Podcasts about tead

Rääkisime tööriistadest, mida üks Python arendaja kindlasti teadma peaks. Külas oli Nortali vanemandmeteadur Hannes Rõõs, kes jagas enda kogemusi ja mõtteid tehnoloogiate kohta, mida Priit ChatGPT-st leidis. -----Tead rohkem, jaga teistelegi meie Discord kanalis: https://discord.gg/8X5JTkDxccEpisoodi veavad Priit Liivak ja Martin KappAlgorütmi toetavad Patchstack https://patchstack.comNortal https://nortal.com/Veriff https://www.veriff.com/

We're back and this time, we're all teaed up. Tea-ed up? Tead up? Tea. Tune in! Also, finally get the answer to the age old question, "how many teas do I need to have a twisted system?"@roadsodaspod on instagramCorrespondence? Comments? Improvements? How dare you. Email us at roadsodaspod@gmail.com Hosted on Acast. See acast.com/privacy for more information.

Tead, vahel on nii, et me teeme küll vegan podcasti, aga veganlusest ei kipu eriti rääkima. See-eest rääkisime paar sõna seentest. Saara ise on kultuuriuurija ja fotograaf ja me ei räägi ka nendest teemadest peaaegu üldse. Küll aga peatume mingil seletamatul põhjusel maailma lähiajalool. Saara tuli tegelikult külla, et tutvustada peatse aset leidvat loomaõiguste konverentsi, mille veatuks toimimiseks Saara oma spetsiifilisi oskusi ja valvsat pilku laenab ja sellest me tõesti rääkisime... episoodiliselt. Käesolev jagu on täielik kaos ja seda kõige paremas mõttes.

Tead, hirmus vahva oli, et Heldi külla tuli. Saime limonaadi juua ja tšillit süüa ja loomulikult rääkida Heldi veganteekonnast ning tema ettevõtmistest Roheboxis ja Eesti Vegan Seltsi juhatuses. Lisaks hekseldasime Heldi uurimustööd teemal, kas loomi üldse tarvitseb biomeditsiinis katsealustena kasutada.

Sõda Ukrainas näitab, kui oluline on kaitsta elanikkonda pommirünnakute, korrusmajades puhkevate tulekahjude ja varingute eest.

Dr. Ping Cao, Co-Founder and CEO of BridGene Biosciences, has developed IMTAC, a platform that can identify molecule ligands for hard-to-drug targets. This platform allows for proteome-wide screening for drug candidates from a small molecule library and has identified over 4,000 protein targets providing numerous opportunities for drug development. The lead candidate, BGI-9004, is a TEAD inhibitor of multiple cancers. BridGene is also in partnership with Takeda to focus on neurodegenerative disorders.   Ping explains, "For small molecule discovery, the major challenge right now is the limited druggable space. Human proteome consists of over 20,000 proteins, and approximately 12,000 of them have been confirmed to play a role in human diseases and may become targets for precision therapy."   "However, statistics analysis shows drugs so far approved by the FDA only target less than 10% of proteins. In other words, most potential drug targets within human proteome do not have associated drugs. Those targets are called hard-to-drug targets due to their biological or structural characteristics. Also, there is less understanding of their mechanism, making them undruggable using traditional methods."   "The significance of proteome-wide screening is that it addresses two kinds of major challenges of drug discovery. One is that some protein drugs contain shadow-binding pockets. The second one is some protein drugs only form transient and temporary binding pockets in live cell environments. For these two types of drugs, by using the chemical proteome approach, we can identify ligands. The process is basically like BridGene's process called IMTAC. They consist of three main components." #BridGeneBio #UndruggableTargets #SmallMolecules #Takeda BridGenebio.com Download the transcript here

Dr. Ping Cao, Co-Founder and CEO of BridGene Biosciences, has developed IMTAC, a platform that can identify molecule ligands for hard-to-drug targets. This platform allows for proteome-wide screening for drug candidates from a small molecule library and has identified over 4,000 protein targets providing numerous opportunities for drug development. The lead candidate, BGI-9004, is a TEAD inhibitor of multiple cancers. BridGene is also in partnership with Takeda to focus on neurodegenerative disorders.   Ping explains, "For small molecule discovery, the major challenge right now is the limited druggable space. Human proteome consists of over 20,000 proteins, and approximately 12,000 of them have been confirmed to play a role in human diseases and may become targets for precision therapy."   "However, statistics analysis shows drugs so far approved by the FDA only target less than 10% of proteins. In other words, most potential drug targets within human proteome do not have associated drugs. Those targets are called hard-to-drug targets due to their biological or structural characteristics. Also, there is less understanding of their mechanism, making them undruggable using traditional methods."   "The significance of proteome-wide screening is that it addresses two kinds of major challenges of drug discovery. One is that some protein drugs contain shadow-binding pockets. The second one is some protein drugs only form transient and temporary binding pockets in live cell environments. For these two types of drugs, by using the chemical proteome approach, we can identify ligands. The process is basically like BridGene's process called IMTAC. They consist of three main components." #BridGeneBio #UndruggableTargets #SmallMolecules #Takeda BridGenebio.com Listen to the podcast here

2023. december 19., kedd 9-10 óra Mesél a múlt rovat. 250 évvel ezelőtt volt a bostoni teadélután. A bostoni teadélutánnak nevezett, 1773. december 16-ai bostoni eseménysorozat (angolul Boston Tea Party) az amerikai függetlenségi háború kitörésének a közvetlen előzménye volt. Katona Csaba, történész. Tőzsdenyitás Deák Dávid üzletkötővel (Equilor Zrt.) Kultmogul, kultúrális rovat. Lemezbemutatókkal, jazz- és világzenei koncertekkel és táncházzal zárja az évet a Fonó.A két ünnep között négy napon át – december 28-tól kezdve - számos koncerttel és táncházzal várja az érdeklődőket a Fonó. A szervezők minden évben különleges programokkal készülnek az ünnepekre, 30-án hagyományosan Jazz Előszilvesztert tartanak, az évet pedig a Fonó Folk Szilveszter, az ország legnagyobb óévbúcsúztató táncháza zárja, ahol a résztvevők szó szerint áttáncolnak az újévbe! Horváth László, a Fonó igazgatója.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.18.545506v1?rss=1 Authors: McNeill, M. C., Chee, F. L., Ebrhimighaei, R., Sala Newby, G. B., Newby, A. C., Hathway, T., Annaiah, A. S., Joseph, S., Carrabba, M., Bond, M. Abstract: 1.0BackgroundVascular calcification (VC) is a prevalent independent risk factor for adverse cardiovascular events and is associated with diabetes, hypertension, chronic kidney disease, and atherosclerosis. However, the mechanisms regulating the osteogenic differentiation of vascular smooth muscle cells (VSMC) are not fully understood. MethodsUsing hydrogels of tuneable stiffness and lysyl oxidase-mediated stiffening of human saphenous vein ex vivo,we investigated the role of extracellular matrix (ECM) stiffness in the regulation of VSMC calcification ResultsWe demonstrate that increased ECM stiffness enhances VSMC osteogenic differentiation and VSMC calcification. We show that the effects of ECM stiffness are mediated via a reduction in the level of actin monomer within the nucleus. We show that in cells interacting with soft ECM, elevated levels of nuclear actin monomer repress osteogenic differentiation and calcification by repressing YAP-mediated activation of both TEA Domain transcription factor (TEAD) and RUNX Family Transcription factor 2 (RUNX2). ConclusionThis work highlights for the first time the role of nuclear actin in mediating ECM stiffness-dependent VSMC calcification and the dual role of YAP-TEAD and YAP-RUNX2 transcriptional complexes. 2.0 GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/545506v1_ufig1.gif" ALT="Figure 1" greater than View larger version (24K): org.highwire.dtl.DTLVardef@10b52aforg.highwire.dtl.DTLVardef@619f4borg.highwire.dtl.DTLVardef@1212f97org.highwire.dtl.DTLVardef@1bb9766_HPS_FORMAT_FIGEXP M_FIG C_FIG 9.0 HIGHLIGHTSO_LIIncreased ECM stiffness promotes VSMC calcification. C_LIO_LIIncreased ECM stiffness reduces levels of nuclear actin monomer. C_LIO_LIOn physiological soft ECM, high levels of nuclear actin monomer inhibits calcification by repressing YAP activation. C_LIO_LIYAP activation promotes calcification by stimulating the activity of TEAD and RUNX2. C_LI Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Ez itt a Paraméter napi hírösszefoglalója, a LÉNYEG. A nap legfontosabb eseményeit szemlézzük, így garantáltan nem marad le semmiről.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.18.520921v1?rss=1 Authors: Anerillas, C., Mazan-Mamczarz, K., Herman, A. B., Munk, R., Lam, G. K., Calvo-Rubio, M., Garrido, A., Tsitsipatis, D., Martindale, J. L., Altes, G., Rossi, M., Piao, Y., Fan, J., Cui, C.-Y., De, S., Abdelmohsen, K., de Cabo, R., Gorospe, M. Abstract: Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Tead see päev, kui sinust sai vegan ja sa mõtlesid, et kõik tahavad sellest teada... mhm... sama siin. Nüüd tahaks kõigile toortoitumisest rääkida. Aga jumal tänatud, Reelyka oli nii tore, et käis külas ja rääkis ise. Vahepeal oli ikka täiesti loll tunne, olgem ausad.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.28.518166v1?rss=1 Authors: Hu, L., Wu, M., He, L., Yuan, L., Yang, L., Zhao, B., Zhang, L., He, X. Abstract: As an output effecter of Hippo signaling pathway, the transcription factor TEAD and co-activator YAP play crucial functions in promoting cell proliferation and organ size. The tumor suppressor NF2 has been shown to activate LATS1/2 kinases and interplay with Hippo pathway to suppress YAP-TEAD complex. But, whether and how NF2 could directly regulate TEAD remains unknown. We identified a direct link and physical interaction between NF2 and TEAD4. NF2 interacted with TEAD4 through its FERM domain and the C-terminal tail, and decreased protein stability of TEAD4 independently of LATS1/2 and YAP. Furthermore, NF2 inhibited TEAD4 palmitoylation and retained the cytoplasmic translocation of TEAD4, resulting in ubiquitination and dysfunction of TEAD4. Moreover, the interaction with TEAD4 is required for NF2 function to suppress cell proliferation. These findings revealed a new role of NF2 as a binding partner and inhibitor of the transcription factor TEAD, and would shed light on an alternative mechanism of how NF2 functions as a tumor suppressor through the Hippo signaling cascade. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.24.513621v1?rss=1 Authors: Hao, S., Fuehrer, H., Flores, E., Demmerle, J., Lippincott-Schwartz, J., Liu, Z., Sukenik, S., Cai, D. Abstract: YAP/TEAD signaling is essential for organismal development, cell proliferation, and cancer progression. As a transcriptional coactivator, how YAP activates its downstream target genes is incompletely understood. YAP forms biomolecular condensates in response to hyperosmotic stress, concentrating transcription-related factors to activate downstream target genes. However, whether YAP forms condensates under other signals, how YAP condensates organize and function, and how YAP condensates activate transcription in general are unknown. Here, we report that endogenous YAP forms sub-micron scale condensates in response to Hippo pathway regulation and actin cytoskeletal tension. The transcription factor TEAD1 actively stabilizes YAP condensates, which also recruit BRD4, a coactivator that is enriched at active enhancers. Using single molecule tracking, we found that YAP condensates slowed YAP diffusion within condensate boundaries, a possible mechanism for promoting YAP target search. These results reveal that YAP condensate formation is a highly regulated process that is critical for YAP/TEAD target gene expression. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Pruunid klõbisevad kohvioad, lõhnav puru ja tassis loksuv tume vedelik on Eestis täiesti harilik osa päevast. Kohvi kodu on aga meist tuhandete kilomeetrite kaugusel paikades, kus see pole teps mitte igapäevane rüübe. Kohvikoolitaja Mihkel Jürimaa juhtimisel rändame seekord paikadesse, kus kohv kasvab ja uurime, mida kõike tuleb teha enne seda, kui kohvioad meieni jõuavad. Möödunud suvel veetis Mihkel koroona kiuste kuu Tansaanias ja töötas seal vabatahtlikuna kohviistanduses, kus ootas teda sadakond kohvitaime ja taamal paistev lumine Kilimanjaro tipp. Mai lõpus, mil ta istandusse saabus, tehti ettevalmistusi saagikoristuseks ning Mihkel sai kohtuda valmivate kohvimarjadega, mis on midagi hoopis muud, kui meile harjumuspärased pruunid kohvioad - ohvipõõsastel siravad punased lihavad ja magused marjad ning nende südames peituvad esialgu rohelised oad. Kuidas hoolitsetakse kohvitaimede eest ja kuidas nopitakse kohvimarju? Mis neist edasi saab? Kas kohvikasvataja ise ka kohvi joob? Kas kliimamuutused ohustavad ka meie hommikurituaale? Vastused neile ja veel paljudele küsimustele leiate saatest. Mihkel on saates ka varem käinud ja juba siis muretsesime kas, kohv saab aastaks 2080 otsa. Saadet juhtisid Keiu Virro ja Liisa Tagel. Küsimused, selgitused, lisandused, parandused ja joogid saatke meile aadressile vala@delfi.ee. Jälgige meie tegevusi ka Facebookis ja Instagramis.

For week 7 of our AAPI Army campaign, we are joined by TEAD teammate Julia Grindstone for a deep drive into the Crouching Tiger-Lady, Hyper-Sexualized Asian Geisha Doll Stereotype. Because although our culture has normalized the ¨I like Asians¨ fetish, this objectification of AAPI women adds layers of violence and vulnerability to our lives and has roots in racism, American Imperialism, and misogyny. To follow the AAPI Army 2021 campaign, visit our website theemotionalabusediscussion.com Follow us on social media: Instagram, Facebook, LinkedIn, Youtube Donate To Our Cause: Support, Paypal Volunteer Opportunities Subscribe! Mailing List

Podcast “Kinnisvarajutud” võtab luubi alla Eesti kinnisvaraturu ning üritab erinevad teemad sügavuti lahti võtta. Eesmärk on rääkida kinnisvarast kui varaklassist (väike)investori vaatenurgast ning olla valdkonnast huvitatutele abimeheks ja meelelahutuseks. Saatejuhid on mikroinvestor ja kinnisvarahuviline Siim Semiskar ja kinnisvaramaakler ning 1Estate Kinnisvara juhatuse liige Algis Liblik. Kuulajad saavad kaasa rääkida, küsimusi küsida või saate kohta tagasisidet anda Facebooki grupis Kinnisvarajutud. Toeta meie tegemisi Patreonis: https://www.patreon.com/kinnisvarajutud NB! Toetajatele pakume kuulamiseks boonusepisoode ja muud lisamaterjali. OSA #41 "Kinnisvarajutud" podcasti 41. osas naaseme tippspordi maailma, kui külaliseks on Eesti korvpallikoondislane ja korduvalt Eesti parimaks korvpalluriks valitud Siim-Sander Vene. Viimastel hooaegadel Lõuna-Euroopas Hispaanias ja Itaalias erinevates klubides leiba teeninud Vene hobiks on investeerimine ning kinnisvaras on mees peamiselt tegutsemas Haapsalu turul. Esmakordselt meie saate ajaloos räägime pikemalt ka garaažidest, kui Venel on portfellis lisaks korteritele ka paar garaažiboksi. Uurime saates, kuidas korvpallihooaja jooksul pikalt välismaal viibival tippsportlasel on organiseeritud objektide vaatamine ja haldus ning milliste tulevikuplaanidega mees oma investeerimisteekonnal liikumas on. Loomulikult pärime Venelt ka, kui levinud on kinnisvarasse investeerimine Eesti korvpallurite hulgas üldiselt ning milline pilt on tema jaoks avanenud välisklubides mängides, kus tippmängijate palgad kindlasti lubaksid päris hoogsat investeerimist. Saame teada, mis on kõige olulisemad asjad, mida USA-st Euroopasse mängima tulevad pallurid oma esimese palga eest kindlasti ostavad. Muuhulgas küsime saates: * Kuidas ja millal jõudsid investeerimise juurde? * Mis Sind motiveeris investeerimisega alustama? * Millal tegid oma esimese kinnisvarainvesteeringu? * Miks just kinnisvara? Mis selle juures köidab? * Mis oli Sinu esimene objekt ja milline on Sinu kinnisvaraportfell tänasel päeval? * Kus suunas oled tegelenud ja mis on Sinu lemmik - pikaajaline üüriäri, lühiajaline rent, flippimine? * Kuidas Sa objekte leiad, millised on kriteeriumid ja tootlusootus? * On Sul lemmik piirkond, kus kõige rohkem tegutsed või tulevikus tahaksid hakata tegutsema? * Oled viimased 10+ aastat korvpalli mänginud välismaal. Kas välismaal kinnisvarasse investeerimisele oled ka mõelnud? * On Sul jagada mõni huvitav või naljakas lugu seniselt investeerimisteekonnalt? * On Sul teada, kui palju Eesti korvpallureid investeerimisega tegeleb? Tead veel kedagi lisaks endale? * Kas korvpallurikarjääri lõppedes plaanidki edasi tegutseda kinnisvaravaldkonnas? * Mis on Sinu kaugem eesmärk kinnisvarasse investeerimisel? * Mida soovitaksid neile, kes soovivad kinnisvarasse investeerima hakata?

Today's guest is an incredibly brave survivor. Her story is one we do not hear often. It is from a woman of color. A queer woman of color. A survivor of same sex abuse, still being contacted by her abuser 4 decades late. . This survivor is now an advocate, having volunteered at the National Domestic Violence Hotline and rape crisis centers. Despite her amazing work, she stated during our interview that they still lack information on how to aid same sex domestic violence survivors. . This is why she is sharing her story. It is her belief, and mine, that by listening to and amplifying the voices of same sex DV survivors, we can create a space where more survivors feel empowered to come forward... and we as a culture can begin to accept, embrace, and aid them properly. . Thank you to this brave woman for trusting me, and you the audience, with this story. . If you are in a same sex domestic violence relationship, you can call the LGBT National Helpline at 1-888-843-4564. Their hours are: Monday through Friday, 4pm - 12am ET. Saturday and Sunday, 12pm - 5pm ET. You can also email them at: help@lgbthotline.org . If you are an LGBTQIA youth in a domestic violence relationship, you can call the LGBT National Youth Hotline at 1-800-246-7743 . Support Buy me a coffee Follow my new non profit TEAD . Join the Discussion thedvdiscussion@gmail.com Instagram Facebook Tik Tok LinkedIn YouTube Twitter

Podcast “Kinnisvarajutud” võtab luubi alla Eesti kinnisvaraturu ning üritab erinevad teemad sügavuti lahti võtta. Eesmärk on rääkida kinnisvarast kui varaklassist (väike)investori vaatenurgast ning olla valdkonnast huvitatutele abimeheks ja meelelahutuseks. Saatejuhid on mikroinvestor ja kinnisvarahuviline Siim Semiskar ja kinnisvaramaakler ning 1Estate Kinnisvara juhatuse liige Algis Liblik. Kuulajad saavad kaasa rääkida, küsimusi küsida või saate kohta tagasisidet anda Facebooki grupis Kinnisvarajutud. Toeta meie tegemisi Patreonis: https://www.patreon.com/kinnisvarajutud NB! Toetajatele pakume kuulamiseks boonusepisoode ja muud lisamaterjali. OSA #24 "Kinnisvarajutud" podcasti 24. osas on meil stuudios esmakordselt külaliseks profisportlane, kui oma toimetamistest üürikinnisvara maailmas räägib jalgpallur Albert Prosa. Eesti koondises 7 mängu pidanud ja Rootsi vastu ka ühe värava löönud Prosa jaoks on Tallinna kinnisvaraturul lemmikasukohaks Lasnamägi, millest meie senises saates põhjendamatult vähe oleme rääkinud. Nüüd parandame selle vea. Juba jalgpallurikarjääri algusaastatest suutis Prosa rahatargalt elades kapitali koguda, et ühel hetkel osta oma esimesed korterid. Sellest, kuidas eeldatavast kodust sai üürikorter ja vastupidi, räägib Prosa saates ülimalt humoorikas võtmes loo, kust selgub, mis juhtub siis, kui kuulutuses panna teadmatusest turuhinnast oluliselt madalam üürihind. Ühtlasi koorub saatest välja ka huvitav põhimõte, et Prosa üürikorterite puhul on sisuliselt alati tekkinud huviliste vahel väike enampakkumine ja lõplik üürisumma kujuneb suuremaks kui on kirjas kuulutuses. Muuhulgas küsisime Albertilt: Kuidas ja millal jõudsid investeerimise juurde ja millistest varaklassidest Sinu teekond alguse sai? Millal tegid oma esimese kinnisvarainvesteeringu? Mis Sind motiveeris investeerimisega alustama? Välismaa tippjalgpallurite palgad on sellised, et võib vabalt erinevates maailma paikades kinnisvara kokku osta. Kuidas on aga Eestis? Mis oli Sinu esimene objekt ja milline on Sinu kinnisvaraportfell tänasel päeval? Kuidas seda ostu finantseerisid ja milline täna Sinu finantseerimismudel on? Kus suunas oled tegelenud ja mis on Sinu lemmik - pikaajaline üüriäri, lühiajaline rent, flippimine? Kuidas Sa objekte leiad, millised on kriteeriumid ja tootlusootus? On Sul lemmik piirkond, kus kõige rohkem tegutsed või tulevikus tahaksid hakata tegutsema? On Sul jagada mõni huvitav või naljakas lugu seniselt investeerimisteekonnalt? On Sul teada, kui palju Eesti jalgpallureid investeerimisega tegeleb? Tead veel kedagi lisaks endale? Oled käinud mängimas ka välisklubides Soomes ja Maltal, kas välismaal kinnisvarasse investeerimisele oled ka mõelnud? Kas jalgpallurikarjääri lõppedes plaanidki edasi tegutseda kinnisvaravaldkonnas? Lõpetuseks, mida soovitaksid neile, kes soovivad kinnisvarasse investeerima hakata? NB! Albert oli lahkesti nõus lisaks põhisaate juttudele võtma täpsemalt lahti ka ühe oma üüriobjekti Kristiines. Boonusosa pakume lähiajal kuulamiseks ja vaatamiseks “Kinnisvarajutud” toetajatele. Vaata lähemalt: https://www.patreon.com/kinnisvarajutud.

Hilissügisene Tartu kutsus meie podcasti külla Aparaadio festivalile. Elinaga koosloob ruumi kreatiivmootori pealt toimiv muusik Silver Sepp, kes on kaasa võtnud pillid, laulud ja mõtisklused – ikka armastuse radadelt. Toeta meie podcasti valmimist ja saa ligipääs erisaadetele: patreon.com/armastusest Jälgi meid: Instagram: instagram.com/podcastarmastusestFacebook: facebook.com/podcastarmastusestTwitter: twitter.com/armastusest Kuula meie Spotify muusikanimekirja.

Episood 110. Selles episoodis me taasavastame oma endiseid parasiitsõnu. Oh seda rõõmu! Agnes räägib meile Willardi hullumajast, mis asub Ovid New Yorkis. Kuna tegemist on siiski 19.sajandi “raviinstitutsiooniga” tuleb juttu mitmetest ravimeetoditest ning põhjustest, miks inimesi sinna saadeti. Eliise räägib mehest nimega Danny Rolling, kellest sai inspiratsiooni filmitegija Kevin Williamson, et tulla välja oma hitt-õudusfilmiga - “Scream” (“Karje”). Tuntud veel kui “The Gainesville Ripper”, see mees tõesti kehastab õudust. Viimane võimalus registreerida end meie eksklusiivsele TASUTA Live’ile, mis toimub Pärnus HUUB’is!

Eestlaste autohuvi on kriisis küll vaibunud ning automüüjatel tulevad rasked ajad, kuid on paar automarki, mis on justkui kõigele immuunsed. Üllataval kombel on tegemist luksus- ja sportmarkidega. Selles valguses räägimegi sellest, millised haruldasemaid ja kallimaid iludusi Eestist osta saab ning kuidas nende müük läinud on. Tead ka mõnest eriti edevast autost, mis hiljaaegu müüdud/ostetud sai? Anna meile kommentaarides teada. Ei saa me taas üle ega ümber GR Yarisest. Daigo Saito on selle oodatud kuumpära nüüd enda kätte saanud ja ka Pandem/Rocket Bunny on oma esimese laienduskomplekti autole juba valmis treinud. Tulemus on muidugi silmapaistev (vt Instagrami pilte siit). Räägime sellest imemasinast saates lähemalt. Proovisõiduauto oli sel nädalal väga eksklusiivne - Bentley Continental GT uusversioon, V8 mootoriga isend. Luksuse poolest jäime selle suhtes eriarvamusele, kuid sõidukogemuse suhtes mitte. Igal juhul tegemist ühe sõiduga, mis pole just igapäevane. Nipinurga asemel on sel nädalal hoopis kirumisnurk. Veli räägib juhiabidest, täpsemalt just äkkpidurdusmehhanismist, mis tema elu kuidagi lihtsamaks ei ole teinud. Ühel korral küll tegi, kuid neid kordi, mil see tema elu häirinud, on kordi rohkem.

Mitme minutiga saab organism kätte vajaliku koguse D-vitamiini ning mida võib tähendada lapsepõlves kogetud päikesepõletus? Kõigile neile ja paljudele teistele päevitamisega seotud küsimustele vastab Mariana Džaniašvili Südameapteegist.

Igal nädalal kostitame sind põneva veebisaatega „Puuduta mind“, kus külalisteks on nõiad, šamaanid, ravitsejad, ufoloogid, haldjad, elukunstnikud, teadlased, koolitajad, hüpnotisöörid ja paljud teised põnevad persoonid. Õhtulehe veebi loovjuhi Anu Saagimi seekordseteks külalisteks on kirjastuse „Million Mindset“ värvikad loojad Toomas Väli ja Alo Tammsalu.

Korvpalliteemasid lahkav Pihtas Põhjas jätkab sealt, kus eelmise aasta maikuus pooleli jäi. Stuudios sama külaline, kelle vastused jäid segaseks ja raskesti mõistetavaks. Küsime uuesti ning üritame aru saada. Viskame huumorit vahele, aitab raskeid teemasid seedida.

1773-ban ezen a napon volt az amerikai történelem egyik legfontosabb eseménye, a bostoni teadélután, erről is megemlékeztünk. Meg arról is, hogy 1917-ben ezen a napon született Sir Arthur C. Clarke angol író, mérnök, aki komoly tudós is volt. Budapest rovatunkban szó volt a New York kávéházról, meg arról is, hogy a hétből hat sebész felmondott a Jahn kórházban, na meg arról is, hogy szétverde nyílt Budapesten. Miért nincs elég gázszerelő? Mi az oka a szakemberhiánynak? Miért nem mennek a fiatalok gázszerelőnek? Illés Zoltán, a Gáziparosok Országos Egyesületének elnöke és Varró Zsuzsa, az egyesület főtitkára válaszolt kérdéseinkre. Európai konjunktúra, magyar kamatdöntés - ilyen és ehhez hasonló adatok érkeznek. Kovács Mihály, az OTP Bank Elemzési Központ elemzője mondta el, mire számít. Itt az X-Europe program! Böszörményi-Nagy Gergely, a Design Terminal vezetője mondta el, mit kell tudni róla.

Conteeent Podcast - Martti + Liina Ootame järgmisteks osadeks teie muresid/küsimusi: SAADA MEIL: hainouanne@gmail.com ANONÜÜMNE KIRI: conteeent.tumblr.com/ask Kallidpaid - Martti ja Liina

Loomulikult tuli Eurovisiooni eel Jüriga jutuks ka lauluvõistlus, millest ta isegi 2016. aastal 21-aastaselt osa võttis. «Tead, ma praegu kardaks palju rohkem kui siis. Ma ei osanud midagi karta, hästi hulljulge olin. Ma arvan, et see oli ka mu pluss sellel ajal,» tunnistas Pootsmann.

On this week’s episode of “Tea’d,” hosts DJ and Jayse talk about the importance of sexual health throughout college. The sips of wisdom highlight steps you can take on being on top of your sexual healthDJ and Jayse also talk about what they’ve learned through their college experience regarding sex. This episode discusses the importance of sexual health throughout college.

On this week’s episode of “Tea’d,” hosts DJ invite special guests, Dr.Murray and MaryKatherine from the women’s center to discuss microaggressions.. The sips of wisdom are guidelines for the audience to help navigate times when they are faced with a microaggression with their colleagues. This episode discusses the lasting effects microaggressions can have on a person.

Saatekülaline ja kaasjuht on seekord Tõnu Ojala Tehnikamaailmast, kellel on trükist tulnud raamat Nõukogude Liidu veoautode kohta. Rohkelt pildimaterjali ja harivat sisu. Pikaajalise autoajakirjanikuna on tal kaasa rääkida ka saate muudes teemades. Alexela ei peagi biolisandiga kütuseid müüma Milline alternatiivne kütus võidab? Eesti Gaas ja Neste näevad tulevikku erinevalt Tesla äritseb CO2-kvoodiga Fiat-Chrysler avas ägeda uue muuseumi Kinno tuleb film Ott Tänakust Ameerikas sai gaasiplahvatuses kannatada haruldane Porschede kollektsioon Stuudios on Autogeeniuse toimetaja Tarmo Tähepõld ja Tõnu Ojala Tehnikamaailmast.

For over 20 years, Jordan "Tead" Vaughn has built a respected reputation in the city's street art scene

Podpilot - Teadélután by Gyarmati Péter

Saates oli külas Traveller Toursi ja Like A Local Guide asutaja ning suur reisisõber Kalev Külaase. Koos saatejuhi Liina Metskülaga arutletakse parimate viiside üle, kuidas soodsalt reisida ning räägitakse selle illustreerimiseks ägedaid lugusid. Lisaks viitame superheadele lennupakkumised Maldiividele, Taisse, Bostonisse ja San Franciscosse ning räägime nädala reisiraamatust!

Sunday message (Video version): 01-13-2013 Tead The Book - Don't Wait for the Movie