, modern haircutting experiences, the right number of donuts for a meal, and if we believe in ghosts. Share with a friend! Contact Us: Facebook Instagram Youtube Email Recommendations: Staring at the Sun (album by Hotel Fiction), the concept of what it means to be a person (philosophical topic), The Alloy of Law (book by Brandon Sanderson)

Send us a textOn this week's episode of Grease the Wheels, we go over some of the highlights and lowlights of automotive management. One of the main things that we have noticed is that in the rise of the corporate owned, multi-location dealership group era, there are a lot less nepo-hires in management. It still happens, especially at smaller family owned dealerships, but on a whole the quality of management in the automotive space has actually gotten significantly better in the last 20+ years! There are still ineffective, and poorly trained management in this space, but many of them are a lot easier to get rid of when they aren't going to show up at family parties. We go over some of the hallmarks of what makes managers successful in this space full of good examples, ideas, tips, and tricks. Bottom line, good management can make a good shop great, and bad management can make a bad shop infinitely worse.   Also Uncle Jimmy knows that he cannot govern the ungovernable! This Episode of Grease the Wheels is brought to you in partnership with Surfwrench Digital! For more on Video MPI Training Visit https://www.surfwrench.com/video-mpi-training-landing/ to learn more. Video MPI Training built in the shop, by your Uncle Jimmy. Use code “GTW” for 50% off your training access!  

A version of this essay was published by firstpost.com at https://www.firstpost.com/opinion/india-us-trade-deal-trump-skepticism-13977047.htmlI am beginning to feel quite like ‘The Boy Who Cried Wolf', who was destined to be ignored. Or maybe I am the boy who cried ‘The Emperor Has No Clothes'. For, I was skeptical last week about the India-EU FTA, which I called a triumph of hope over experience. Now I am equally skeptical about the so-called India-US trade ‘deal', which in fact is not a deal at all, but a sort-of statement of direction about the way to an actual deal.I expressed my caution on a Malayalam TV program where the host was a retired Ambassador. He was less skeptical than me, but he understood where I was coming from: after all, a diplomat's job is to put the best spin on the news (good or bad) from his country's perspective. And I spent much of my professional career in marketing: I can tell spin when I see it. Reason No. 1: Trump is famous for exaggeration and U-turns.The very first reason for the scepticism about the Indo-US lovefest is that it was announced by President Trump, who, in the past six months, has, in his whimsical way, executed any number of U-turns, as well as Z-turns, and various other pretzel-logic twists, so much so that anything he says, and its opposite, can be equally true, in a quantum Schrodinger's Cat sort of way. It is prudent not to take him at face value when he swears eternal allegiance to India. Again.Quoth he: “It was an Honor to speak with Prime Minister Modi, of India, this morning. He is one of my greatest friends, and a Powerful and Respected Leader of his Country. We spoke about many things, including Trade, and ending the War with Russia and Ukraine. He agreed to stop buying Russian Oil, and to buy much more from the United States and, potentially, Venezuela. This will help END THE WAR in Ukraine, which is taking place right now, with thousands of people dying each and every week! Out of friendship and respect for Prime Minister Modi and, as per his request, effective immediately, we agreed to a Trade Deal between the United States and India, whereby the United States will charge a reduced Reciprocal Tariff, lowering it from 25% to 18%. They will likewise move forward to reduce their Tariffs and Non Tariff Barriers against the United States, to ZERO. The Prime Minister also committed to “BUY AMERICAN,” at a much higher level, in addition to over $500 BILLION DOLLARS of U.S. Energy, Technology, Agricultural, Coal, and many other products. Our amazing relationship with India will be even stronger going forward. Prime Minister Modi and I are two people that GET THINGS DONE, something that cannot be said for most. Thank you for your attention to this matter!”Okay. Very interesting. There has been no Indian readout corroborating a number of these claims, especially on agriculture, which I imagine is a redline, a no-go, for India.Besides, these are supposed to be ‘reciprocal' tariffs. If Indian tariffs go to zero on US products, why is the US imposing 18% on Indian products?Reason No. 2: Desperation of ‘jilted lovers'The ‘shotgun wedding' vibe was present in the India-EU FTA as well: a sort of desperation. There is not much choice: you simply have to do this. I am not the only one saying this. Here is a tweet from a senior EU leader, former PM of Sweden and co-chair of the EU Council for foreign relations. Of course you could say that he would say this, wouldn't he? But it happens to be true. The number of suitors is declining rapidly, so you compromise. But that is not a recipe for the longevity of the relationship, nor for faithfulness. You can expect er… adultery (early and often). The roving eye roveth.Reason No. 3: Agriculture and dairy red-linesWe really don't know much about the fine print. I am aware that sales and marketing people tend to promise anything (even things they are completely aware are impossible) just to get the sale. Thus, when India diversifies away from the US market, and its Q3 numbers are not badly affected by the Trump tariffs, it is incumbent upon Trump and Navarro, Bessent, Lutnick et al to reverse their previous abuse, and be all milk and honey.The problem here, as always, is the agriculture and dairy product front. It is an absolute red line for India: no government can afford to piss off its farmers, nor to open up the country, home of much of the world's genetic diversity, to Genetically Modified Organisms (GMO) including Terminator Seeds (that would forever put farmers at the mercy of Cargill and friends).Not only that, non-veg milk (that is, milk from cows that have been fed, among other things, ground-up animal bodies) is abhorrent to a large number of Indians. Not to mention the risk of things like Creuzfeldt-Jakob Disease or mad-cow disease (transmitted via feed that includes the ground-up brains of diseased cattle: see also the fatal brain disease Kuru, transmitted between cannibals in Papua New Guinea).The US rather urgently needs to get rid of its soybean and corn mountains and milk lakes (in contrast with the EU's butter mountain and wine lakes) and in both, exporters salivate at the prospect of the proverbial billion-customer market. (The Chinese expertly used this rather illusory meme to attract foreign makers of consumer goods. That didn't end well).In the case of India, there is no demand for soybeans, and the one place where I can see demand for corn is in ethanol, especially for blending into petrol. That would be a win-win, because it would reduce the need for India to grow highly thirsty sugarcane, thus drawing down the already alarmingly depleted water-table.Reason No. 4: Russian oil and energy in generalThe unseemly pressure over Russian oil raises hackles on the Indian side. After all, this is not the only time India has been pushed to the wall by American sanctions: there was the post-'Buddha is smiling' period, and the prevention of the sale of ex-Soviet cryogenic rocket technology, as immortalized in Nambi Narayanan's story in “Rocketry: The Nambi Effect”. Earlier, there was the embargo on supercomputers.In each of these cases, India rode out the sanctions and denials. But the question arises: why should India not use Russian oil if it makes commercial sense to India? Just because there is a conflict between Russia and Ukraine? That is really not India's problem: India does not have a dog in that fight.Now there is the allegedly impending US attack on Iran. India has been denied Iranian oil for some time, and now under US pressure, it is being forced to ramp down its involvement in Chabahar Port in Iran that India built, and views as a gateway to Central Asia. Notably, China continues to import Iranian crude. Is India getting some relief there?It is not realistic to imagine that large amounts of Venezuelan crude will now flow to India if it abjures the Russian stuff. For one, even though Reliance's Jamnagar refiner can process the heavy, sour Venezuelan oil, it is said that Venezuela will take some time and a lot of money to ramp up its output because of years of neglect, lack of naphtha to dilute and pump out the crude, and so on.Reason No. 5: Non-tariff barriers and subsidies.The US claims that India will drop all its non-tariff barriers, but what is the guarantee that the US will not raise an impenetrable wall on their side? It is a simple matter to impose difficult-to-comply-with rules that basically say “Your products are not welcome”. These may include environmental, carbon tax, quality, and various other demands.For example, there is the Merchant Marine Act of 1920 that insists that only American owned/built/crewed ships can transport goods between US ports. Then there are Buy American Act procurement restrictions that handicap foreign-origin products. Furthermore, quality standards e.g. on hormone-treated meat products, and on certification that seafood is tuna-safe have been used to keep out imported products.The US Farm Bill provides gigantic subsidies for five major crops – corn, soy, wheat, rice and cotton – amounting to $9.3 billion in 2024. Reports suggest that crop insurance and new benefits from the ‘bridge payments' announced in 2025 may add another $10 billion+ to this sum. That is an enormous subsidy, pricing competitors out of the market.Reason No. 6: Loss of trustFinally, there is a sixth and critical reason: the loss of trust. For the longest time, India had convinced itself that it was an essential strategic partner to the US, if for nothing else to contain China. But that illusion is now gone, quite possibly because the US has decided to create a G2 condominium with China and retreat into Fortress America. The US administration now considers India, at best, a transactional vassal, and at worst, a potential rival to apply the Thucydides Trap to: and what better than to do war by economic means? India has to adjust.On the other hand, there are indeed positives. In the interest of fairness, here are the immediate views of Citibank and Bank of America, who both considered it a net positive for India.If you accept the tariff reductions by the US at face value, then India at 18% is doing marginally better than several other nations, including Vietnam, Thailand and Bangladesh. Ironically, Trump's recent best-friend-forever Pakistan is hit with 19%. There was a video circulating showing Raghuram Rajan, the economist who wants to be to Rahul Gandhi who Manmohan Singh was to his mother, gloating earlier that India was suffering from 50% tariffs compared to Pakistan's 19%.That brings up one more observation: the Opposition in India is screaming bloody murder about this supposed India-US ‘deal' not because they claim India is getting a bad deal, but apparently because they think India is getting a good deal. They should see Trump's latest triumph.Opposition, fear not: Trump is making even more entertaining claims about his ‘deal' with Xi. The sum and substance: “Please buy my soybeans”. This, despite the fact that China is the biggest buyer of oil from both Russia (48% of exports) and Iran (80%). Clearly, there is a lot of marketing going on, and it's too early to tell what the reality is. The devil is in the details.1750 words, 5 Feb 2026 This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit rajeevsrinivasan.substack.com/subscribe

In this episode Chris delivers Opinion Scholarship on the great quantum physicist--Erwin Schrodinger--through the ideas expressed in his 1956 book Mind and Matter. Things get unexpectedly mystical almost immediately as Schodinger discusses the implications of the "observer effect" and the Copenhagen interpretation of Quantum Mechanics. It only gets better from here as Schodinger explores the role of consciousness in physics, the unity of 'mind' and the qualities of mind that are equally qualities of God.  Enjoy ;)

After reflecting on our last bracket where we went through @VHSDates and played matchmaker, our resident bracketologist Drinks w/ Ron came up with the perfect solution for the problem of what to do this month. So: because this wondrous and beautiful account of newly unearthed video personal ads turned out to be a brilliant improv troupe, we decided to discuss hoaxes. And not just any hoaxes, but ones that got us good. Everything from Andy Kaufman to the Blair Witch Project. All that, and more!And if you enjoy what we are doing here at the Pit and would like to support us further, please check us out our patreon, where we have exclusive extended episodes! Today, we discuss Schrodinger's Cat AND we break Google's AI.Twin Peaks Tuesdays!EtsyLinktreeYoutubeAralessThe Half-Assed Podcast Networksong at end of episode: Old Man - AralessInstagram:@ruining_your.childhood@feral_williams@aralessbmn@blackmagicnoize206@strangeloopanimation

It's been a week of romance in AEW. Yeah, we know, we weren't really expecting it from a show called Maximum Carnage either. (00:00:00) Ins and outs at AEW: The Rascalz, Hechicero, Persephone, and Mascara Dorada in, Will Hobbs out (00:14:12) Mercedes Moné is a crashout icon (00:16:37) Who's been sending Mina Shirakawa flowers? (00:23:11) Can we have a big meaty feud between Kris Statlander and Thekla please? And should we be overthinking the Cosmic Babes of Wrath's black gear? (00:33:42) Darby Allin is a fake and a fraud until he fights Marina Shafir (00:39:09) Marked safe from FTR vs Young Bucks... for now (00:42:03) Schrodinger's Bandido and a gold star for Maxwell (00:50:05) A Hangman-Kenny sandwich with a Swerve filling (01:05:30) JetSpeed Hangballs (01:12:19) The things that made us happy this week Follow us on Bluesky: wafflybollox.bsky.social Email us: wafflybollox@gmail.com Buy things: ko-fi.com/wrassletrash/shop Learn more about your ad choices. Visit podcastchoices.com/adchoices

Are we in a 'plastic moment,' an inflection point where the future of the Middle East can finally be reshaped? Veteran peace negotiator Dr. Tal Becker joins the podcast to analyze the shifting tides of regional diplomacy. Reflecting on his recent discussions in Abu Dhabi, Becker describes the Abraham Accords as an emerging "Judeo-Muslim civilization" where the focus isn't on "who the land belongs to," but the realization that "we all belong to the land."  Beyond geopolitics, Becker addresses the trauma of rising Western antisemitism—which he likens to a "zombie apocalypse"—and calls for a resurgence of liberal nationalism. This episode is a masterclass in navigating a zero-sum world to build a future of prosperity, courage, and shared belonging. Key Resources: The Abraham Accords, Explained AJC CEO Ted Deutch Op-Ed: 5 Years On, the Abraham Accords Are the Middle East's Best Hope AJC's Center for a New Middle East Listen – AJC Podcasts: Architects of Peace The Forgotten Exodus People of the Pod Follow People of the Pod on your favorite podcast app, and learn more at AJC.org/PeopleofthePod You can reach us at: peopleofthepod@ajc.org If you've appreciated this episode, please be sure to tell your friends, and rate and review us on Apple Podcasts or Spotify. Transcript of the Interview: Manya Brachear Pashman:   As the international community looks to phase two of the cease fire between Israel and the Hamas terror group in Gaza, the American Jewish Committee office in Abu Dhabi invited Dr Tal Becker to participate in discussions about what's next for the region. Dr Becker is one of Israel's leading experts on international humanitarian law and a veteran peace negotiator with Palestinians, Lebanese and Syrians. He is currently vice president of the Shalom Hartman Institute, and he joins us now right after the conference in Abu Dhabi to share some of the insights he contributed there.  Tal, welcome to People of the Pod. Tal Becker:   Thank you very much, Manya. Manya Brachear Pashman:   So Tal, you have just returned from a conference in Abu Dhabi where you really took a deep dive, kind of exploring the nature of Arab-Israeli relations, as we are now entering the second phase of the ceasefire between Israel and Gaza.  So I'm just curious, you've been steeped in this for so long, for decades, do you sense, or did you sense a significant shift in the region when it comes to Arab-Israeli relations and the future? Tal Becker:   So I think Manya, we're at a very kind of interesting moment, and it's hard to say exactly which direction it's going, because, on the one hand, we have had very significant military successes. I think a lot of the spoilers in the region have been significantly set back, though they're still there, but Israel really has had to focus on the military side of things a lot. And it, I think, has strained to some extent, the view of what's possible because we're being so focused on the military side.  And I think it is a moment for imagining what's possible. And how do we pivot out of the tragedy and suffering of this war, make the most of the military successes we've had, and really begin to imagine what this region could look like if we're going to continue to succeed in pushing back the spoilers in this way.  Israel is a regional power, and I think it for all our vulnerability that requires, to some extent, for Israel to really articulate a vision that it has for the region. And it's going to take a little bit of time, I think, for everybody to really internalize what's just happened over these last two years and what it means for the potential for good and how we navigate that. So I really think it's kind of like what they call a plastic moment right now. Manya Brachear Pashman:   A plastic moment, can you define that, what do you mean by plastic? Tal Becker:   So what I mean by a plastic moment, meaning it's that moment. It's an inflection point right where, where things could go in one direction or another, and you have to be smart enough to take advantage of the fluidity of the moment, to really emphasize how do we maximize prosperity, stability, coexistence? How do we take away not just the capabilities of the enemies of peace, but also the appeal of their agenda, the language that they use, the way they try to present Muslim Jewish relations, as if they're a kind of zero sum game. So how do we operate both on the economic side, on the security side, but also on the imagining what's possible side, on the peace side. As difficult as that is, and I don't want to suggest that, you know, there aren't serious obstacles, there are, but there's also really serious opportunities. Manya Brachear Pashman:   So what did you sense when you were there, in terms of the perception of Israel? I mean, were people optimistic, for lack of a better term? Tal Becker:   So first of all, it was, you know, a great opportunity to be there. And having been involved, personally, very intensively in the Abraham Accords, I always feel a bit emotional whenever I'm in the Emirates in particular, and Morocco and Bahrain and so on. And to be honest, I kind of feel at home there. And so that's a lovely thing.  I think, on the one hand, I would say there's a there's a relief that hopefully, please God, the war in Gaza is is behind us, that we're now looking at how to really kind of move into the phase of the disarmament of Hamas and the removal of Hamas from governance, you know, working with the Trump team and the Trump plan. And I think they have a bunch of questions. The Emiratis in particular, are strategic thinkers. They really want to be partners in advancing prosperity and stability across the region in pushing back extremism across the region, and I think they're eager to see in Israel a partner for that effort. And I think it puts also a responsibility on both of us to understand the concerns we each have. I mean, it takes some time to really internalize what it is for a country to face a seven-front war with organizations that call for its annihilation, and all the pressure and anxiety that that produces for a people, frankly, that hasn't had the easiest history in terms of the agenda of people hating the Jewish people and persecuting them. So I think that takes a bit of appreciation.  I think we also, in the return, need to appreciate the concerns of our regional partners in terms of making sure that the region is stable, in terms of giving an opportunity for, you know, one way I sometimes word it is that, we need to prepare for the worst case scenario. We need to prevent it from being a self fulfilling prophecy.  Which really requires you to kind of develop a policy that nevertheless gives an opportunity for things to get better, not just plan for things to get worse. And I think our partners in the Gulf in particular really want to hear from us, what we can do to make things better, even while we're planning and maybe even a bit cynical that things might be very difficult. Manya Brachear Pashman:   So you mentioned the Abraham Accords, and I'm curious if you feel that Israel, I know Israel has felt isolated, at times, very isolated, and perhaps abandoned, is even the correct word.  Do you feel that is the case as we enter the second phase of the ceasefire? Do you feel that is less so the case, and do you feel that that might be less so the case because of the Abraham Accords existence? Tal Becker:   Well, so let's first talk about the Abraham Accords and their significance.So I think a lot of people present the Abraham accords as kind of an agreement that is about shared interests and shared challenges and so on, and that's definitely true. But they are, in my view, at least aspirationally, something much bigger than that. First of all, they are almost the articulation of what I call a Judeo Muslim civilization, the view that Jews and Muslims, or that all different peoples of the Middle East belong to this place and have a responsibility for shaping its future. The way I describe the Abraham Accords is that they're a group of countries who basically have said that the argument about who the land belongs to is not as important as the understanding that we all belong to the land. And as a result of that, this is kind of a partnership against the forces of extremism and chaos, and really offering a version of Israeli Jewish identity and of Muslim Arab identity that is in competition with the Iranian-Hezbollah-Hamas narrative that kind of condemns us to this zero sum conflict.  So the first thing to say is that I think the Abraham Accords have such tremendous potential for reimagining the relationship between Muslims and Jews, for reimagining the future of the region, and for really making sure that the enemies of peace no longer shape our agenda, even if they're still there. So in that sense, the opening that the Abraham Accords offers is an opening to kind of reimagine the region as a whole. And I think that's really important. And I think we have now an opportunity to deepen the Accords, potentially to expand them to other countries, and in doing so, to kind of set back the forces of extremism in the region. In a strange way, I would say Manya that Israel is more challenged right now in the west than we are in the Middle East. Because in the West, you see, I mean, there's backlash, and it's a complicated picture, but you can see a kind of increasing voices that challenge Israel's legitimacy, that are really questioning our story. And you see that both on the extreme left and extreme right in different countries across the West, in different degrees. In the Middle East, paradoxically, you have at least a partnership around accepting one another within the region that seems to me to be very promising.  And in part, I have to say it's really important to understand, for all the tragedy and difficulty of this war, Israel demonstrated an unbelievable resilience, unbelievable strength in dealing with its its adversaries, an unbelievable capacity, despite this seven front challenge, and I think that itself, in a region that's a very difficult region, is attractive. I think we do have a responsibility and an interest in imagining how we can begin to heal, if that's a word we can use the Israeli Palestinian relationship, at least move in a better direction. Use the Trump plan to do that, because that, I think, will also help our relationship in the region as a whole, without making one dependent on the other. Manya Brachear Pashman:   So I want to follow up with what you just said, that Israel faces perhaps many more challenges in the west than in the region. What about the Jewish people, would you apply that same statement to the Jewish people? Tal Becker:   Well, I think, you know, we've seen, we've seen the rise of antisemitism. And in my view, one way to think about October 7 is that October 7 marks the end of the post-Holocaust era. So there were a few decades there where, even if antisemitism existed, there were many circles in which it was socially unacceptable to give it voice. And something has shattered in the West in particular that it seems to be more socially acceptable to express antisemitism or antisemitic-adjacent type views, and that, I think has has really shocked and shaken many Jews across the western world.  I guess the thing I would say about that is, you know, some of the Jews I come across in the West were under, in my view, a bit of an illusion, that antisemitism had somehow been cured. You feel this sometimes in North America, and that essentially, we had reached a stage in Jewish history where antisemitism was broadly a thing of the past and was on the margins, and then the ferocity with which it came back on October 8 was like a trauma. And one of the definitions of trauma is that trauma is a severe challenge to the way you understand the world and your place in it.  And so if you had this understanding of your reality that antisemitism was essentially a thing of the past in North America in particular. And then all of a sudden it came back. You can see that traumatic experience. And what I want to argue or suggest is that the problem isn't that we had the solution and lost it. I think the problem was we had an illusion that there was a solution in the first place. Unfortunately, I think the Jewish people's history tells the story that antisemitism is kind of like the zombie apocalypse. It never exactly disappears. You can sometimes marginalize it more or marginalize it less. And we're now entering an era which I think Jews are familiar with, which is an era that it is becoming more socially acceptable to be antisemitic. And that to some extent, Jewish communal life feels more conditional and Jewish identity, and while being accepted in the societies in which you live also feels more conditional.  And while that is a familiar pattern, we are probably the generation of Jews with more resources, more influence, more power, more capacity than probably at any other time in Jewish history. And so it would be a mistake, I think, to think of us as kind of going back to some previous era. Yes, there are these challenges, but there are also a whole set of tools. We didn't have the F35 during the Spanish Inquisition.  So I think that despite all these challenges, it's also a great moment of opportunity for really building Jewish communities that are resilient, that have strong Jewish identity, that are that have a depth of Jewish literacy, and trying to inoculate as much as possible the societies in which we live and the communities in which we live from that phenomenon of antisemitism perhaps better than we had had done in previous iterations of this.  Manya Brachear Pashman:   I also want to go back and explore another term that you've used a couple of times, and that is enemies of peace. And I'm curious how you define the enemies of peace. Who are you talking about? And I'm asking you to kind of take a step back and really broaden that definition as much as possible. Tal Becker:   I mean, it goes back to that idea that I mentioned about the Abraham Accords, which is an understanding that there are different peoples in the Middle East that call it home, and each of those peoples deserves a place where they can nurture their identity and cultivate it and have their legitimacy respected, and in that sense, those who are engaged in a kind of zero sum competition, that feel that their exist, existence depends on the obliteration of the other. I see those as enemies of peace.  Now, I believe that both Jews and Palestinians, for example, have a right to self determination. I think that both belong in the sense that both deserve the capacity to cultivate their own identity. But the right to self determination, for example, the Palestinian right to self determination doesn't include the right to deny the Jewish right to self determination. It doesn't include the right to erase Jewish history.  In the same way that we as Jews need to come to terms with the fact that the Palestinian people feel a real connection to this place. Now, it's very difficult, given how radicalized Palestinian society is, and we have to be very realistic about the threats we face, because for as long as the dominant narrative in Palestinian society is a rejection of Jewish belongingness and self determination, we have a very difficult challenge ahead of us. But I essentially, broadly speaking, would say, the enemies of peace are those who want to lock us into a zero sum contest. Where essentially, they view the welfare of the other as a threat to themselves. Y You know, we have no conflict with Lebanon. We have no conflict with the people of Iran, for example. We have a conflict, in fact, a zero sum conflict with an Iranian regime that wants to annihilate Israel. And I often point to this kind of discrepancy that Iran would like to destroy Israel, and Israel has the audacity to want not to be destroyed by Iran. That is not an equivalent moral playing field. And so I view the Iranian regime with that kind of agenda, as an enemy of peace. And I think Israel has an obligation to also articulate what its aspirations are in those regards, even if it's a long time horizon to realize those aspirations, because the enemies are out there, and they do need to be confronted effectively and pretty relentlessly. Manya Brachear Pashman:   For our series on the Abraham Accords, Architects of Peace, I spoke with Dr Ali Al Nuami, and we talked about the need for the narrative to change, and the narrative on both sides right, the narrative change about kind of what you refer to as a zero sum game, and for the narrative, especially out of Israel, about the Palestinians to change. And I'm curious if you've given that any thought about changing, or just Israel's ability or obligation to send a message about the need for the Palestinians indeed to achieve self determination and thrive. Tal Becker:   Well, I think first, it's important to articulate how difficult that is, simply because, I mean, Israel has faced now two years of war, and the sense that I think many Israelis felt was that Palestinian society at large was not opposed to what happened on October 7, and the dominant narratives in Palestinian society, whether viewing Israel as some kind of a front to Islam, or viewing Israel as a kind of colonial enterprise to then be like in the business of suggesting a positive vision in the face of that is very difficult, and we do tend Manya, in these situations, when we say the narrative has to change, we then say, on the other side, they have to change the narrative, rather than directing that to ourselves. So I think, you know, there is an obligation for everyone to think about how best to articulate their vision.  It's a huge, I think, obligation on the Palestinian leadership, and it's a very one they've proved incapable of doing until now, which is genuinely come to terms with the Jewish people's belongingness to this part of the world and to their right to self determination. It's a core aspect of the difficulty in addressing this conflict. And having said all that, I think we as Israeli Jews also have an obligation to offer that positive vision. In my mind, there is nothing wrong with articulating an aspiration you're not sure you can realize, or you don't even know how to realize. But simply to signal that is the direction that I'm going in, you know?  I mean Prime Minister Netanyahu, for example, talks about that he wants the Palestinian people to have all the power to govern themselves and none of the power to threaten Israel. Which is a way of saying that the Palestinian people should have that capacity of self determination that gives them the potential for peace, prosperity, dignity, and security, But not if the purpose of that is to essentially be more focused on destroying Israel than it is on building up Palestinian identity. Now that I think, can be articulated in positive terms, without denying Israel's connection to the land, without denying the Jewish people's story, but recognizing the other. And yes, I think despite all the difficulties, victory in war is also about what you want to build, not just what you want to destroy. And in that sense, our ability to kind of frame what we're doing in positive terms, in other words, not just how we want to take away the capacities of the extremists, but what we want to build, if we had partners for that, actually helps create that momentum. So I would just say to Dr Ali's point that, I think that's a shared burden on all of us, and the more people that can use that language, it can actually, I think, help to create the spaces where things that feel not possible begin to maybe become possible. Manya Brachear Pashman:   Which in many ways Trump's 20 point plan does that. It doesn't just only talk about disarming Hamas. It talks about rebuilding Gaza. Are there other ways in which Israel can assure the success of the Palestinian people and push forwards. Can you envision other ways? Tal Becker:   Well, I mean, I'm sure there's lots that people can do, but there is a burden on the Palestinian people themselves, and I do find that a lot of this discourse kind of takes agency away from the Palestinian people and their leadership. In a way, there's a kind of honesty to the Trump plan and the Security Council resolution that was adopted endorsing the plan that has been missing for quite a while. The Trump plan, interestingly, says three things.  It says, on this issue of a kind of vision or pathway. It says, first of all, it basically says there is no Palestinian state today, which must have come as a bit of a shock for those countries recognizing a Palestinian state. But I think that is a common understanding. It's a little bit of an illusion to imagine that state.  The second thing is how critical it is for there to be PA reform, genuine reform so that there is a responsible function in Palestinian governing authority that can actually be focused on the welfare of its people and govern well.  And the third is that then creates a potential pathway for increasing Palestinian self-determination and moving potentially towards Palestinian statehood, I think, provided that that entity is not going to be used as a kind of terror state or a failed state. But that, I think, is a kind of honest way of framing the issue. But we don't get around Manya the need for responsibility, for agency. So yes, Israel has responsibility. Yes, the countries of the region have responsibilities.  But ultimately, the core constituency that needs to demonstrate that it is shifting its mindset and more focused on building itself up, rather than telling a story about how it is seeking to deny Jewish self determination, is the Palestinian leadership. And I do think that what's happening in Gaza at least gives the potential for that.  You have the potential for an alternative Palestinian governance to emerge. You have the potential for Hamas to be set back in a way that it no longer has a governing role or a shape in shaping the agenda. And I think if we can make Gaza gradually a success story, you know, this is a bit too optimistic for an Israeli to say, but maybe, maybe we can begin to create a momentum that can redefine the Israeli Palestinian relationship. Manya Brachear Pashman:   So I asked what can Israel do to move forward to assure the Palestinians that they are behind their success and thriving? What can Israel do to make sure that it's respected, that is not facing the challenges from the West, from that region. What can Israel do? What is Israel's obligation, or is that an unfair question, to ensure its success and its moving forward? Tal Becker:   I think it's a really difficult question, because the criticism that Israel has gotten throughout this war and the threats to its legitimacy in the way that they've erupted, I think, is a really complicated phenomena that has many moving parts. So some part of it, I think, rightly, is about Israeli policy and Israeli language and the way it has framed what it has been doing, and really the unbelievable moral dilemmas that the war in Gaza posed, and how Israel conducted itself in the way of those dilemmas. And people can have different views about that.  I think there's a misunderstanding, very significantly, of the nature of the battlefield and how impossible Hamas in its deliberate kind of weaponization of the civilian population, made that. So there's one component that has to do with Israel. There's another component that we can't ignore, that has to do with antisemitism. And that, I think, for that group right who almost define themselves through their hostility towards the Jewish people and towards the very idea of Jewish self determination, it's hard to think anything that Israel says or does that actually matters, right? These were the people who were criticizing Israel even before it responded.  And so in that sense, I think putting too much on Israel is a problem. Maybe I'll just focus on the area that I think is most interesting here, and that is, in my view, a lot of the argument about Israel in the West, we'll take the US, for example, is actually not an argument about Israel, but more an argument about the US that is channeled through Israel. In other words, a lot of people seem to be having their argument about America's story of itself channeled through their argument about Israel. And what they're actually arguing about is their vision of America.  And you can see different versions of this. There's a story of America as perhaps a kind of white Christian country that was exploited by immigrants and is exploited by other countries in the world, and that narrative kind of tends pushes you in a direction of having a certain view, in my view, mistaken, in any event, about Israel. That is more to do about your story of America than it has anything to do with what Israel is doing or saying. And then you hear this very loudly, and I'm not suggesting these are exactly even.  But on the more radical kind of progressive left, you have a story of America as essentially a country that never came over the legacy of slavery, a country that has to kind of apologize for its power, that it sees itself as a colonial entity that can't be redeemed. And when you're kind of locked in that version of America, which I kind of think is a kind of self hating story of America. Then that then projects the way you view Israel more than anything Israel says or does. So this has a lot to do with America's, and this is true of other countries in the West, that internal struggle and then the way different actors, especially in the social media age, need to position themselves on the Israel issue, to identify which tribe they belong to in this other battle.  So in my view, people who care about the US-Israel relationship, for example, would be wise to invest in this, in the battle over America's story of itself, and in that sense, it's less about Israeli public diplomacy and less about Israeli policy. It's much more about the glasses people wear when they look at Israel. And how do you influence those glasses? Manya Brachear Pashman:   I could sit here and talk to you all day, this is really fascinating and thought provoking. I do want to ask two more questions, though, and one is, I've been harping on what can Israel do? What are Israel's obligations?  But let me back up a step. What about the Arab states? What are the other neighbors in the region obligated to do to assure the Palestinians that they're going to succeed and thrive? Tal Becker:   Yeah, I mean, it's a really important question and, and I think that for many, many years, we suffered from, I would say, a basic lack of courage from Arab states. I'm generalizing, but I hope that others would advance their interests for them. And in some sense, I think the Abraham Accords really flipped that, because Abraham Accords was the Arab states having the courage and the voice to say, we need to redefine our relationship with with Israel, and in that way, create conditions, potentially for Palestinians to do, to do the same.  I would say that there are a whole set right, and, not my position to kind of be the lecturer, and each country is different in their own dynamics. I think the first from an Israeli perspective, of course, is to really push back against this attempt to delegitimize the Jewish people's belonging in the Middle East, and not to allow this kind of narrative where the only authentic way to be a Palestinian or a Muslim is to reject the idea that other peoples live in the region and have a story that connects them to it, and Israel is here to stay, and it can be a partner. You can have disagreements with it. But the idea that it's some kind of illegitimate entity, I think, needs to be taken out of the lexicon fundamentally. I think a second area is in really this expectation of Palestinian especially in the Israeli Palestinian context, of being partners in holding the Palestinians accountable not to have the kind of the soft bigotry of low expectations, and to really recognize Palestinian agency, Palestinian responsibility and also Palestinian rights, yes, but not in this kind of comic strip, victim villain narrative, where Israel has all the responsibilities and the Palestinians have all the rights. My colleague, Einat Wilf, for example, talks about Schrodinger's Palestine. You know, Schrodinger's Cat, right? So Schrodinger's Palestine is that the Palestinians are recognized for rights, but they're not recognized for responsibilities. And Israel has rights and responsibilities. And finally, I would say in terms of the the taking seriously the spoilers in the region, and working with Israel and with our partners to make sure that the spoilers in the region don't dictate the agenda and don't have the capacity to do so, not just hoping that that, you know, Israel and the US will take care of that, but really working with us. And I think a few countries are really stepping up in that regard. They have their own constraints, and we need to be respectful of that, and I understand that.  But I think that, you know, this is a strategic partnership. I sometimes joke that with the Emirates, it's a Jewish and a Muslim state, but it's a Catholic marriage. We've kind of decided to bind together in this kind of strategic partnership that has withstood these last two years, because we want to share a vision of the Middle East that is to the benefit of all peoples, and that means doing kind of three things at once. Meaning confronting the spoilers on the one hand, investing in regional integration on the other, and seeing how we can improve Israeli Palestinian relations at the same time. So working in parallel on all three issues and helping each other in the process and each other thrive. I mean, there's a whole bunch of stuff beyond the conflict. There's, you know, AI and fighting desertification and irrigation and defense tech and intelligence, and a whole host of areas where we can cooperate and empower each other and be genuine partners and strengthen our own societies and the welfare of our own peoples through that partnership for ourselves, for each other and for the region. So there's a lot to do. Manya Brachear Pashman:   And my last question – I've asked, what do the Arab states need to do? What does Israel need to do? What do Jewish advocates around the world need to do?  Tal Becker:   So I think the most important thing at this moment for me, Manya, is courage. There is a danger, because of the rise in antisemitism and the kind of hostility that one sees, that Jews in particular will become more silent. And they'll kind of hide a little bit in the hope that this will somehow pass them. And I think what our history has taught us, is generally, these are phenomena that if you don't stand up against them early, they become extremely powerful down the line, and you can't, and it becomes very, very costly to confront them.  So it takes courage, but I would say that communities can show more courage than individuals can, and in that sense, I think, you know, insisting on the rights of Jews within the societies in which they live, fighting for those kind of societies, that all peoples can prosper in. Being strong advocates for a kind of society in which Jews are able to thrive and be resilient and prosper, as well as others as well. I think is very important.  Just in a nutshell, I will say that it seems to me that in much of the world, what we're seeing is liberalism being kind of hijacked by a radical version of progressivism, and nationalism being hijacked by a version of ultra-nationalism. And for Jews and for most people, the best place to be is in liberal nationalism. Liberal nationalism offers you respect for collective identity on the one hand, but also respect for individual autonomy on the other right. That's the beautiful blend of liberal nationalism in that way, at least aspirationally, Israel, being a Jewish and democratic state, is really about, on the one hand, being part of a story bigger than yourself, but on the other hand, living a society that sees individual rights and individual agency and autonomy. And that blend is critical for human thriving and for meaning, and it's been critical for Jews as well. And so particularly across the diaspora, really fighting for liberal national identity, which is being assaulted from the extremes on both sides, seems to me to be an urgent mission. And it's urgent not just for Jews to be able not to kind of live conditionally and under fear and intimidation within the societies they live, but as we've seen throughout history, it's pretty critical for the thriving of that society itself.  At the end of the day, the societies that get cannibalized by extremes end up being societies that rot from within. And so I would say Jews need to be advocates for their own rights. Double down on Jewish identity, on resilience and on literacy, on Jewish literacy. At the same time as fighting for the kind of society in which the extremes don't shape the agenda. That would be my wish. Manya Brachear Pashman:   Making liberal nationalism an urgent mission for all societies, in other words, being a force for good. Tal Becker:   Yes, of course. Manya Brachear Pashman:   Our universal mission. Thank you so much. Thank you so much for sharing all of these thoughts with us and safe travels as you take off for the next destination. Tal Becker:   Thank you very much, Manya. I appreciate it. Manya Brachear Pashman:   As we approach the end of the year, and what a year it's been, take some time to catch up on episodes you might have missed along the way, rewind and listen to some of my more memorable interviews, such as my conversation with former Israeli hostage Shoshan Haran, abducted with her daughter, son in law and grandchildren during the Hamas terror attack on October 7, 2023. Meet doctors or hen and Ernest Frankel, two MIT professors who amid anti Israel academic boycotts, are trying to salvage the valuable research gains through collaboration with Israeli scholars. And enjoy my frank conversation with Jonah Platt, best known for playing Fiyero in Broadway's wicked who now hosts his own hit podcast Being Jewish with Jonah Platt. Hard to believe all of this and more has unfolded in 2025 alone. May 2026 be peaceful and prosperous for us all.  

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JCO Editor-in-Chief Dr. Jonathan Friedberg is joined by colleagues Dr. Jennifer Woyach, Dr. Wojciech Jurczak, and Dr. Matthew Davids to discuss simultaneous publications presented at ASH 2025 on pertibrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Jonathan Friedberg: I'm Jonathan Friedberg, editor of Journal of Clinical Oncology, and welcome to JCO After Hours, where we are covering two manuscripts that were presented at the American Society of Hematology meeting 2025 in Orlando, Florida. I am delighted to be joined by colleagues on this call to discuss these pivotal manuscripts which cover the topic of pirtobrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. I will first just introduce our guests, Dr. Woyach. Dr. Jennifer Woyach: Hi, my name is Jennifer Woyach. I am from the Ohio State University. Dr. Wojciech Jurczak: Hello, I am Wojciech Jurczak, working at the National Research Institute of Oncology in Krakow, Poland. Dr. Matthew Davids: Hi, I am Matthew Davids from Dana-Farber Cancer Institute in Boston. Dr. Jonathan Friedberg: We are going to start by just learning a little bit about these two trials that were both large, randomized phase 3 studies that I think answered some definitive questions. We will start with your study, Jennifer. If you could just describe the design of your study and the patient population. Dr. Jennifer Woyach: Absolutely. So this is the BRUIN CLL-314 study, and this is a phase 3 randomized trial of pirtobrutinib versus ibrutinib in patients with CLL or SLL who had not previously been treated with a covalent BTK inhibitor. The patients were both treatment-naive and relapsed/refractory, about one-third of the patients treatment-naive, the rest relapsed/refractory, and they were stratified based upon 17p deletion and the number of prior lines of therapy. The primary objective was looking at non-inferiority of overall response rate over the entire treated population as well as the relapsed/refractory patient population. Key secondary objectives included progression-free survival in the intention-to-treat and the smaller relapsed/refractory and treatment-naive populations. Dr. Jonathan Friedberg: And just comment a little bit on the risk of the patients. Dr. Jennifer Woyach: This study was fairly typical of this cohort of patients. Within the relapsed/refractory patient population, there was a median of one prior line of therapy in each of the groups, up to nine prior lines of therapy in the patients included on the study. For the overall cohort, about two-thirds of the patients were IGHV unmutated, about 15% had 17p deletion, 30% had TP53 mutations, and about 35% to 40% had a complex karyotype, which is three or more abnormalities. Dr. Jonathan Friedberg: And what were your findings? Dr. Jennifer Woyach: Regarding the primary outcome, which is the focus of the publication, we did find that pirtobrutinib was indeed non-inferior and actually superior to ibrutinib for overall response rate throughout the entire patient population and in both the relapsed/refractory and treatment-naive cohorts. PFS is a little bit immature at this time but is trending towards also being significantly better in pirtobrutinib-treated patients compared with ibrutinib-treated patients. Probably most significantly, we found this to be the case in the treatment-naive cohort where there was a striking trend to an advantage of pirtobrutinib versus ibrutinib. Dr. Jonathan Friedberg: And the follow-up that you have on that progression-free survival? Dr. Jennifer Woyach: So we have about 18 months follow-up on progression-free survival. Dr. Jonathan Friedberg: The second study, Wojciech, can you just go through the design and patient population that you treated? Dr. Wojciech Jurczak: Thank you, Dr. Friedberg, for this question. So the BRUIN CLL-313 study was, in fact, the first phase 3 study with pirtobrutinib in exclusively untreated CLL patients. It was a randomized study where we challenged pirtobrutinib versus bendamustine-rituximab. At the time we designed the protocol, bendamustine-rituximab was an option as a standard of care, and Bruton tyrosine kinase monotherapy was used far more commonly than nowadays. The primary target of the study was progression-free survival. We took all untreated patients except for those with 17p deletions. Therefore, it is a good representation for intermediate risk. We had about 60% of the population, 56 to be precise, which was unmutated, evenly distributed into two treatment arms. 17p deleted cases were excluded, but we had about 7% and 8% of TP53 mutated patients as well as about 11% and 7%, respectively, in the pirtobrutinib and bendamustine-rituximab arm of patients with complex karyotype. The progression-free survival was in favor of pirtobrutinib and was assessed by an independent review committee. What is important is that the progression-free survival of the bendamustine-rituximab arm was actually similar to the other studies addressing the same questions, like the comparison with ibrutinib in the ALLIANCE study or zanubrutinib in the SEQUOIA study. What was different was the hazard ratio. In our study, it was 0.20. It was one of the longest effect sizes noted in the frontline BTK study. It represented an 80% reduction in progression-free survival or death. If we compare it to ibrutinib or zanubrutinib, it was 0.39 and 0.42 respectively. Presumably, this great effect contributed towards a trend of overall survival difference. Although survival data are not mature enough, there is a clear trend represented by three patients we lost in the pirtobrutinib arm versus 10 patients lost in the bendamustine-rituximab arm. This trend in overall survival is becoming statistically significant despite the fact that there was a possibility of crossover, and effectively 52.9 patients, which means 18 out of 34 patients relapsing in the bendamustine-rituximab arm, were treated by pirtobrutinib. Dr. Jonathan Friedberg: I am going to turn it over to Matt. The question is: why study pirtobrutinib in this patient population? And then with these two studies, how do you find the patients that were treated, are they representative of people who you see? And do you see this maybe being approved and more widely available? Dr. Matthew Davids: I think in terms of the first question, why study this in a frontline population, we have seen very impressive data with pirtobrutinib in a very difficult-to-treat population of CLL patients. This was from the original BRUIN phase 1/2 study where most of the patients had at least two or three lines of therapy, often both a covalent BTK inhibitor and the BCL2 inhibitor venetoclax, and yet they were still responding to pirtobrutinib. The drug was also very well tolerated in that early phase experience. And actually, we have seen phase 3 data from the BRUIN 321 study comparing pirtobrutinib to bendamustine and rituximab in a relapse population as well. So I think that really motivated these studies to look at pirtobrutinib as a first therapy. You know, often in other cancers of course, we want to use our best therapy first, and I think these studies are an initial step at looking at that. In terms of the second question around the patient population, these are pretty representative patient populations, I would say, for most frontline CLL studies. We see patients who are a bit younger and fitter than sort of the general population of CLL patients who are treated in clinical practice, and I think that is true here as well. Median age in the sort of mid-60s here is a bit younger than the typical patients we are treating in practice. But that is not different from other CLL frontline studies that we have seen recently, so I think it makes it a little bit easier as we kind of think across studies to feel comfortable that these are relatively similar populations. Dr. Jonathan Friedberg: How do you see this either getting regulatory approval or potentially being used compared to current standard of care options? Dr. Matthew Davids: So my understanding is that both of these trials were designed with registrational intent in the frontline setting, and they are both positive studies. That is certainly very encouraging in terms of the potential for an approval here. We have seen in terms of the FDA recently some concerns around the proportion of patients who are coming from North America, and my understanding is that is relatively low on these two studies. But nonetheless, the datasets are very impressive, and so I think it is certainly supportive of regulatory approval for frontline pirtobrutinib. Dr. Jonathan Friedberg: I will ask Jennifer a question. The control arm in your study was ibrutinib, and I think many in the audience may recognize that newer, second-generation BTK inhibitors like acalabrutinib and zanubrutinib are more frequently used now if monotherapy is decided. How do you respond to that, and how would you put your results in your pirtobrutinib arm in context with what has been observed with those agents? Dr. Jennifer Woyach: Yeah, that is a great question. Even though in the United States we are predominantly using acalabrutinib or zanubrutinib when choosing a monotherapy BTK inhibitor, this is actually not the case throughout the entire world where ibrutinib is still used very frequently. The head-to-head studies of both acalabrutinib and zanubrutinib compared to ibrutinib have shown us pretty well what the safety profile and efficacy profile of the second-generation BTK inhibitors is. So even though we do not have a head-to-head study of acalabrutinib or zanubrutinib versus pirtobrutinib, I think, given the entirety of data that we have with all of the covalent BTK inhibitors, I think we can safely look at the pirtobrutinib arm here, how the ibrutinib arm compares or performs in context with those other clinical trials. And though we really can not say anything about pirtobrutinib versus acalabrutinib or zanubrutinib, I think we can still get a good idea of what might be the clinical scenarios in which you might want to choose pirtobrutinib. Dr. Jonathan Friedberg: And Wojciech, do you agree with that? Obviously, I think you have acknowledged that chemoimmunotherapy is rarely used anymore as part of upfront treatment for CLL. So, I guess a similar question. If you were to put the pirtobrutinib result in your study in context with, I guess, more contemporary type controls, would you agree that it is competitive? Dr. Wojciech Jurczak: Well, I think that that was the last study ever where bendamustine-rituximab was used as a comparator arm. So we should notice that smashing difference. Because if we look at the progression-free survival at two years, we have 93.4% in pirtobrutinib arm versus 70.7% in bendamustine-rituximab arm. Bendamustine-rituximab arm did the same as in the other trials, like ALLIANCE or SEQUOIA. Pirtobrutinib did exceptionally well, as pirto is not just the very best BTK inhibitor overcoming the resistance, but perhaps even more important for the first line, it is very well tolerated and is a very selective drug. Now, if we look at treatment-related adverse events, the discontinuation rate, they were hardly ever seen. If we compared the adverse events in exposure-adjusted incidence, literally all adverse events were two or three times higher in bendamustine-rituximab arm except for the bleeding tendency, which however was predominantly in CTCAE grade 1 and 2 with just 0.7% of grade 3 hemorrhage. Therefore, I think that we should actually put the best and the safest drugs upfront if we may, and pirtobrutinib is, or should be, the first choice if we choose monotherapy. Now, I understand that we are not presenting you the data of pirtobrutinib in combination with anti-CD20 or with BCL2 inhibitors, but that is to come. Dr. Jonathan Friedberg: Matt, how would you envision, were regulatory approval granted and this were an option, using this in the upfront patient population? Is there anybody who you would preferentially use this or start on this treatment? Or would this be something that you would tend to reserve for second line? Dr. Matthew Davids: So I would say that in general for most of my patients who would want to start with a continuous BTK inhibitor, I would still use a covalent BTK inhibitor, and I say that for a couple of reasons despite the very promising data from these studies. The first is that the follow-up for both of these phase 3 trials is still quite short, in the range of a median 18 to 24 months. And we know that CLL is a marathon, not a sprint, and these patients are going to probably be living for a very long time. And we do have much longer follow-up from the covalent BTK inhibitors, median of 10-year follow-up with ibrutinib and five to six years with zanubrutinib and acalabrutinib respectively. And you know, I do not think that the pirtobrutinib is going to fall off a cliff after two years, but on the other hand, I think there is a lot of value to long-term data in this disease, and that is why I think for most of my patients I would stick with covalent BTK inhibitors. But the other important factor that we need to consider is patients who are younger and may have many different CLL treatments over the years. We have to be very careful, I think, about how we sequence these drugs. We know right now that we can start with covalent BTK inhibitors and then subsequently patients will respond well to the non-covalent inhibitor pirtobrutinib in later lines of therapy. But right now we do not have prospective data the other way around. So how will the patients on these studies who progress on pirtobrutinib respond to covalent BTK inhibitors? We do not know yet. There have not been a lot of progression events, which is great, but we would like to see some data in that respect to feel more comfortable with that sequence. Now, I do think that particularly for older patients and those who have significant cardiovascular comorbidities, if they wanted to go on a continuous BTK inhibitor, I do think these data really strongly support using pirtobrutinib as the BTK inhibitor of choice in that population. In particular, the cardiovascular risks with pirtobrutinib seem to be quite low. I was very struck in the comparison with BR that the rate of AFib was equivalent between the two arms of the study. And that is really the first time we have seen that with any of these BTK inhibitors, no elevated risk of AFib in a randomized study. I think that is the population where it will get the most traction first, is the upfront, sort of older patient with significant cardiovascular comorbidities. And as the data from these studies mature, I think that we will start to see more widespread use of pirtobrutinib in the frontline setting. Dr. Jonathan Friedberg: Jennifer, I am just curious if you have any personal experience or heard anecdotally about after progression on pirtobrutinib the use of other BTK inhibitors and whether there is a growing experience there. Dr. Jennifer Woyach: I do not think that there is much clinical experience, you know, as Matt alluded to, it certainly has not been tested yet. There has been some data in relapsed CLL suggesting that in people who have resistance mutations to covalent BTK inhibitors after treatment with pirtobrutinib, sometimes those mutations go away. I think most of us are concerned that they are probably not actually gone but maybe in compartments that we just have not sampled, suggesting that sort of approach where you might sequence a covalent inhibitor after a non-covalent in somebody who had already been resistant probably would not work that well. But, you know, in this setting where people had never been exposed to a covalent BTK inhibitor before, we really have no idea what the resistance patterns are going to be like. We assume they will be the same as what we have seen in relapsed CLL, but I think we just need some longer follow-up to know for sure. Dr. Wojciech Jurczak: If I may confront Dr. Davids about the use of covalent BTK inhibitors upfront, well, I think that we should abandon the idea of using the first and the second and the third generation, at least if we don't have medical lines. If we endlessly block the same pathway, it is not going to be effective. So if pirtobrutinib gets approval in first, second line, we do not necessarily have to use it in the first line. I am not here in a position to defend that we should treat patients with pirtobrutinib upfront and not BCL2 time-limited regimen. However, the way I look at CLL patients when choosing therapy is not just how should I treat them now, but what would be the best regimen in 5, 10 years if I have to re-treat them. And in some instances, the idea may be that in this setting we would like to have a BTK inhibitor upfront to have a BCL2 inhibitor later to make it time-limited. Although I understand and I agree with Matthew that if we have an elderly, fragile population, then the charm of having a drug taken once a day in a tablet with literally few cardiovascular adverse events might be an option. Dr. Jonathan Friedberg: And I will give Matt the last word whether he wants to respond to that, and also just as a forward-looking issue, I know both investigators have implied that there will be future studies looking at combinations with pirtobrutinib, and if you have any sense as to what you would be looking for there. Dr. Matthew Davids: The field really is heading toward time-limited therapy for most patients, I would say. There is a bit of a discrepancy right now in the field between sort of what we are doing in academic practice and what is done sort of more widely in community practice. And so right now we are going to see evolving datasets comparing these approaches. We are already seeing data now from the CLL17 study with ibrutinib comparing continuous to time-limited venetoclax-based therapy, and we are seeing similar efficacy benefits from these time-limited therapies without the need for continuous treatment. And so that is where I think some of the future studies with pirtobrutinib combining it with venetoclax and other partners are so important. Fortunately, several of these studies are already ongoing, including a phase 3 trial called CLL18, which is looking at pirtobrutinib with venetoclax, comparing that to venetoclax and obinutuzumab. So I am optimistic that we are going to be developing these very robust datasets where we can actually use pirtobrutinib in the frontline setting as a time-limited therapy as a component of a multi-drug regimen. So far, those early data are very promising. Dr. Wojciech Jurczak: Perhaps last but not least, in a single center we have treated over 300 patients with pirtobrutinib. So eventually some of them relapsed. And I must say that our experience on BCL2 inhibitors, not just venetoclax but including sonrotoclax, are appealingly good. Therefore, by using pirtobrutinib even earlier, we do not block the efficacy of other compounds. Dr. Jonathan Friedberg: All right. Well, I want to thank all of our speakers. I also want to congratulate our two guests who presented these very influential papers at the ASH Annual Meeting, and chose to publish them in JCO, so we thank you for that, and Dr. Davids for your commentary - really appreciated. That is this episode of JCO After Hours. Thank you for your attention. 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. Wojciech Jurczak Consulting or Advisory Role: BeiGene, Lilly, Abbvie/Genentech, Takeda, Roche, AstraZeneca Research Funding: Roche, Takeda, Janssen-Cilag, BeiGene, AstraZeneca, Lilly, Abbvie/Genentech Dr. Jennifer Woyach Consulting or Advisory Role: Pharmacyclics, Janssen, AstraZeneca, Beigene, Loxo, Newave Pharmaceutical, Genentech, Abbvie, Merck Research Funding: Company name: Janssen, Schrodinger, beone, Abbvie, Merck, Loxo/Lilly Dr. Matthew Davids Honoraria: Curio Science, Aptitude Health, Bio Ascend, PlatformQ Health, Plexus Consulting or Advisory Role: Genentech, Janssen, Abbvie, AstraZeneca, Adaptive Biotechnologies, Ascentage Pharma, BeiGene, Lilly, Bristol-Myers Squibb, Genmab, Merck, MEI Pharma, Nuvalent, Inc., Galapagos NV, Schroedinger Research Funding: Ascentage Pharma, Novartis, MEI Pharma, AstraZeneca  

Joe talks about fair weather Conservatives, what was going on in Obama's DEA, Schrodinger's narco terrorist, and what our favorite Michigan representative is up toSee omnystudio.com/listener for privacy information.

– What about Schrodinger’s Shares? – What Estate Taxes apply to Australians investing in the USA? – Scott betrayed me! – If Bitcoin is just money, why buy it? – A Bitcoin question from a guide dog trainerSee omnystudio.com/listener for privacy information.

Schrodinger's blowjob and the curious case of the Epstein files flip flop.Bannon's Epstein ties and the gayest thing in the world.Ratcheting up the crank.The only winning move against the machine is to not play.J.D. Vance's rise to power helped by an actual gay vampire.Sumo's neighborhood witch.Sumo's fight with Tani, when given opportunities people don't say no to the system. Self-righteousness is your sin.A Lutheran goblin man and the It.Sumo tries to make the show not X-rated.Mother HateGodward and a real Jew join the podcast.Becoming a Jew, Sedevacantism, the fault of logic, voluntary rape.The Red Pill, what is it?Pre-marital sex, sexual ethics and throwing dildos around the street.A litany of degeneracy.How to talk to your kids about things, don't force anyone to take the red pill. Living your time in the cave.Can there be a solution?A bit of ending Flat Earth talk.Support the showMore Linkswww.MAPSOC.orgFollow Sumo on TwitterAlternate Current RadioSupport the Show!Subscribe to the Podcast on GumroadSubscribe to the Podcast on PatreonSubscribe to the Podcast on BuzzsproutBuy Us a Tibetan Herbal TeaSumo's SubstacksHoly is He Who WrestlesModern Pulp

This is only a preview of the delights contained herein.  Phil McDuff is back for some Labour Catharsis and (mostly) coherent yelling as we efficientise the cast, look back on the Schrodinger's Coup, and the New Statesman does some Noticing. . How on earth are we ruled by people this mediocre? Subscribe for two whole bonus episodes a month: https://www.patreon.com/praxiscast  Watch streams: https://www.twitch.tv/praxiscast Buy shirts: https://praxiscast.teemill.com/ Follow Phil: https://bsky.app/profile/mcduff.bsky.social Cast: David - https://bsky.app/profile/sanitarynaptime.bsky.social Rob - https://bsky.app/profile/trufflehog.bsky.social  

Qasem Waleed is a 28-year-old physicist who has lived in Gaza his whole life. In 2024, he joined a chorus of Palestinians sharing videos and pictures and writing about the chaos and violence they were living through, as Israel's military bombardment devastated their lives. But Qasem was trying to describe his reality through the lens of the most notoriously confusing and inscrutable field of science ever, quantum mechanics. We talked to him, from a cafe near the Al-Mawasi section of Gaza, to find out why. And over the course of several conversations, he told us how this reality-breaking corner of science has helped him survive. And how such unspeakable violence actually let him understand, in a visceral way, quantum mechanics' most counter-intuitive ideas. Special thanks to Katya Rogers, Karim Kattan, Allan Adams, Sarah Qari, Soren Wheeler, and Pat WaltersEPISODE CREDITS: Reported by - Lulu MillerProduced by - Jessica Yungwith mixing help from - Jeremy BloomFact-checking by - Emily Kreigerand Edited by  - Alex NeasonEPISODE CITATIONS:Videos - A Brief History of Quantum Mechanics with Sean Carroll, The Royal Institution (https://www.youtube.com/watch?v=5hVmeOCJjOU)Introduction to Superposition, with MIT's Allan Adams (https://www.youtube.com/watch?v=lZ3bPUKo5zc)The Quantum Wavefunction, Explained (https://www.youtube.com/watch?v=sOI4DlWQ_1w)Articles - Read a selection of Qasem's published essays about his life in Gaza and the quantum world: I am stuck in a box like Schrodinger's in Gaza (https://zpr.io/ALDVi9E5bRt8) Israel has turned Gaza's summer into a weapon (https://zpr.io/YS4WK4hVQC5T)The Physics of Death in Gaza (https://zpr.io/hxsgxicVqPAd) Signup for our newsletter!! It includes short essays, recommendations, and details about other ways to interact with the show. Sign up (https://radiolab.org/newsletter)!Radiolab is supported by listeners like you. Support Radiolab by becoming a member of The Lab (https://members.radiolab.org/) today.Follow our show on Instagram, Twitter and Facebook @radiolab, and share your thoughts with us by emailing radiolab@wnyc.org.Leadership support for Radiolab's science programming is provided by the Simons Foundation and the John Templeton Foundation. Foundational support for Radiolab was provided by the Alfred P. Sloan Foundation.

This conversation delves into the life and legacy of Francis Crick, co-discoverer of the DNA structure. Dr. Matthew Cobb, the guest, explores Crick's multifaceted personality, his poetic inspirations, collaborative nature, and his later pursuits in consciousness. The discussion also touches on the controversies surrounding his work, particularly regarding the contributions of Rosalind Franklin, and reflects on Crick's complex character, blending modern scientific thought with outdated socio-political ideas.Takeaways Crick's story is often simplified to his DNA discovery. He had a deep appreciation for poetry and its connection to science. Collaboration was a key aspect of Crick's success. His early life was marked by average academic performance. Crick's transition to biology was driven by a desire to understand life. The discovery of DNA was a complex, collaborative effort. Controversies exist regarding the ethics of scientific discovery. Crick's later work focused on the nature of consciousness. He had a unique blend of intuition and logical thinking. Crick's outdated socio-political views contrast with his scientific modernity.Chapters 00:00 The Legacy of Francis Crick 01:13 Introduction to Matthew Cobb and His Book 03:43 The Influence of Francis Crick 06:19 Crick's Unique Approach to Science 07:19 Crick's Early Life and Self-Perception 10:04 The Impact of Naval Service on Crick 12:34 Crick's Transition to Biology 15:06 The Role of Schrodinger's Work 17:26 The Dynamic Between Watson and Crick 20:13 The Discovery of the Double Helix 23:02 The Controversy of Rosalind Franklin's Contribution 28:23 The Diplomatic Row and Pauling's Mistake 29:38 The Discovery of DNA's Structure 34:31 Crick and Brenner's Collaboration 38:41 Crick's Exploration of Consciousness 43:03 Crick's Complex LegacyFollow Matthew on Twitter, and find his new book here.Subscribe to Breaking Math wherever you get your podcasts.Follow Breaking Math on Twitter, Instagram, LinkedIn, Website, YouTube, TikTokFollow Autumn on Twitter, BlueSky, and InstagramBecome a guest hereemail: breakingmathpodcast@gmail.com

Welcome back to another episode of the Online Warriors Podcast! Happy Halloween! This week were going to revisit Schrodinger's Cat Burglar! We'll get an inside look at the development of Schrödinger's Cat Burglar.   Schrödinger's Cat Burglar - Tell us a about yourself - I understand you're an animator turned game designer, so kind of walk us through your personal journey a little bit? (0:54) - When developing the game, did you start with the story and character animations, or did you jump right into the programming and let the game sort of build itself? (3:57) - Do you have any personal attachment to cats or animals in general that might have influenced the creation of Mittens? (5:23) - The game clearly suggest heavy use of quantum physics. Beyond the classic Schrodinger's cat example, did you find yourself really studying this topic to deepen your own understanding and then use that learning to create new challenges/ abilities? (6:18) - The demo gives players a taste of what's to come. What are you most excited about for players to experience in the full version of the game? (8:52) - Are there any other animals in the game like rats since they are common test subjects? Does lazy Susan have abilities for example? (10:31) - You started this project as a solo developer, but your team has grown over time. What were some pros and cons to working alone versus having a small team behind your work? (12:01) - So, you described some moments during the development process when you had to step back and rethink a design choice or direction. How did you approach making those tough decisions? (15:20) - *Schrödinger's Cat Burglar* allows for both couch and remote co-op. How did you approach designing the gameplay with multiplayer in mind, and what sort of challenges did that present? (18:11) - How did you approach designing the various puzzles in the game? What was the process of making them challenging but fair? (19:59) - For others interested in making their own game, any words of wisdom? (21:52) - Any last words he wants the listeners to know - when we might be able to expect a release date? (23:34)   Special shoutout to our Patreon Producers: Steven Keller and Loyd Weldy!   We'd like to thank each and every one of you for listening in every week. If you'd like to support the show, you can drop us a review on your favorite podcast platform or, if you're feeling extra generous, drop us a subscribe over at Patreon.com/OnlineWarriorsPodcast. We have three tiers of subscriptions, each of which gives you some awesome bonus content! As always, we appreciate you tuning in, and look forward to seeing you next week! Stay safe and healthy everyone! Find us all over the web: Online Warriors Website: https://www.onlinewarriorspodcast.com Online Warriors Twitter: https://twitter.com/onlinewarriors1 Illeagle's Twitter: https://twitter.com/OWIlleagle86 Nerdbomber's Twitter: https://twitter.com/OWNerdbomber Techtic's Twitter: https://twitter.com/OWTechtic Facebook: https://www.facebook.com/onlinewarriorspodcast Instagram: https://www.instagram.com/onlinewarriorspodcast/ YouTube: https://www.youtube.com/channel/UCwOwzY6aBcTFucWEeFEtwIg Merch Store: https://onlinewarriorspodcast-shop.fourthwall.com/

A screencast from Chapter 3 in CH 221 entitled “Schrodinger and the Four Quantum Numbers”

What happens when you fall into a black hole? Neil deGrasse Tyson and Chuck Nice give us the step-by-step on spaghettification, explain Schrodinger's cat, and explore quantum tunnelling… Or do they? NOTE: StarTalk+ Patrons can listen to this entire episode commercial-free here: https://startalkmedia.com/show/things-you-thought-you-knew-quantum-cat/Thanks to our Patrons Peter Nguyen, Noah Narh, Oliver Anderson, Oleksandr, TULAKAR JHA, Marziee, Carmen, Erica Trebesch, Joan Cotkin, Steve, Kevin, renee porter, Knatrueall Phliights, Jacque Walker, ThatOofcaGuy, Ian Ulsh, Robert Vest, Oslo Johnson, Colin T, Patricia Brennan, Mac Lamken, Josh, Derek Holiday, ShieldsGaming18, Adam Gotch, Mike Starnes, Ryan, AnJ, William Rosati, Chris Ose, Becker the Brewer, Jennings.Bass, LAZU, Alissa Wilson, Logical Haus, Dave Blair, Brad, Kaleo Hubert, soogun shongwe, Caleb Pelletier, Toby Murray, McGrumps the Curmudgeon, Joshua, Knutte Söderberg, Albert Dávid, Jim Prescott, John Wooters, Chris Raines, neoghaleon, Roy Roddey, PJ, TC, Micheal Bartmess, Arwa, Hasemano, Brian Thompson, Stetson, Goerc Goerc, Dennis Shields, Spike, Ian Hebert, Kasheia Williams, Tess, Aren Moy, Robert, LittleBoBliue, Paul, Rick Hanes, Donivan Porterfield, Tony Smith, Penny B, Brett R, Nicholas Falvey, and Stymie Sulik for supporting us this week. Subscribe to SiriusXM Podcasts+ to listen to new episodes of StarTalk Radio ad-free and a whole week early.Start a free trial now on Apple Podcasts or by visiting siriusxm.com/podcastsplus. Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

A tale of two dentists. Foiled again by luxurious packaging, Amy unwittingly buys geriatric floss from her once beloved brand, Cocolab (shame! shame! shame!). Melissa puts her own spin on Schrodinger's Cat with Asperger's Periodontist, aka her local tooth shop staffed by Drs. Butterfingers and Vacusuck. The story, you guys. I can't. Just play it. Trust me.  It's thooooooooorrrrrrroooooouuugggggghhhhhh. All this ya whore, on today's Brilliant Observations. 

Join the crew of Adam, Tyler, Jason, and Justin as they talk through the back-end of Season 1 of Stargate SG-1 with "Singularity", "Cor-ai", "Enigma", and "Solitudes". Among other things, they grapple with being played like a damn fiddle, the Nuremburg defense, Schrodinger the Cat, space simps, and hypothermia. Please consider donating to the National Network of Abortion Funds: abortionfunds.org/donate If you've been enjoying the podcast, please consider supporting us at https://www.patreon.com/DeepListens If you like our new art and want to commission some of your own, reach out to Tyler at tylerorbin.net

Firms like Recursion and Schrodinger are using artificial intelligence to model how drugs work, reducing the need for lab testing on animals. Learn more about your ad choices. Visit podcastchoices.com/adchoices

JCO PO author Dr. Alison M. Schram at Memorial Sloan Kettering Cancer Center shares insights into her JCO PO article, “Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors.” Host Dr. Rafeh Naqash and Dr. Schram discuss relevant genomic and clinical features of patients with BRCA-altered uterine sarcoma and the efficacy of PARPis in this population. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and associate professor at the OU Health Stephenson Cancer Center. Today, we are excited to be joined by Dr. Alison Schram, Associate Attending Physician and Section Head of Oral Therapeutics with Early Drug Development and Gynecologic Medical Oncology Services at the Memorial Sloan Kettering Cancer Center, and the senior author of the JCO Precision Oncology article titled, "Retrospective Analysis of BRCA-Altered Uterine Sarcoma Treated With Poly(ADP-ribose) Polymerase Inhibitors." At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Schram, thank you for joining us today. I am excited to be discussing this very interesting, unique topic based on what you published in JCO PO. Dr. Alison Schram: Thank you for having me. Dr. Rafeh Naqash: What we like to do for these podcasts is try to make them scientifically interesting but at the same time, keep them at a level where our trainees and other community oncology professionals understand the implications of what you've published. So I'd like to start by asking you, what is leiomyosarcoma for those of us who don't necessarily know a lot about leiomyosarcoma, and what are some of the treatment options for these uterine sarcomas? Dr. Alison Schram: Uterine leiomyosarcoma is a rare subtype of uterine cancer, and it represents about 1% of all female cancers in the reproductive tract. This is a rare malignancy that arises from the myometrial lining of the uterus, and it is generally pretty aggressive. In terms of the standard therapy, the standard therapy for uterine leiomyosarcoma includes chemotherapy, generally combination chemotherapy, but despite a few regimens that tend to be effective, the duration of effectiveness is relatively short-lived, and patients with advanced uterine leiomyosarcoma eventually progress and require additional therapy. I will say that localized uterine leiomyosarcoma can be treated with surgery as well. Dr. Rafeh Naqash: Thank you for that description. Now, there are two aspects to what you published. One is the sarcoma aspect, the leiomyosarcoma, and the second is the BRCA mutation. Since we are a precision medicine journal, although we've discussed BRCA a couple of times before, but again, for the sake of our listeners, could you highlight some of the aspects of BRCA and PARP sensitivity for us? Dr. Alison Schram: Yes. So BRCA is a gene that's important for DNA repair, and BRCA mutations can be either inherited as a germline mutation, so one of your parents likely had a BRCA mutation and you inherited one copy. In patients who have an inherited BRCA mutation, the normal cells tend to have one abnormal copy of BRCA, but if a second copy in the cell becomes altered, then that develops into cancer. And so these patients are at increased risk of developing cancers. Specifically, they are at an increased risk of developing ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, and a few others. These cancers are considered BRCA-associated tumors. Alternatively, some patients, more rarely, can develop BRCA-altered cancers completely sporadically. So it's a mutation that happens in the tumor itself, and that can lead to impaired DNA repair and promote cancer progression. And those patients are not, they don't have any inherited risk, but just a random event caused a BRCA mutation in the tumor. The reason this is important is because, in addition to it being potentially important for family members, there are certain treatments that are more effective in BRCA-altered cancers. And the main example is PARP inhibitors, which are small molecule inhibitors that inhibit the PARP enzyme, and there is what we call synthetic lethality. So PARP is important for DNA repair, for single-stranded DNA repair, BRCA is important for double-stranded DNA repair, and in a patient that has a cancer that has a BRCA mutation, that cancer becomes more reliant on single-stranded DNA repair. And if you inhibit it with a PARP inhibitor, the cancer cells are unable to repair DNA, and the cells die. So we call that synthetic lethality. PARP inhibitors are FDA approved in several diseases, predominantly the BRCA-associated diseases I mentioned: breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. Dr. Rafeh Naqash: That was very beautifully explained. Honestly, I've heard many people explain BRCA before, but you kind of put it in a very simple, easy to understand format. You mentioned this earlier describing germline or hereditary BRCA and somatic BRCA. And from what I gather, you had a predominant population of somatic BRCA, but a couple of germline BRCA as well in your patient population, which we'll go into details as we understand the study. You mentioned the second hit on the germline BRCA that is required for the other copy of the gene to be altered. In your clinical experience, have you seen outside of the study that you published, a difference in the sensitivity of PARP for germline BRCA versus a somatic BRCA that has loss of both alleles? Dr. Alison Schram: So we will get into what's unique about uterine sarcomas in just a minute. In uterine sarcomas, what we have found is that the BRCA mutations tend to be somatic and not germline, as you mentioned. That is in contrast to the other diseases we mentioned, where the vast majority of these tumors are in patients that have germline BRCA alterations. So one thing that's really unique about the uterine sarcoma population and our paper, I believe, is that it is demonstrating an indication for PARP inhibitors in a population that is not characterized by germline BRCA alterations, but truly these by somatic BRCA alterations. If you look at the diseases that PARP inhibitors are validated to be effective in, including the, you know, the ones I mentioned, the BRCA-associated tumors, there's some data in specific context that suggests that perhaps germline alterations are more sensitive to PARP inhibitors, but that's not universal, and it's really tricky to do because the genetic testing that we have doesn't always tell you if you have two hits or just one hit. So you need more complex genetic analysis to truly understand if there is what we call a biallelic loss. And sometimes it's not a second mutation in BRCA. Sometimes it's silencing of the gene by hypermethylation or epigenetics. Some of our clinical trials are now incorporating this data collection to really understand if biallelic loss that we can identify on more complex genetic testing predicts for better outcomes. And we think it's probably true that the patients that have biallelic loss, whether it be germline or somatic biallelic loss, are more likely to benefit from these treatments. That still needs to be tested in a larger cohort of patients prospectively. Dr. Rafeh Naqash: In your clinical experience, I know you predominantly use MSK-IMPACT, but maybe you've perhaps used some other NGS platforms, next-generation sequencing platforms. Have you noticed that these reports for BRCA alterations the report mentioning biallelic loss in certain cases? I personally don't- I do lung cancer, I do early-phase lung cancer as well, but I personally don't actually remember if I've seen a report that actually says biallelic loss. So after this podcast, I'm going to check some of those NGS reports and make sure I look at it. But have you seen it, or what would be a learning point for the listeners there? Dr. Alison Schram: Exactly. And they usually do not. They usually do not explicitly say, “This looks like biallelic loss,” on the reports. The exception would be if there's a deep deletion, then that implies both copies of the gene have been deleted, and so then you can assume that it's a biallelic loss. But oftentimes, when you see a frameshift alteration or a mutation, you don't know whether or not it's a biallelic loss. And you may be able to get some clues based on the variant allele frequencies, but due to things like whole genome duplication or more complex tumor genomics, it's not clear from these reports, and you really do need a more in-depth bioinformatic analysis to understand whether these are biallelic or not. So that is why I suggest that this really needs to be done in the context of a clinical trial, but there is definitely a theoretical rationale for reporting and treating patients with biallelic losses perhaps more so than someone who has a variant of unknown significance that seems to be monoallelic. The other tricky part, as I mentioned, is the fact that there could be epigenetic changes that silence the second copy, so that wouldn't be necessarily evident on a DNA report, and you would need more complex molecular testing to understand that as well. Dr. Rafeh Naqash: Sure. Now, going to your study, could you tell us what prompted the study, what was the patient population that you collected, and how did you go about this research study design? Dr. Alison Schram: It's actually a great story. I was the principal investigator for a clinical trial enrolling patients regardless of their tumor type to a combination of a PARP inhibitor and immunotherapy. And this was a large clinical trial that was being done as a basket study, as I mentioned, for patients that have either germline or somatic alterations with advanced solid tumors that had progressed on standard therapy. And the hypothesis was that the combination of a PARP inhibitor and immunotherapy would be synergistic and that there would be increased efficacy compared to either agent alone and that patients who had BRCA alterations were a sensitive population to test because of their inherent sensitivity to PARP inhibitors and perhaps their increased neoantigen burden from having loss of DNA repair. So this large study, it's been published, really did show that there was efficacy across several tumor types, but it didn't seem to clearly demonstrate synergy between the immunotherapy and the PARP inhibitor as compared to what you might expect from a PARP inhibitor alone, and in addition to a couple of cases, perhaps attributable to the immunotherapy. So maybe additive rather than synergistic efficacy. However, what really struck me looking at the data was that there were three patients with uterine leiomyosarcoma with BRCA deletions who had the best responses of anyone on the study. So incredible, durable responses. One of my patients with a complete response that continues to not have any evidence of cancer eight years after the initiation of this regimen. And for those of us that treat uterine leiomyosarcoma, this is unheard of. These patients generally, as I mentioned, respond, if they do respond to chemotherapy, it's generally short-lived and the cancer progresses. And so a complete response nearly a decade later turns heads in this field. The other interesting thing was that these uterine leiomyosarcoma patients had somatic alterations rather than a germline alteration with a second hit, and the diseases that are best validated for being responsive to PARP inhibitors include the BRCA-associated diseases, the ones that you're at increased risk for if you have a germline BRCA mutation, including breast, pancreas, prostate, and ovarian. And so it was very interesting that this disease type that seemed to be uniquely sensitive to PARP inhibitors with immunotherapy was also different in that patients with uterine leiomyosarcoma don't tend to have a high frequency of BRCA alterations, and in patients that are born with a BRCA alteration, there doesn't seem to be a clearly increased risk of uterine sarcomas. So this population really jumped out as a uniquely sensitive population that differed from the prior indications for PARP inhibitors. Given this patient and these couple of patients that we observed on the combination, in addition to some other case reports and case series that had started to come out in small numbers, we wanted to look back at our large cohort of patients at Memorial Sloan Kettering to see if we could really get a better sense of the numbers. How many patients at Sloan Kettering with uterine sarcomas have BRCA alterations? Are they generally somatic or germline? Are there unique features about these patients in terms of their clinical characteristics? How many of them have received PARP inhibitors, and if so, is this just luck that these three patients did so well, or is this really a good treatment option for patients with BRCA-altered uterine sarcomas? And so we did this retrospective analysis identifying the patients at Sloan Kettering who met these criteria. So in total, we found 35 patients with uterine sarcomas harboring BRCA alterations, and the majority were leiomyosarcoma, about 86% of them had leiomyosarcoma, which is interesting because there are other uterine sarcomas, but it does seem like BRCA alterations tend to be more often in the leiomyosarcomas. And 13 of these patients with uterine leiomyosarcoma were treated with PARP inhibitors in the recurrent or metastatic setting with about half of those patients having an overall response, so that's a significant tumor shrinkage that sustained, and a clinical benefit rate of 62%. And if we look at the patients that had these BRCA2 deep deletions, which was the patient I had that had this amazing response, the overall response rate jumped to 60% and the clinical benefit rate to 80%. And we defined clinical benefit rate as having maintained on the PARP inhibitor without evidence of progression at six months. So this is really impressive for patients with a difficult to treat disease. And we couldn't do a randomized controlled trial comparing it to chemotherapy, but looking retrospectively at outcomes on chemotherapy studies, this was very favorable, particularly because many of these patients were heavily pretreated. So to get a sense of, you know, how this might compare to chemotherapy, we tried to use patients as their own internal controls, and we looked at how long patients were maintained on the PARP inhibitor as compared to how long they were on the treatment just prior. And we used a ratio of 1.3 to say if they were on the PARP inhibitor for 1.3 times what their previous treatment was or longer, that is pretty clearly better, more of a benefit from that regimen. And the majority of patients did meet that bar. So 58% had a PFS ratio greater than 1.3, and the average PFS ratio was 1.9, suggesting, you know, you would expect the the later lines of therapy to actually not work as well, but this suggests that it's actually working better than the immediately prior line of therapy, to me, suggesting that this is truly a good treatment option for these patients. Dr. Rafeh Naqash: Very interesting. And you mentioned that individuals with tumors having deep deletions were probably more responsive. How did you figure out that there was biallelic loss or deep deletions? Was that part of an extended analysis that was done subsequently? Dr. Alison Schram: So the deletions reported on our report, if it's a biallelic deletion, that is the one biallelic molecular alteration that would be reported. So those are, by definition, biallelic, and I think that that may be one of the reasons that's a good biomarker. But also, what's interesting is that if you have both copies deleted of BRCA, you can't develop reversion mutations. So one of the the known mechanisms of resistance to PARP inhibitors in patients who have BRCA alterations are something called a reversion mutation where, if you have a frameshift alteration, for example, in BRCA that makes BRCA protein nonfunctional, you can develop a second mutation that actually puts the DNA back in frame, and a functional protein is now made. And so a mechanism of resistance to PARP inhibitors is actually reverting BRCA to a wild-type protein, and then BRCA's synthetic lethality no longer makes sense and is no longer effective. But if you've deleted both copies of BRCA, you don't have the ability to restore the function, and you can't develop reversion mutations. And that's perhaps why, you know, my patient and others have had these prolonged responses to PARP inhibitors because you don't have the same ability to develop that mechanism of resistance. Dr. Rafeh Naqash: I remember thinking a year and a half back, I had an individual with prostate cancer and with BRCA2, and using liquid biopsy, I had a reversion mutation that we caught. In your practice, have you seen the utility of doing the serial liquid biopsies in these individuals to catch these reversion mutations? Dr. Alison Schram: Yes, absolutely. And in patients that have the ability to develop a reversion mutation, serial cell-free DNA can catch it, but the caveat is that it doesn't always. So if you see an acquired reversion mutation in cell-free DNA, that can be helpful, particularly if you're planning on putting the patient on another line of therapy that might require a dysfunctional BRCA. So if you're putting them on a clinical trial with a PARP combination and the rationale is that they're sensitive because they don't have a functional BRCA, you would want to know if they developed a reversion mutation, and serial cell-free DNA can definitely identify these reversion mutations. Some of the major clinical trials in ovarian cancer have done serial cell-free DNA and have demonstrated the utility of that approach. The caveat is that some of these reversion mutations are not readily caught on cell-free DNA because they're more complex reversion mutations, or they're not, the part of the gene that develops the reversion mutation is not tiled on the panel. And so it doesn't always catch the reversion mutations. Also, depends on the cell-free DNA shedding, depends on the tumor volume and other factors. And we published a related paper of a patient, it was a really interesting case of a patient with prostate cancer who was on a PARP inhibitor and developed what appeared to be a single reversion mutation on one sample, had negative cell-free DNA, single reversion mutation in a tissue biopsy, and then developed disease progression. And we did an autopsy, and the patient kindly consented to an autopsy, and at the time of autopsy, there were 10 unique reversion mutations identified across 11 metastases. So almost each metastasis had a unique reversion mutation, and only one of them had been seen premortem on a tissue biopsy and not on a cell-free DNA. But that autopsy really drove home to me how much we're missing by doing clinical testing in real time and we really don't know the entire genomic complexity of our patients by doing single samples. And theoretically, cell-free DNA can catch DNA from all the metastases, so you might think that that would be a solution, and it definitely can catch reversion mutations that are not seen in a single biopsy, but you really need to do it all. I mean, you need to do the tissue biopsy sampling, you need to do cell-free DNA, and probably one cell-free DNA test is not enough. Dr. Rafeh Naqash: Thank you, again, for that very nice explanation. Now, one quick provocative question. I remember when I was training, the lab that I used to work in, they used to do a lot of phosphorylation markers for DNA damage response, like phospho NBS, RAD51. Have you seen anything of that sort on these biallelic BRCA mutations where tumors are responding, but they also have a very high signature on the phosphorylation side, and it may or may not necessarily correspond to HRD signatures, but have you noticed or done any of that analysis? Dr. Alison Schram: I think that it would be great to do that analysis. And some of the work we're doing now is actually trying to dig a little bit deeper in our cohort of patients to understand are these HRD-positive tumors? Does HRD positivity correlate with response to BRCA alterations? In terms of the functional assays, I would love to be able to do a functional assay in these samples. One of the challenges is that this was a retrospective study and many of the patients were previously treated as standard of care or off-label with these agents, and so we didn't have prospective tissue collection, and so we're really limited by the tissue that was collected as part of standard of care and the consent forms that the patient signed that allow us to do genomic and molecular testing on their samples. So, I think that is hopefully future work that we will do and others will do. Dr. Rafeh Naqash: Sure. Shifting gears to your career trajectory, I'd like to spend a couple of minutes there before we end the podcast. So Dr. Schram, you've obviously been a trailblazer in this space of drug development, early-phase trials. Can you give us a brief synopsis of your journey and how you've successfully done what you're doing and what are some of the things that drive you? Dr. Alison Schram: Well, thank you for saying that. I don't know if that's true, but I'll take the bait. I've been interested in oncology since college and was always very interested in not only the science of oncology but of course, treating patients. And in medical school, I did basic science research in a laboratory and it was very inspiring and made me want to do research in oncology in addition to clinical care. When I became an oncology fellow, I was presented with a very difficult question, which is, “Do you want to be a lab PI and be in the lab, or do you want to do clinical care and clinical research?” And I couldn't choose. I found a mentor who thankfully really had this amazing vision of combining the two and doing very early drug development, taking the data that was being generated by labs and translating it into patients at the earliest stage. So, you know, phase one drug development in molecularly targeted therapies. And so I became very interested as a fellow in early drug development and this ability to translate brand new molecular insights into novel drugs. And I joined the- at Sloan Kettering, there was the Early Drug Development, it was actually a clinic, it was called something different, and it was very fortuitous. My last year of fellowship, the clinic became its own service with the ability to hire staff at Sloan Kettering, and I was the first ever hire to our Early Drug Development Service. And that really inspired me to try and bring these drugs to patients and to really translate the amazing molecular insights that my colleagues here at Sloan Kettering are discovering, and you know, of course, at other institutions and in pharma. And you know, there 's been an amazing revolution in in drug development over the last several years, and I feel very grateful that I've been here for it. You know, I've been able to take the brilliant insights from my colleagues and put these drugs in patients, and I have the amazing privilege of watching patients in many cases that benefit from these treatments. And so I do mostly phase one drug development and molecularly targeted therapies, and truthfully, I am just very fortunate to be around such brilliant people and to have both patients and labs trust me to be able to deliver these new drugs to patients and hopefully develop better drugs that move forward through FDA approval and reach patients across the country. Dr. Rafeh Naqash: Thank you so much. That was very nicely put. And hopefully our trainees and junior faculty find that useful based on their own career trajectories. Thank you, Dr. Schram, for joining us today. Hopefully, we'll see more of your subsequent work in JCO PO. Thank you for giving us all these insights today. Dr. Alison Schram: Thank you for having me. Dr. 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/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Alison Schram Disclosures Consulting or Advisory Role Company: Mersana, Merus NV, Relay Therapeutics, Schrodinger, PMV Pharma ,Blueprint Medicines, Flagship Pioneering, Redona Therapeutics, Repare Therapeutics, Endeavor BioMedicines Research Funding Company: Recipient: Your Institution  Merus, Kura, Surface Oncology, AstraZeneca, Lilly, Pfizer , Black Diamond Therapeutics, BeiGene, Relay Therapeutics, Revolution Medicines,  Repare Therapeutics, PMV Pharma, Elevation Oncology, Boehringer Ingelheim Travel, Accommodations, Expenses Company: PMV Pharma 

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.Eli Lilly has invested $1.3 billion in a partnership with Superluminal, an AI/ML startup focusing on endocrine and cardiometabolic diseases to develop new small molecule obesity medications. Schrodinger has discontinued the development of an early-stage blood cancer drug after two patient deaths. Trump has delayed pharma tariffs citing other priorities. RFK Jr. has been criticized for canceling Barda contracts related to mRNA vaccine research, leading to more vaccine misinformation. Genscript announces a new era of innovation and trust. Other news includes Vedanta downsizing, Abata shutting down.

in this episode we talk about the Epstein list and rather if they exist or not!

Book your free discovery call directly, visit: www.robertjamescoaching.com Welcome to the OCD and Anxiety podcast with Robert James, where we explore the intriguing parallels between Schrodinger's cat thought experiment and the challenges faced by those struggling with OCD and anxiety. In this episode, Robert discusses the human tendency to seek certainty and how learning to live with uncertainty can actually foster freedom and resilience. Dive into a conversation about superposition, where holding two possibilities at once can sometimes feel like being stuck in a box. Learn how OCD feeds on the need for definitive answers and discover strategies to break free from this cycle. For those looking for support, Robert offers a Break Free from OCD program designed to help individuals reclaim control by navigating uncertainty more effectively. To learn more, a free discovery call is available through his website. Enjoy the episode and consider subscribing to stay updated on future insights Disclaimer: Robert James Pizey (of Robert James Coaching) is not a medical professional and is also not providing therapy or medical treatment. Robert James Pizey recommends that anyone experiencing anxiety or OCD to seek professional medical help straight away to get a medical opinion and rule out other conditions or illnesses. The comments and opinions as written on this site are simply that and are not to be taken as professional medical opinions. Robert James Pizey provides coaching, education, accountability and peer support around Anxiety through his own personal experiences.    

Send us a message! Really!This week on the Get More Smarter Podcast, the 2026 Primary field for Colorado Democrats up and down the ticket is getting crowded! And we've got a big announcement for you on what that means for the podcast! Then, are you a human being, with a body, and, skin, and organs, and stuff like that which needs occasional tending to? Well, your healthcare is about to get a lot more expensive, and most likely, not any better! Next, Schrodinger's Epstein Files are the scandal of the decade. Or they don't exist. Or...maybe BOTH, depending on whom you talk to. But one thing is certain: Donald J Trump is absolutely in them! Then, do recissions cause recessions? We're about to find out, unfortunately; Big Bird and your local public radio station are on the chopping block because of it. And finally, in a country that has seen some progress on fighting gerrymandering and making elections and democracy more fair, representative, and reflective of the will of the people, one part in one state says…to hell with all that, we want power! Can you guess who it is? Can you? 

Justin and William witness if women want to be pets, the tech job juggler, and the Coldplay Kiss Cam affair. Justin also reviews I Know What you Did Last Summer (2025).

When we ask C The Superior to present on a topic as our apprentice host, she always brings the research. She takes me through some of the premier Anime properties and their relationship to mythologies. Primarily Shintoism. But Taoism and Chinese myths are visited. Especially when we talk about how Goku and Dragonball Z is The Monkey King and Journey to the East!Along the way, there are the usual diversions and meanderings. Including a restatement on kung fu witches built like Baywatch in school girl uniforms. Do we find other mythological parallels? Why is Schrodinger referenced and what does this have to do with Pinocchio or Anime? 

Join Jordan, Commish, Pitt Girl, Canadian Correspondent Joey, Big Sky Brigit and Beth/Ghost Beth, along with our VP of Podcast Production Arthur. We discuss SEC Media Days, Aggie War Hymn for Sark? Brian Kelly's Grand Canyon vacation, Schrodinger's LSU Tiger, loved Diego Pavia's bowtie, SirPaul Cheeks, Rich Rod get General Booty too, the Bison is back for Indiana, Razzball's Most Terrifying Mascot's by State map, CUSA & Nebraska Furniture Mart, Robbing Home runs in the Home Run Derby, a portion of our interview with Big Sky Commish Tom Wistrcil and SUPER SICKO SPINNING SELECTION SEASON PREVIEW FORECAST: SSSSSPF aka the 5SPF for the Big Sky Conference and much, much more!!See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Hello!Today we talk about how the Epstein story and Schrodinger's client list has fractured the right and whether this might finally be the thing that ol' Donny Trump can't wriggle out of. And we talk about climate change and the floods on the east coast as Tyler puts back on his environmental studies professor hat. Enjoy! This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit goodbye.substack.com/subscribe

The Sams Report: Game Pass Profitability - Schrodinger Chimes In by Brad Sams

John discusses the news that the Justice Department and the FBI found no evidence that Jeffrey Epstein had a "client list" or that he blackmailed prominent associates. The findings contradict past statements from Attorney General Pam Bondi about an alleged list of Epstein clients. Then, he talks with Professor Corey Brettschneider about the troubling case of Kilmar Abrego Garcia and Trump's blatant defiance of due process, followed by the AAUP lawsuit challenging the administration's unprecedented crackdown on free speech. Also, they discuss how Trump's recent suspicious silence on the Epstein case is splitting the MAGA base and they examine whether ICE agents can finally be held accountable in court. Next, John interviews the DC Bureau chief and columnist for The Nation magazine - Chris Lehmann. They chat about his new book " The Money Cult: Capitalism, Christianity, and the Unmaking of the American Dream ". And rounding it out, Comedy Daddy AKA Keith Price returns to joke with John and listeners about pop culture and trending news.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Stephanie discusses the news that the Justice Department and the FBI found no evidence that Jeffrey Epstein had a "client list" or that he blackmailed prominent associates. The findings contradict past statements from Attorney General Pam Bondi about an alleged list of Epstein clients. She also talks about TACO Trump this time sending tariff letters to 7 countries and again extending the deadline. The duties threatened in the letters effectively match the 1st reciprocal tariffs Trump imposed on the countries back in April. Guests - Charlie Pierce and Brian Karem.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

✩ Audio Version ✩ ► https://superderekrpgs.com/hitpoint/ SOCIAL LINKS --------------------------------------------------- ✩ Derek ✩ ►Twitch: https://www.twitch.tv/SuperDerekRPGs►Bluesky: https://bsky.app/profile/superderekrpgs.com ►Youtube: https://www.youtube.com/@SuperDerek ►Discord: https://discord.me/superderek✩ Baku ✩ ►Twitch: https://www.twitch.tv/BakusanOG►Bluesky: https://bsky.app/profile/bakusanog.bsky.social ►Youtube: https://www.youtube.com/WeebSauce ►Discord: https://discord.me/ABC UPCOMING RELEASES --------------------------------------------------- ►PATAPON 1+2 REPLAYhttps://www.youtube.com/watch?v=1Fq_AalxmD0 GAME ANNOUNCEMENTS --------------------------------------------------- ►Atelier Resleriana: The Red Alchemist & the White Guardianhttps://www.youtube.com/watch?v=NdI_7oGdftg ►Little Nightmares IIIhttps://www.youtube.com/watch?v=v4e0_c1etSk ►Project Code Mhttps://www.youtube.com/watch?v=UHj4ms0mOeE ►Schrodinger's Callhttps://www.youtube.com/watch?v=FsCQq00bDFs ►Full Metal School Girlhttps://www.youtube.com/watch?v=-IVtzcKl89k ►Cats Awayhttps://www.youtube.com/watch?v=HGCIfckPzew ►Dear me, I was…https://www.youtube.com/watch?v=GKNlsV2z2bY ►Blood Messagehttps://www.youtube.com/watch?v=FAdXbf-gYyQ TIMESTAMPS---------------------------------------------------0:00:00 Welcome Back to Hit Point!0:01:11 Intro0:02:08 Baku how are you doing?0:03:29 Derek how are you doing? Updates & DLC Round-Up0:11:38 WitchSpring R Free DLC0:17:01 Chained Echoes DLC Ashes of Elrant - 07.August.20250:21:56 Rift of the Necrodancer DLCUpcoming Releases This Week 0:24:40 Patapon 1+2 Replay New Game Announced:0:28:11 Atelier Resleriana: The Red Alchemist & the White Guardian - 26.September.20250:36:10 Little Nightmares III - 10.October.20250:38:35 Project Code M0:46:06 Schrodinger's Call - 20260:49:39 FULL METAL SCHOOLGIRL - 23.October.20250:53:20 Cats Away - 10.July.20250:55:47 Der me, I was... - 20251:02:28 Blood Message Industry News:1:09:00 Alzara: Radiant Echoes canceled1:34:58 Bamco Showcase was on 02.July.20251:41:19 SEGA mistakenly reveals sales numbers1:46:08 Silent Hill Remake1:50:43 BitSummit the 13th1:55:54 Persona 5 Live ConcertResponding to Super Chats & Outro 1:59:55 Super Chat 1: Happy Sunday! I recently watched an old episode from years ago...2:00:37 Super Chat 2: Baku what is your personal game of the year so far? 2:05:37 Outro

We've long admired Schrodinger's cat here on ride, but today we're talking about two new scientific concepts - the Pavlovian dog and spontaneous generation. Mary Beth opens up about her time working in the service industry and Benny revisits Powell's candy shoppe (sp?).Please note that this episode may contain paid endorsements and advertisements for products and services. Individuals on the show may have a direct or indirect financial interest in products or services referred to in this episode.Sponsors:Head to crapeyewear.com to shop and use code RIDE at checkout for 20% off full priced items. Get 15% off your first order of $100 or more at hillhousehome.com with code RIDE15Article is offering our listeners $50 off your first purchase of $100 or more. To claim, visit ARTICLE.COM/RIDE and the discount will be automatically applied at checkout. Go to cokeurl.com/SimplyPOP to find out where you can try Simply Pop! Start paying rent through Bilt and take advantage of your Neighborhood Benefits by going to joinbilt.com/ride. Produced by Dear Media.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

(00:00-12:25) The Cardinal closer situation. Who closes if Helsley gets hurt or traded? Helsley's value. Matt Damon lip syncing in Euro Trip. Jackson tells us how to consume television. Prod Joe offering up a sweet little prize for today's E-Mail of the Day.(12:34-25:23) The F Troop theme song hasn't aged well. On this date in 2007. Schrodinger's cat. Did Tony die? If Helsley makes that save last night, are people more ope to Schrodinger's Cat?(25:33-35:15) Doug missed out on lots of primetime television. NHL Commissioner Gary Bettman not happy with Biz Nasty. Audio of Biz and Bettman talking about the no state tax in Florida. Why is Bettman so hated?See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

What happens when the ocean's deadliest creatures meet natural disasters? You get a podcast! And not just any podcast, but TGTBTM. This week, we tackle the SyFy cult classic, Sharknado, and honestly, we are long overdue for it. What drinking game did Devon play while watching this movie? Which student of Lukas' bested him in class over Schrodinger's cat? And what kind of care would a lava covered tarantula with 6 pack abs drive? Tune in this week to find out all this and more, but only on "The Good, The Bad, & The Movies"!P.S. Check out these links to stay connected with TGTBTMDiscord: https://discord.gg/rKuMYcKvYoutube: https://youtu.be/7NGI9sqJT0w

Shelley and I check out a cute little card game that's reminicent of Liar's Dice or Perudo Schrodinger's Cats by Heather and Christopher O'Neill, and Adriel Wilson recently re-published by AMIGO and then we pull a favorite off the shelf and add a new expansion: Barcelona with the Passeig de Gracia expansion by Dani Garcia from Board&Dice Thanks as always to our sponsor Bezier Games! You can support the podcast directly by becoming a sponsor www.patreon.com/garrettsgames OR you can check out our estensive list of games that no longer fit on our shelves, but belong on your table: https://docs.google.com/spreadsheets/d/16ovRDNBqur0RiAzgFAfI0tYYnjlJ68hoHyHffU7ZDWk/edit?usp=sharing  

Welcome back to another episode of the Online Warriors Podcast! This week we have a very special episode! The gets an inside look at the development of Schrödinger's Cat Burglar and covers some superhero news!   Schrödinger's Cat Burglar - Tell us a about yourself - I understand you're an animator turned game designer, so kind of walk us through your personal journey a little bit? (0:54) - When developing the game, did you start with the story and character animations, or did you jump right into the programming and let the game sort of build itself? (3:57) - Do you have any personal attachment to cats or animals in general that might have influenced the creation of Mittens? (5:23) - The game clearly suggest heavy use of quantum physics. Beyond the classic Schrodinger's cat example, did you find yourself really studying this topic to deepen your own understanding and then use that learning to create new challenges/ abilities? (6:18) - The demo gives players a taste of what's to come. What are you most excited about for players to experience in the full version of the game? (8:52) - Are there any other animals in the game like rats since they are common test subjects? Does lazy Susan have abilities for example? (10:31) - You started this project as a solo developer, but your team has grown over time. What were some pros and cons to working alone versus having a small team behind your work? (12:01) - So, you described some moments during the development process when you had to step back and rethink a design choice or direction. How did you approach making those tough decisions? (15:20) - *Schrödinger's Cat Burglar* allows for both couch and remote co-op. How did you approach designing the gameplay with multiplayer in mind, and what sort of challenges did that present? (18:11) - How did you approach designing the various puzzles in the game? What was the process of making them challenging but fair? (19:59) - For others interested in making their own game, any words of wisdom? (21:52) - Any last words he wants the listeners to know - when we might be able to expect a release date? (23:34) - Ironheart (26:59) - Superman (35:31) - Spider-Noir (42:58)   Then we talk about what the gang has been up to: - Techtic goes golfing and watches Drive Away Dolls (49:13) - Nerdbomber reads Empire of Storms and goes to brunch (52:36)   Special shoutout to our Patreon Producers: Steven Keller and Loyd Weldy!   We'd like to thank each and every one of you for listening in every week. If you'd like to support the show, you can drop us a review on your favorite podcast platform or, if you're feeling extra generous, drop us a subscribe over at Patreon.com/OnlineWarriorsPodcast. We have three tiers of subscriptions, each of which gives you some awesome bonus content! As always, we appreciate you tuning in, and look forward to seeing you next week! Stay safe and healthy everyone! Find us all over the web: Online Warriors Website: https://www.onlinewarriorspodcast.com Online Warriors Twitter: https://twitter.com/onlinewarriors1 Illeagle's Twitter: https://twitter.com/OWIlleagle86 Nerdbomber's Twitter: https://twitter.com/OWNerdbomber Techtic's Twitter: https://twitter.com/OWTechtic Facebook: https://www.facebook.com/onlinewarriorspodcast Instagram: https://www.instagram.com/onlinewarriorspodcast/ YouTube: https://www.youtube.com/channel/UCwOwzY6aBcTFucWEeFEtwIg Merch Store: https://onlinewarriorspodcast-shop.fourthwall.com/

Cover1's Anthony Prohaska joins us to look at everything the 2025 Draft gave us - TJ Sanders, Beane's on-air tirade, "Schrodinger's WR" & a look at how BBB'S approach to the position actually makes sense!

Today is recognized as World Quantum Day, an international event focused on raising awareness and understanding of quantum physics and technology. As we draw closer to Easter, the Christian resurrection story of Jesus can be seen as a major quantum entanglement. Christ is both dead and alive, crucified and resurrected. In Christian theology, Christ exists in states of contradictory duality. Moreover, the expression of the Godhead or the Holy Trinity bursts into real time - the genuine God in human flesh as one is forced to wonder about the aspect of the Divine Architect that exists outside of time and all linear restrictions. Tonight on Ground Zero (7-10 pm, pacific time on groundzeroplus.com), Clyde Lewis talks about QUANTUM EASTER - SCHRODINGER'S CHRIST. #GroundZeroPlus #ClydeLewis #Quantum #MandelaEffect #SchrodingersCat #easter

BOSSes Anne Ganguza and Andy Roth delve into the nuances of voice acting from the perspective of a seasoned casting director. They explore strategies for success in auditions, emphasizing the importance of authenticity and making genuine choices. Listeners will gain insights into the casting process, understanding the client's vision, and the significance of following instructions. The episode addresses the impact of AI on the industry while reinforcing the irreplaceable value of human connection and unique interpretation. Anne and Andy also discuss practical advice for creating compelling auditions, handling limited information, and cultivating a resilient mindset in the face of industry challenges.   00:04 - Anne (Host) Hey, what's up bosses? Join our VI peeps today and gain access to over 350 hours of pre-recorded workshops designed to enhance your voiceover skills. From industry insights to practical techniques, our workshops cover a wide range of topics. As a VI peeps member, you'll also receive a 15% discount on current workshops and free monthly workshops to keep your skills sharp. Don't miss out on this opportunity. Sign up for VI Peeps membership now at vopeeps.com    00:39 - Speaker 2 (Announcement) It's time to take your business to the next level, the boss level. These are the premier business owner strategies and successes being utilized by the industry's top talent today. Rock your business like a boss, a VO boss. Now let's welcome your host, Anne Ganguza.    00:58 - Anne (Host) Hey, hey everyone. Welcome to the VO Boss Podcast. I'm your host, Anne Ganguza, and today I am so excited to have a very special guest Andy Roth with me here today. Andy has a career that has spAnned three decades and he is an award-winning casting director, voice director, producer and writer and is known for you Would Do it Too, too Hot to Handle Valeria, the Animal People, the Forest, my gosh this list Andy is going on and the Peculiar Adventures of Willoughby Starr. He's also served as casting director on over a thousand commercials. That is a lot of commercials. So welcome to the podcast, Andy. It's so wonderful to have you.    01:40 - Andy (Host) Thanks, I'm excited to be here. Thank you.    01:43 - Anne (Host) Gosh, I met you not so long ago and I'm not quite sure why it took so long for me to meet you, but I thank Jessica Blue for introducing us because I feel like I've known you forever and you're just amazing and I want the bosses to know how amazing you are as well. And so let's talk about you and your long, spanning career of gosh over a thousand commercials and all these productions. It's amazing. How did you get started?    02:11 - Andy (Host) Honestly and yes, I think I have worked on more commercials than any human being should probably ever really be exposed to. I got started in this business actually back in 1994. A friend of a friend heard about an opening for an assistant at a talent agency which was called CED at the time. Now it's called CESD and it was in the voiceover department and so I became an assistant there, did that for several years, then became their in-house casting director and did that till 2007 and then left on my own and I actually I didn't even know when I started that voiceover was its own thing.    02:49 - Anne (Host) I was going to ask you, did you get the experience on the job as you were casting?    02:53 - Andy (Host) Yeah, like I mean, of course I always knew about commercial voiceover and animation and things like that, but I didn't know how vast it was until I was really in the heart of it and I just I fell in love with it.    03:05 - Anne (Host) I can't imagine. I mean and so how has the industry changed and evolved over the years?    03:10 - Andy (Host) for you, Well, it's gotten bigger. So many changes I mean, it's been 30 years since I went through a couple of strikes. It was the explosion of the non-union entity, which has become a whole other thing, of the non-union entity, which has become a whole other thing. Yeah, it's become its own area of the business. I've discovered that voiceover is anytime there's something new. Voiceover is the first thing there. Oh, how interesting. Anytime there's a new piece of technology, somebody wants to put a voice on it. Siri's a voiceover. Yeah, Alexa is a voiceover. Holograms have voiceovers. Augmented reality, virtual reality. When I started in this business, it was basically 13 chAnnels and people really mostly only cared about four of them. Yes, yes.    03:58 - Anne (Host) I hear you on that.    04:00 - Andy (Host) And then cable became a thing and you had this box with three numbers on it so you could have 999 chAnnels. And now with streaming, it's just icons. I mean it's unlimited. It goes on forever. And people have discovered content from other countries that's exploded and become a thing and voices are everywhere. We are the first area of the business to adapt and change and we're sticky Once we're in a place voiceover is just going to be there.    04:32 - Anne (Host) I love that. I love that, and especially because you've been in the industry for so long and we talked about, you know, the explosion, like the technology explosion too, I mean, with first it was all union, then non-union kind of came aboard, because of the pay to place, I'm sure, and the online casting, and now we're under the threat of AI. But I guess I'd love to hear your thoughts on that, because here you are with all these wonderful, hopeful things that you're saying about voiceover, which I love and I like to tell my bosses out there as well. I mean, I think there's always a place for human voiceover.    05:00 - Andy (Host) What are your?    05:00 - Anne (Host) thoughts on that.    05:02 - Andy (Host) I think there are certain areas of the business that may be a little safer from AI, especially animation. People love to go to cons to meet the voice of their character. You can't really replace that with AI. Is it 100% safe? Maybe not, but there are people dealing with it, fortunately, and AI does a lot of good things for the world too. I mean, I've seen programs where people who have no ability to speak can speak because AI helps them. It helps search engines. I mean there is definitely a place for AI. But as far as the possibility of replacing humans in this business, there are people out there that are concerned about it, that are helping, and fortunately they've been on it since it really became apparent it could be a thing. I'm optimistic. I'm realistic in that there will be some areas where AI is going to be there. It already is, but I'm very, very optimistic about protections.    06:02 - Anne (Host) Me too, me too.    06:03 I really am. There's a lot of people fighting and, with the strike going on, which you know, fingers crossed, people are listening. I mean, I think what it is is we have voices and hopefully they're being heard, because a lot of people out there, like back in the beginning, when I got into voiceover, like what is that? Even, and even when you said you started, like what is that? Even. I think bringing awareness to the global community about voiceover and what we do as creatives and how important the creative process is, I think is really impactful in helping get us protections as we move forward. And I am a tech girl and I believe there is a lot of space for AI in the world, but I also believe there's a lot of space for human and human engagement and human creativity and I think that people crave that, no matter how good. And let's talk about this because an AI voice is perfect, and so you and I also with my students, we talk a lot about like I don't want a perfect voice when I'm directing my students.    07:02 I mean I want to hear that imperfection because that makes it real and that makes me engage and connect with it. Let's talk a little bit about that, about really, what should voice actors be doing now to really separate themselves from the crowd and also from AI?    07:19 - Andy (Host) Well, honestly, being a presence having a discussion, you don't connect to AI the way you connect to another human when it reaches its pinnacle and it's really ready to go, which it's not totally now. But the good thing about AI is it's going to do whatever you ask it to do whenever you ask it to do it. The bad thing about AI is it's going to do whatever you ask it to do whenever you ask it to do it. There are some moments that have come out of projects I've worked on. I mean, I've voice directed I think like 22 shows now that are on the air. The great thing is you give a direction and the human being interprets it their way, and sometimes you're right on the money and you're really simpatico and it's exactly what I asked for. Thank you. Sometimes we figure things out together. Sometimes they come up with something they thought was what I asked for but was actually a lot better.    08:13 When you get two independent minds with human experience, with a life, with a history of interacting with other human beings, there's a thought process there that, at least at the moment and honestly, in my opinion, for the foreseeable future, can't really be duplicated. I mean, ai is intelligence, but it is artificial and we cast based on human interaction. We connect with roles we direct. This whole industry is built on human interaction. So, to a certain point, yes, ai can get things going and smooth out maybe some of the bumps, but it's not really going to be the base on which this industry is built for human beings to connect to other human beings. That being said, not everybody sees it this way, so be vigilant and be aware of it. But as far as how people can stand out honestly, the best way for people to stand out is to be themselves. There are a lot of people I know that send me auditions that I can hear they're trying to be what they think the right thing is. Yes, absolutely.    09:19 And if I've asked you to audition, you're already the right thing. I don't know if you'll get the job, but I know that you can do the job. And I've had auditions that people didn't book lead to other jobs that they didn't even audition for. That actually just happened on a show I am on right now. I cast somebody and he was like did I audition for this? I'm like well, sort of you auditioned, like two shows ago.    09:43 - Anne (Host) I love that. Yeah, I think that's very encouraging for those actors out there who it's such a personal thing, right.    09:50 When you submit an audition, it's so hard not to get personally attached to it or feel like, oh gosh, like I really, really want this, and but then you don't hear anything or you may never get feedback and then ultimately that is, I think, when people are first starting out in this industry. It's something very hard for them to kind of let go of because it is such maybe a personal connection. But I love that you're talking about bringing yourself and the human element to the audition, because that's really what makes you unique. I'll even tell my students, because I do a lot of work in the long format narration like corporate and e-learning, and most people feel like that shouldn't have like a point of view or a feeling, but most absolutely it does, because I tell people to think about like okay, if you're going to do an e-learning module like what was it when you were going to school that made someone your favorite teacher?    10:37 Like did you have a subject that maybe you hated, but then all of a sudden, the teacher was amazing and then that's what made it interesting. And that's the type of voice that I want to come out. And there's always a point of view in that, believe it or not, it's a point of view that says I care about you as a student, that I care that you learn, and so that comes through in the voice and if you're just reading the words, or even if you're just reading the words in the sound in which you hear them all the time, which typically is very robotic for a lot of e-learning, I go on and on about why that happened for so many years. Because nobody chucked us on it and nobody was an actual teacher.    11:09 And I say that because I was a teacher in front of the classroom for 20, some odd years. But still, even if you think in what you hear, I have so many students that say, but I hear it on the commercial, it sounds like this and I'm like, yeah, but that might not have been what got them cast. It might be at the moment that someone directed them to be. And even you, if I ask, if you're directing someone, do you not only sometimes have to like talk to the client to see?    11:33 if that's what the client is thinking is good, and even what you might be like, this is great. This actor's got it nailed. The client might want something different.    11:41 - Andy (Host) Well, I work with the actor for the client. The actor is sort of the most profound connection artistically. That's the relationship that ultimately creates a thing. But I do work for the client and ultimately what they want.    11:57 I kind of think of it like this: this is a hive mind and there's a queen bee somewhere in an office with a checkbook and the rest of us are workers trying to make sure the hive is ready before it rains. So I very, very much listen to the client, want to do what the client says. I'm very much back and forth with the client. If it's a dubbed show that I'm directing, I am constantly because I could get a read that I'm like that's brilliant, that's amazing, I love it. And then I'm like that's brilliant, that's amazing, I love it. And then I'm like let's compare it to the original, because if it doesn't match or do the same thing, I'm like I love it, but we have to shelve it and we have to do what the client wants.    12:34 - Speaker 2 (Announcement) But at the end of the day.    12:35 - Andy (Host) The client has built a container that they want filmed with humAnness and it is my job to fill it up, and that happens just through us connecting. Part of what I listen for on an audition is do I get you? And I don't mean like, are you a Pisces? Or something like that. I mean Long walks on the beach, right exactly Pina coladas getting caught in the rain, not that I have a problem with pina coladas or getting caught in theaters, or long walks on the beach.    13:05 - Anne (Host) Long walks on the beach.    13:06 - Andy (Host) Let's be fair, but I do feel like I want to feel like there's a human there, because that makes me feel like I know what's going to happen in the studio, and I don't want any of us to do more work than we absolutely have to do. I want us to connect, do something, play with it, do it again, move on, and it needs to be within the container that the client has given me to fill. Does that make sense?    13:29 - Anne (Host) Yeah, absolutely so. Then if there are casting specs, and someone is paying attention to the casting specs, which a lot of times. Casting specs sometimes seem fairly generic and sometimes not. How much should they be paying attention to that and trying to like create that versus bringing their most human self to that read?    13:49 - Andy (Host) Well, I will say this about casting specs and yeah, sometimes they kind of suck and I'm sorry about that, but they are designed to help you. They are coming from somebody's mind to kind of get you to the place where you can be you in the relevant context. Sometimes they're just not actable, sometimes they are a little generic, sometimes they're not understandable, but more often I think they are. And even if we don't realize every nuance, just reading them often will get us to an emotional place where we can be ourselves, because happy you is very different than sarcastic you or sad you or angry you. I say, always pay attention to them, always read them. But If you can't make a choice based on them, then maybe sort through or throw them away, but they are always there to help you.    14:42 I mean, I do know some people that are like, oh, I never read the specs. I don't think that's the best way to go. Sure, yeah, always. But I mean again, you don't have to be beyond completely throwing them away. They're garbage or they're just completely not you, but they weren't paying attention to. Also, sometimes we put things in there like naming conventions, if I say I want the file named role underscore full name.    15:12 And I get something that's named a different way Well before I've even listened to it. You've told me you don't really care what I have to say. So yeah, I would say, always pay attention to them.    15:21 - Anne (Host) I like how you turned that into the message right.    15:24 So a lot of people I'll be like I don't understand why I will have my students name files a particular way, because they submit their homework via Dropbox and they have to name it a certain way. And if they don't, I spend half of their session looking for their file and what happens is they seem to think I'm insane for asking them to name it a certain way. And I'm like, in reality, there's a method to my madness here. I mean because if you audition, you're going to have to name that file specifically the way they're asking, otherwise it's going to get tossed to the side. I like how you mentioned that. Yeah, you've already shown that you have respect for the process by naming the file correctly, and it shouldn't be a task to do that. And if it is a task, then I think maybe you should get some computer training that can help you to do that task and to pay attention, because that's part of our job when we're submitting.    16:14 - Andy (Host) I mean, you're going to name it something.    16:16 - Anne (Host) Yeah, exactly, why not name it what we're asked?    16:19 - Andy (Host) You're not just going to send me a file with nothingmp3. Also, I find that some of these rules, although they may not be the creative process, they may not be the most fun thing, they actually do help their creative process. I was talking to somebody who is an on-camera person. They're working on their own project and it's great. And I said have you ever interned or worked at a studio? You know, it's California, there's no shortage of them. If you can't intern, well, I think that that would get in the way of my creativity and I don't want to. And it's like okay, I understand that, because you'll be in their world with their creativity, but nobody writes a screenplay and says I can't wait to gaff this.    17:08 I'm so excited to hire security and craft services. Working at a place where all of these things are just laid out, where, okay, I have to get security, I have to get craft services, I have to go file permits, I have to do all this. Working at a place that's going to make the part you don't really want to do easy, is going to free you up to focus on the creative and it's actually going to make you creatively freer because, whether it's a horror movie or a romance or a comedy, getting a permit is getting a permit. It's the same and getting used to saying, okay, I know how they want to do this. It's the reason I have people name certain things is because often I want all characters grouped together.    17:44 - Anne (Host) Yeah, absolutely yeah. There's a good reason for that, yeah.    17:47 - Andy (Host) Right, and if yeah, like you said, if I have to go searching through it, you made my job harder finding you than it was for you. To just name it what I asked you.    17:55 - Anne (Host) Don't give you homework, like I shouldn't be giving you homework.    17:58 - Andy (Host) If I'm submitting an audition, it should not be homework for you to find it and to listen to it, and yeah, absolutely, and I just may not do it.    18:06 - Anne (Host) Yeah, exactly Because you know you're that student that sits in the back of the class. I mean, I already know this about you, having met you briefly, but those are the most fun students.    18:18 Those are the creative ones that usually you know they're geniuses in the back because they're causing all kinds of trouble, but you don't want to give your talent agent or your casting director or whoever it is you're submitting your audition to. You don't want to give them homework. So what other things would you recommend are strategies for maybe creating a great audition or getting to the humAnness and the point of view that you're looking for in terms of this is the actor I want to cast.    18:45 - Andy (Host) Don't try to get it right. Don't deliberately get it wrong, like if the role obviously needs you laughing. Don't cry uncontrollably to stand out, because you will stand out.    18:55 - Anne (Host) It's got to make sense.    18:56 - Andy (Host) Yeah, you will stand out, just not necessarily in the way that you want to, but being free. So many people hang so much on every audition it's like, oh, this is the job, and if I don't get this job I failed. And that's not true. Every audition can get you more auditions. An audition is really a way to establish or reaffirm a relationship, and you'll get opportunities and jobs in this business. For one reason Somebody wants you to have that opportunity, or that job.    19:30 It's not who you know in this business, it's who knows you. Ah, I like that in an audition. I mean there's nothing anybody can teach you that's going to guarantee you're going to book everything. But being yourself making simple choices, Okay, the first line is oh my God, I'm so happy, I'm going to make a simple choice, I'm going to smile, I'm going to be happy, I'm going to listen back to it, see if it needs more or less, maybe something else, but trying to be like what did they mean by? You know, let me stand out, let me get? You don't know enough at the audition point to stand out. You haven't heard the other auditions. You don't know about the conversations the casting director's having with the client. You don't know who else is cast. You don't know. You don't know any of the parameters. Sometimes somebody wants somebody who's done a million jobs because of a time frame or there's a relationship.    20:22 Sometimes we specifically don't want that person because that person has been heard on eight other projects. You don't know any of that. What you can know is that if we've reached out to you with an audition, it's because there's already something there that lets us at least believe we know who you are. I don't need some weird ethereal happy, I just need your happy. It's also not about not needing to be directed. It's about us getting you so we can ask can you be?    20:52 - Anne (Host) happier. Can you be less happy?    20:53 - Andy (Host) Yeah, keep it simple, there's a thing.    20:57 I call the four disagreements yeah, if you want to serve the script, don't worry about serving the script. If you want to get it right, don't worry about getting it right. If you want to play the moments, don't worry about playing the moments. And if you want to make the casting director happy, don't worry about making the casting director happy. Make the choice or choices that you feel are right for the script, for the context and any other information you may have.    21:23 Was somebody that I felt was really, really right for a role. I thought they were great, they were perfect for it. I read them, I gave my little write-up about why I thought they were terrific, sent it off. The director really, really liked them and it came down to that person and one other and the other person ultimately got it. That's what the director was feeling and it was a great person. I mean, the person who got it was terrific and I liked them and I worked with them all the time. But I was like, not the way I would have gone, but fine. So season two.    22:08 I ended up directing season two and I called this actor and I said do you mind if I submit you? And they said sure, what do you want me to read? I said I don't. I want to resubmit your audition from last season. And they said but it didn't get me the job. I said no, but there's different brains involved now and we'll see. And the person who booked it last time can't do it again because they did it last time and it's a different role. And I resubmitted it with the same write-up and they ended up getting a lead role. So we hang so much on everything that we micromanage, we microanalyze. Don't look for information you don't have and not going to have. Say this is what I feel is right. I'm not an idiot. I know the business, I know my choices are right. I sometimes book. I get asked to audition again. Do them, and I'm not going to say forget about it, because that's not always how brains work.    23:03 - Anne (Host) Try to forget about it. Yeah, exactly, don't let it mentally hassle with your yeah yeah, don't schedule an extra therapy session for it or anything. Yeah, exactly.    23:12 - Andy (Host) Yeah, I mean it'll be in your head and it's fine, but know that your audition is out there working for you. Just be you. Make simple choices, things you know you can do, things you feel are right and do them.    23:24 - Anne (Host) Now here's a question which I know is on a lot of people that are just getting into the industry, or students that are just getting into the industry. It's about the lack of. They're like the words are on the page and they don't make sense to the student, because they're talking about some visual that's probably already been done or it's in the process, or the person that wrote the copy knew what visuals were going to be along with it. But yet here's the copy, but yet no storyboard. There's no other information except for maybe like casting specs about oh, we want female age, blah, blah, blah, blah. And so then they're like well, how do I interpret this? How do I even because I'll okay, who are you? Who are you talking to? You know, create that scene. And when I'm just like well, look, as long as you're committed right, you're committed to those words and they make sense, you can make up whatever scene you want that allows you to be authentic and genuine with it.    24:15 And sometimes I'm very surprised at stuff that I've done. When I look at what comes out afterwards, I'm like whoa, okay, I didn't expect that. So why is that? Are we a step in the process where we don't get fed more information, like is there a reason why there's not more storyboards or there's not more you know what I mean information given at the time of the audition, or just curious?    24:36 - Andy (Host) I never asked anybody this and I will say this. It sometimes is as frustrating for me. I would love for the actor to have everything the actor needs, but sometimes you can't. Sometimes projects are secretive. Sometimes there actually is a storyboard. I'm just not allowed to tell you. Sometimes there's information about what show it is or what the product is. I remember when Apple first started advertising the iPhones and we were casting in person because it was a long time ago and we weren't even allowed to put iPhone on the door. We weren't even allowed. It would be secret product, you know, and people would be like oh, a phone that does stuff.    25:17 - Anne (Host) But we weren't allowed to say it.    25:19 - Andy (Host) So there'd be like on the door it would say like jet plane or freezer burn or just some random word, so you would know where you should go. I worked on a show recently where there were these athletes going to this really important game and one of them is looking out the window and it's starting to rain and he's nervous and he's like, wow, it's raining out there. And the coach looks at him and goes, yeah, but it's raining for the other team too. Whatever information you don't have, neither does anybody else.    25:54 Whatever problems you have, everybody else it's raining for the other team too Sure.    25:59 - Anne (Host) Sure, I love that. It's so nice for you to validate that you know, what.    26:03 - Speaker 2 (Announcement) I mean.    26:03 - Anne (Host) Because I think a lot of times people are like but why, how? Come I don't know anymore. Why can't?    26:07 - Speaker 2 (Announcement) I.    26:08 - Anne (Host) I said it's very rare in any of my jobs in all these years that I've ever gotten a storyboard. I mean after. I get it maybe I'll get a storyboard. There'll be times I'll get storyboards with a commercial audition, but I think it's gotten less over the years. Yeah.    26:23 - Andy (Host) You get what people feel you need, and they're not always right.    26:26 - Anne (Host) And a lot of times they change again. Yeah.    26:30 - Andy (Host) And it's very much. You get what you get. You don't get upset, but you will always have everything you need to do your job. You may not feel it, it may not be as much as you want, but it is enough to get you to a place where you can come up with specifics. Even if you make them up, you can come up with a.    26:50 - Anne (Host) I'm happy, I'm sad. I'm a wise ass.    26:53 - Andy (Host) This business. We do everything we can to give you everything you need to do your job and only be as specific as you can. Don't go to a place where you're making up a whole scenario so you can feel more complete as a performer that I'm not going to get. Does that make sense?    27:12 - Anne (Host) Yeah.    27:13 - Andy (Host) Know that when we send this out, we are ready to fill in these blanks in the job Right.    27:19 - Anne (Host) And usually, if I'm not mistaken, the voiceover is probably one of the tail end of the things to be filling in, or no Is? That not a correct Like. Usually the media is finished, the things have been written. Usually there's visuals somewhere along the line that have been made and then the last thing to be cast is a voice, but maybe not when we're talking on camera. I mean, that could be. That's a different part of the process.    27:40 - Andy (Host) Yeah, well, I mean, I would say probably, I mean anytime there's an actor involved. A lot of work has been done before. Yeah, before we even start talking to actors, and a lot of work's going to be done after the actors are gone. So, yeah, on camera, yeah, of course you're on set for a little bit longer probably than voiceover, but, yeah, often things are in place and we do our best to ask is that what you're saying? Yeah, yeah, absolutely yeah, yeah, but there's a lot that happens before anybody asked me to do anything.    28:12 - Anne (Host) There's a lot that happens before the mixer's involved or anything yeah, yeah, I think it's good to know that we're only one tiny piece of like an entire project and sometimes, I think, in our own little worlds. We tend to forget that in our booths right. We're like oh the voiceover is like front and center and in reality there's so many other components to probably creating this project or commercial or movie or whatever it is.    28:38 There's so many other parts and we get so wrapped up in just our part of it that I think we have to realize that we're just a cog in the wheel so to speak, it's an important cog I mean, the machine won't work without it. Exactly.    28:50 - Andy (Host) But we do mesh. It's a great analogy, metaphor simile, simile, it's a great simile. Yeah, right, I thought I was an English teacher. There you go, simile, there you go. Oh, I love it. I love it, it's a great, yeah, simile.    29:10 Yeah, because, like I said, we're all worker bees yes, yeah, I know that we have a lot of the same issues too. There's stuff I can't know, there are things I'm not allowed to be a part of, and there's a lot of processes. So, yeah, just do your job. Don't worry about what we want or what somebody else is looking for or somebody else is hiding. We're not, we're not hiding anything. We just need you to be you, to know what that cog is.    29:26 And again, I have anxiety attacks when I get a job, sometimes because there's just so much stuff I haven't gotten to sit down with it yet. I haven't seen a script, I don't have a cast. Sometimes I don't have all the episodes of a show or all the spots in the commercial campaign. There's a lot I don't know either. And I understand it can be isolating. It could feel lonely, you know, when you're alone in your booth it could feel like everybody's working more than you, everybody's auditioning more than you, everybody in the industry does have that. It's been a few weeks. Am I ever going to work again?    30:02 - Anne (Host) Do I belong in this industry? It just becomes very dramatic sometimes.    30:06 - Andy (Host) I state something. I offered a potato chip. Did that offend somebody? And we spiral out. Every single person involved does it. Oh, nice to know, I'm not alone, right, I mean, because even after all these, years.    30:20 - Anne (Host) Sometimes it's so hard not to get those thoughts in the way. I swear that, like everything that we do, sometimes it's so hard not to get those thoughts in the way I swear that, like everything that we do, is sometimes it's not a God given talent.    30:28 Well it is, but it's the most important thing, is our mental state about it all, because it can affect so much I mean the fact is is that we can just like let those feelings and ideas spin around in our head and be like oh my God, did I do something to offend? Am I good enough? Am I? You know all that talk in your head is the stuff that I think is probably some of the most dangerous talk and things that you could have as a voice actor.    30:52 - Andy (Host) Yeah, it's. It's like Schrodinger's audition the audition is simultaneously good, bad and not submitted. There you go.    31:02 - Anne (Host) I love it. Oh my goodness. So then I would say, with the thousands of commercials that you have directed or produced, what? Would you say, is the cast that you've cast? What's the best thing a talent can do? In hopes of maybe getting cast. And what's the worst thing that you've seen a talent do that wouldn't get them cast?    31:22 - Andy (Host) Yeah, I don't know that I'm going to say the worst thing.    31:24 - Anne (Host) Or yeah, maybe not a smart thing. So yeah, that kind of tends to be pretty specific to a person.    31:30 - Andy (Host) And if it's the worst thing I've seen, it means probably only one person did it and so I'm not going to tell, I would say, the most probably impractical thing that.    31:39 I've seen people do is be like, okay, I'm going to be the person who is going to get the job. I'm going to try to fool you into thinking that I'm the person you're really going to hire, and so I'll get a read and somebody's clearly doing this and it's like well, I know it's a car commercial, but I didn't ask for that and that person is available and they work for what you work for.    32:04 If I reached out to you, I don't want an impression of that person or people that change their voice into a better version of you know, it's like if I called somebody because they have a certain depth to their voice.    32:19 - Anne (Host) This is my voiceover voice, right, yeah?    32:21 - Andy (Host) And if I haven't asked you to do that and I might I mean there are things but if I haven't asked you to do that, don't do that. It may even turn into that at the end of the day.    32:32 - Anne (Host) Isn't that the truth, right? It may turn into that at the end. That's what. I end up getting is people be like. But I listened to the commercial and it sounds just like this and I'm like but that doesn't mean that that performance got you the job.    32:43 - Andy (Host) Yeah, I've had people come up to me. Andy, I heard that spot, I could have done that. Why didn't you ask me to do that? And I'm like is it your first day in the business, have you never? It's like nobody did that. The person who booked it didn't do that and the client liked the director is directing and they call the client and the client's like can we hit this word a little bit more? And I feel like we're not pushing.    33:07 - Anne (Host) Yeah, and I always say that the person who's actually making decisions like it depends on, like what they hear in their head, right. And maybe they're a 65 year old person that's been listening to announcery commercials all their lives and that's what they hear in their head. And that's what ends up getting directed, or whatever it is. I think our voices become a product of the years and years that we've had and your musical, I know this right Of hearing things right.    33:31 And so that's why when we go in and we say this is what we think you want to hear, because we're mimicking over a period of years that's why in our head there's a certain melody Also. I think there's a certain melody also. I think there's a scientific and tell me and if you think I'm right, I think there's a scientific like reason why people, when they read words, they read them in a melody. That's very expected, because I can tell you exactly like.    33:52 Here's a paragraph, I can mimic exactly what you're going to do. If you're not thinking about like acting and you're just thinking about reading along a melody, I know that melody already and it's funny because I'm right like 99.9% of the time with that melody. And what is that? That's a scientific study that you read words in a certain melody.    34:11 - Andy (Host) Well, I'm not a neuroscientist, Damn it Andy, why? Not, you're everything else. That was my fallback, that was plan B, just in case yeah, I mean you've got that medical background. But the brain doesn't think in words, the brain doesn't think in images. The brain thinks in little synaptic flashes, billions and billions and billions of them. You're sounding like a scientist, thank you.    34:36 Thank you very much For anybody who's like questioned me on that, which, fine, by all means question. My answer is what's the word that keeps you balanced? What's the word that keeps your heart beating? What's the? Your brain doesn't need words. Your brain just does little flashy things like a microchip. Your brain's basically a macrochip, holds, I think, about 10 terabytes of information and it processes it certain ways. So when you look at a word, it doesn't actually see a word, it sees an image that sparks a whole sequence of synaptic flashes. The people that organized those words in the form of a script or a book or whatever learned the language. The way you learned the language. They learned it by hearing it. And even if it's your second language, yeah, okay, maybe there's some schooling, but at the end of the day, you're really learning it conversationally, by hearing people do it. So your brain doesn't just process. Okay, this is this sequence of words with a dot or a line at the end of it, or a squiggle or something.    35:36 It actually processes the whole thing as a rhythm. The rhythm that was born into it will probably be the rhythm that comes out. And yeah, is it 100%? No, sometimes there's typos, sometimes things are weird, but it's also why, like, there's this thing online where there's a whole paragraph and every word has first, last and middle letter in the right place, but the rest of the words are just jumbled.    36:03 - Anne (Host) Oh yeah, and we know what that.    36:04 - Andy (Host) yeah, I've seen those and you can still read them, you can still get the rhythm, you can still do all that. So acting is a physics term is one of the things I say in my class. Acting is doing something that has an effect on a receiver. You say something, it affects somebody else. It hits a series of triggers. A script is the same thing. A script is a series of things that will trigger you in most cases, which?    36:30 is why somebody leaves a word out of a line. You often may not even notice that word's not there. Your brain's just going to put it in. So, yeah, exactly like you said, you're going to be right most of the time, because it is how your brain now thinks. And sometimes you won't be. But those are flukes. Those are rare. They do happen. They're. Certainly those will be the ones that we look at and focus on, because they're messed up and we'll use them to define ourselves. Oh, I'm terrible. How could I have made that mistake? But the truth is, usually things go right, and so trust yourself. It's why one of the four disagreements if you want to get it right, don't worry about getting it right.    37:11 Yeah, don't worry about getting it right, absolutely yeah, read it listen to it and, to be honest, if it's terrible, throw it away. Nobody's going to hear it.    37:18 - Anne (Host) Right, it's so funny. I remember when I was teaching in front of the class and I would get so excited. Sometimes, like my brain, I'd be like, oh, and I want to tell them about this, and then what would come out of my mouth sometimes didn't follow, because I was so excited, but the funny thing is is that I never once had a classroom that didn't forgive me for that, do you?    37:35 - Speaker 2 (Announcement) know what I mean?    37:36 - Anne (Host) Yeah, yeah, because I was so intent on sharing, and excited and passionate that they forgave the mistakes I made, and I truly believe that that's how you need to approach your copy, because it's more about how you're making me feel really. And, like you said, it's a series of synapses or reactions or the words are there to trigger something and so the acting is reacting, kind of thing.    37:59 And so that really needs to be built into all of your auditions, all of your performances in some form or fashion. And yeah, worrying about making it perfect is spending too much time worrying about making it perfect and not enough time worrying about how are you going to make someone feel or how are you going to engage with them and tell that story.    38:17 - Andy (Host) Yeah, it's not your job to not have a problem. It's your job to have a problem in a way that nobody else thinks it's going to become their problem. It's your ability to deal with it. Yeah, exactly, we worry about so much One of the things that I tell you have to do a do you can't, do a don't. I'm going to be happy. That's a do you can do that, I'm going to talk fast.    38:39 That's a do. I'm going to talk slow. I'm going to talk with an accent. I'm going to be really big or I'm going to be really small, I'm going to whisper Any of these things. These are things you can do. You can't do a don't. I don't want to be wrong is not a choice. I don't want to mess it up is not a choice. I'm trying to not be too fast, or I'm trying to not.    38:59 Those are not choices, those are don'ts. I would rather have you be too fast and ask you to slow down which is an inevitability of our relationship as director and actor anyway than have somebody who's delivering at the perfect pace but the copy is sounding like this and there's no humAnness to it. Cool, we learn more from our successes than our mistakes. HumAnness to it. Cool, we learn more from our successes than our mistakes. Everything you're good at, you've gotten good at by doing it right over, over, over, over over and sometimes messing it up, but being able to fix it because your brain knows what the right is. So whoever's listening to it or interacting with you in an audition is going okay. When they stumble, it's not going to be a big deal.    39:44 - Anne (Host) Yeah, exactly, we'll move on yeah.    39:45 - Andy (Host) Yeah, nobody cares.    39:46 - Anne (Host) I want the intent.    39:47 - Andy (Host) Yeah, nobody cares if you screw up, I mean, and the reality of it is is.    39:50 - Anne (Host) I mean unless you're being live directed right. I mean we're all human. Everybody understands that. If you're not and you're doing it later on, I mean good Lord, we can just edit it.    40:01 - Speaker 2 (Announcement) I mean, so if you stumble on a word.    40:03 - Anne (Host) I mean, we all do it. I'd love to speak perfectly 100% of the time, but I certainly don't. And so, yeah, we all make mistakes and so it's just you fix it. And so when I'm having somebody read for me live, I don't care if they stumble, I want their acting, I want to hear their acting. And if they stumble, it's okay because inevitably they're going to get it right. If I'm paying them $10,000 for the job, I mean they're going to go do it until they get it right.    40:25 And so if you're going to stumble in front of me, that's fine. I just want to feel you and hear you.    40:30 - Andy (Host) Yeah, just don't have a meltdown in front of me about it, don't beat yourself up, don't apologize. I want to be a director. I don't want to be a therapist.    40:39 - Anne (Host) You probably are for most of the time.    40:41 - Andy (Host) I don't want to. I don't want to do that. Yeah, I mean like people can go bleh, you know, and do a pickup. I don't mind a blip, that's huge. But I've seen people really like beat themselves up and feel like they're less than or feel like they're stupid I mess up words that I'm making up.    41:00 - Anne (Host) I mess up words when I talk in everyday conversation.    41:03 - Andy (Host) Yeah, yeah, and I don't even have a script, I'm just making that up. Yeah, exactly.    41:07 - Anne (Host) That's brain to mouth.    41:09 - Andy (Host) Oh, I screwed that up, yeah there's a lot that happens between synapse and noise and there can be a problem at any step of that process, so worry less about that, bosses. Yeah, worry less. There's a phrase that I hate practice makes perfect.    41:26 - Anne (Host) I mean, I don't know, if you say it, I'm sorry if you do, I probably. No, I don't okay. Good, I mean because it's never happened.    41:30 - Andy (Host) I mean, how long does something have to not happen before we stop acting like it's going to? The purpose of practice isn't to become some theoretical idea. The purpose of practice is to make you comfortable with the inevitability of your imperfection.    41:48 - Anne (Host) Yeah, I like that.    41:49 - Andy (Host) Yeah, you'll be reading a sarcastic role, or a happy role or an angry role. You'll be selling hamburgers or beer or a car. Scripts will change, attitudes will change, voices may change, but messing up a word and dealing with it doesn't. Yeah, yeah, you know that's the same. A typo, that doesn't change you. Getting mush mouth or dry mouth, that doesn't change. So the purpose of practice to get you comfortable with the fairly limited number of ways you're going to have a problem yeah, yeah, yeah yeah so that it's not a big deal.    42:23 I like that.    42:24 - Anne (Host) I'm always saying if there's a mistake in the script, and especially well, for me it makes sense because typically long-format narration scripts go through rounds and rounds of approvals, through like corporate hands and even like your stuff, I'm quite sure, goes through many hands of approval and so like, if you're going to be that actor that's going to point out a mistake in a script, no, don't be that actor.    42:44 Be the actor that reads it exactly the way it is but makes it sound like there's no mistake you know what I mean, that's your job is to make it sound beautiful, like, even if a word's missing or I mean if it's really really obvious then you just graciously. Hey, here's an alternate take, just. But don't ever like point out the mistake. Goodness gracious, no, nobody wants to be that person.    43:03 - Andy (Host) And if you have an opportunity to ask say is there a missing word? Sure, by all means, but sometimes you just don't have that opportunity. Sometimes you don't have an answer it's raining for the other team too.    43:14 - Anne (Host) Yeah, I love that. It's like that's such a great takeaway. That's such a great takeaway, that and just not worrying right and not worrying about being perfect, and I think that that has just been a wonderful takeaway and I feel like we need to have part one, two and three of this interview.    43:30 I would love that it's so wonderful. Thank you so much for chatting with me today and imparting those words of wisdom. Are you available, Like if people want to find out more about you? I mean, do you have a website? I mean, is it one of those things that people can reach out to you?    43:47 - Andy (Host) I do have a website. I have Andyrothcasting.com.    43:51 - Anne (Host) Okay.    43:52 - Andy (Host) Yeah, that is my website. I can't really always talk about things I'm working on, Of course. I mean almost everything is NDA, but things I've done are there. If I do have a class coming up or something, it's listed there.    44:03 - Anne (Host) And speaking of though, we do have a class coming up. I'm going to have you for my VO Peeps guest director guys. So boss is coming up.    44:11 Make sure you sign up, and I will say that when I met you at Mavo, you were doing a couple of classes and people were just raving about you and so, and they were really like taking a lot away from your classes. So I can't wait, I can't wait for you to be and you're going to be in. What did we decide? It was, oh my gosh, it's like May, may, march.    44:34 - Andy (Host) April, april or April or May, I don't know.    44:36 - Anne (Host) Peeps check the calendar because he's going to be here and Andy Roth, make sure you sign up, and I'm so excited for that.    44:44 - Andy (Host) Me too, me too. I'm really excited, and every opportunity to hang out and talk with you. Yay, I will take every one of those opportunities, awesome.    44:52 - Anne (Host) Well, hey, I can't wait to do this again. Thank you so much, thank you For being with me today, and a big shout out to my sponsor, ipdtl. You too, can connect and network like bosses. Find out more at IPDTLcom. Bosses, you have an amazing week. I just sounded Jersey. I think it's because I'm talking to you, Andy. I said bosses, have an amazing week and we'll see you next week. Bye, guys.    45:16 - Speaker 2 (Announcement) Join us next week for another edition of VO Boss with your host, Anne Ganguza, and take your business to the next level. Sign up for our mailing list at vobosscom and receive exclusive content, industry revolutionizing tips and strategies and new ways to rock your business like a boss. Redistribution with permission. Coast-to-coast connectivity via IPDTL. 

This week, Mary and Chappell discuss episode 7 of Extracted.

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The haphazard release of the Epstein files by so-called government influencers is an apparent hoax and looks like another one of those bait and switch situations where we have to call it for what it is- a sort of Schrodinger documents play. The records include redactions performed by prosecutors on the case to protect the identities of potential victims. Also published is Epstein's so-called "black book" that has previously been made public. Brace yourselves- it is all theater. It is all a distraction, and so many people are falling for it. Tonight on Ground Zero (7-10 pm, pacific time on groundzeroplus.com), Clyde Lewis with private investigator, Ed Opperman, about THE NEXT FILES.