Podcasts about bh3

Game Exercise: Close your eyes and follow along with an entire Chess game using the audio below. On each move, try to conceptualize the position clearly and understand how it has changed. Try to follow the game until the end to stretch the amount of moves you can see ahead. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: Tartakower vs Euwe (Venice, 1948) 2. 1. e4 e5 2. Nf3 Nc6 3. Bc4 Bc5 4. c3 Bb6 5. d4 Qe7 6. O-O d6 7. h3 Nf6 8. Re1 O-O 9. Na3 Nd8 10. Bf1 Ne8 11. Nc4 f6 12. a4 c6 13. Nxb6 axb6 14. Qb3+ Ne6 15. Qxb6 g5 16. Bc4 h6 17. h4 Kh7 18. hxg5 hxg5 19. dxe5 dxe5 20. Be3 Rh8 21. g3 Kg6 22. Kg2 Nf4+ 23. gxf4 Bh3+ 24. Kg3 exf4+ 25. Bxf4 Qd7 26. Nh2 gxf4+ 27. Kxf4 Rh4+ 28. Ke3 Bg2 29. Nf3 Rxe4+ 30. Kxe4 Nd6+ 31. Kd3 Qf5+ 32. Kd4 Qf4+ 33. Kd3 Qxc4+ 34. Kc2 Bxf3 35. b3 Be4+ 36. Kb2 Qd3 37. Rg1+ Kf7 38. Rac1 Qd2+ 39. Ka3 Nc4+ 40. bxc4 Rxa4+ 41. Kxa4 Qa2+ 42. Kb4 Qb2+ { White resigned. } *

Game Exercise: Close your eyes and follow along with an entire Chess game using the audio below. On each move, try to conceptualize the position clearly and understand how it has changed. Try to follow the game until the end to stretch the amount of moves you can see ahead. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: [White "Fendrich, David"] [Black "Madebrink, Lars"] 1.Nf3 Nf6 2.g3 b5 3.Bg2 Bb7 4.Na3 a6 5.c4 bxc4 6.Nxc4 c5 7.Nce5 d6 8.Nxf7 Kxf7 9.Qb3+ d5 10.Ne5+ Ke6 11.Qxb7 Kxe5 12.Qxa8 Kd6 13.d4 cxd4 14.Bd2 Qb6 15.Rc1 Nc6 16.Bh3 g5 17.Rxc6+ Qxc6 18.Bb4+ Kc7 19.Ba5+ Kd6 20.Qb8+ 1-0

Black holes are everywhere. There could be a hundred million black holes that are the remnants of dead stars in the Milky Way Galaxy alone. But because they’re completely dark, they’re hard to find. That applies even to the biggest member of the class yet discovered. It’s 33 times the mass of the Sun – more than half again the mass of the galaxy’s previous record holder. The black hole is in a system known as BH3. It was discovered by the Gaia space telescope, which is mapping more than a billion stars in the galaxy. The system is almost 2,000 light-years from Earth. The black hole revealed its presence only because it has a “normal” companion star. The companion is nearing the end of its life, so it’s becoming a giant – bigger and brighter than the Sun. Gaia measured a wobble in the star’s motion. Astronomers analyzed the wobble, and decided that it was caused by the gravitational pull of a black hole. The black hole probably formed when a supergiant star collapsed at the end of its life. That happened billions of years ago, when the galaxy was young – a conclusion supported by the age of the companion. The composition of the supergiant allowed it to form an especially heavy black hole – the biggest remnant black hole in the galaxy. BH3 is to the left of the bright star Altair, the breast of the eagle, which is in the east at nightfall. But the system is much too faint to see without a big telescope. Script by Damond Benningfield

durée : 00:04:50 - Avec sciences - par : Alexandra Delbot - Si Sagittarius A*, le trou noir supermassif au centre de la Voie Lactée est assez visible avec les bons instruments, d'autres plus petits et moins actifs se cachent de nos yeux. Grâce au satellite Gaïa, une nouvelle étude rapporte la découverte de BH3, le plus gros trou noir stellaire de la galaxie.

Prepare for a cosmic revelation in SpaceTime Series 27 Episode 49, as we journey through the Milky Way to uncover a celestial heavyweight—the most massive stellar black hole ever discovered in our galaxy. Detected by the vigilant eyes of the European Space Agency's Gaia mission, this black hole, known as Gaia BH3, imposes a peculiar wobble on its companion star, betraying its presence. Weighing in at a colossal 33 solar masses and residing a mere 2,000 light-years away in the constellation Aquila, BH3 redefines our understanding of stellar remnants and the mysterious dance of gravity and mass that shapes them.Then, we take a detour through the evolutionary tracks of white dwarf stars, which have long been the cooling embers of the cosmic campfire. Recent observations from Gaia have spotted a group of these stellar corpses defying the natural order, mysteriously ceasing to cool. This perplexing behavior is challenging astronomers to rethink the very nature of these ancient stars, which may not be the reliable cosmic clocks once thought.We'll also explore the technological advancements propelling humanity's reach into the cosmos with the development of a new, more capacious Cygnus cargo ship. Set to enhance supply missions to the International Space Station, this vessel promises to double the payload space and carry up to five tonnes of cargo, marking a significant leap forward in our orbital endeavors.And in our Science Report, we celebrate the end of the 2023-24 El Niño weather pattern, but with a watchful eye on the horizon for a potential return to La Niña conditions. Plus, we delve into the health risks of sugary and artificially sweetened drinks, the discovery of a jaw-droppingly large marine reptile, and the curious case of an extensive paranormal archive that sparks more questions than answers.For the full cosmic journey, visit our website at https://spacetimewithstuartgary.com and support the show at https://www.spreaker.com/show/spacetime. Discover the universe's wonders with us on SpaceTime.This week's episode is brought to you by NordPass. Navigate the digital universe with confidence using a password manager you can trust. Secure your cosmic exploration at www.bitesz.com/nordpass.Listen to SpaceTime on your favorite podcast app and follow us on X (Twitter) @stuartgary, Instagram, YouTube, and Facebook.Become a supporter of this podcast: https://www.spreaker.com/podcast/spacetime-with-stuart-gary--2458531/support.

As the Co-Founder and Co-CEO of BH3, Mr. Freedman oversees Investments, Financial Analysis, and Capital Markets across all BH3 transactions, and has expertise in financial analysis, credit, and underwriting. Before cofounding BH3, Mr. Freedman was a principal in a private lending company based in South Florida that financed bridge loans on commercial and residential real estate and oversaw capital markets relationships, loan/special servicing, and workouts.On this episode, Jake and Greg discuss:How to identify A-PlayersThe best way to comp people in REPEOrganization-defining dealsCapital structuresLinks:BH3 ManagementGreg on LinkedInConnect & Invest with Jake:Follow Jake on Twitter: https://twitter.com/jwurzakTake the Hospitality Investing Masterclass: https://learn.jakewurzak.com/Learn How to Invest with DoveHill: https://bit.ly/3yg8PwoTopics:(00:00:00) - Intro(00:02:48) - Greg's career and background(00:14:41) - How to identify A-players(00:16:43) - What's the best way to comp people in REPE?(00:19:47) - Recruiting talent(00:23:20) - Being both entrepreneurial and institutional(00:28:40) - Organization-defining deals(00:41:10) - The world of South Florida condo development (01:00:26) - Developing relationships(01:05:00) - Capitalizing deals(01:17:34) - Waterfall structures(01:22:16) - Buying debt(01:27:41) - What is your favorite hotel?

1.e4 e5 2.Bc4 Bc5 3.b4 Bxb4 4.c3 Bc5 5.d4 exd4 6.cxd4 Bb4+ 7.Kf1 Ba5 8.Qh5d5 9.Bxd5 Qe7 10.Ba3 Nf6 11.Bxf7+ Qxf7 12.Qxa5 Nc6 13.Qa4 Nxe4 14.Nf3 Bd7 15.Nbd2 Nxd2+ 16.Nxd2 O-O-O 17.Rb1 Qd5 18.Nf3 Bf5 19.Rd1 Rhe8 20.Bc5 {Diagram} 20...Qxf3 21.gxf3 Bh3+ 22.Kg1 Re6 23.Qc2 Rxd4 24.Bxd4 0-1

Acute myeloid leukemia (AML) is notoriously difficult to treat. Only 28 percent of patients survive beyond 5 years after diagnosis. Mitophagy, a process in which damaged mitochondria are eliminated to prevent the transmission of death signals, has been identified as a key mechanism that allows leukemia cells to resist the effects of the widely prescribed drug venetoclax, according to a recent study published in Cancer Discovery and led by scientists from Perlmutter Cancer Center at NYU Langone Health. Today on OncTimes Talk, we interview Dr. Christina Glytsou, lead author of the study, and discuss the reasons behind leukemia cells’ resistance to venetoclax, a BH3 mimetic drug that promotes cancer cell death in individuals with AML. Dr. Glytsou holds a joint appointment as an Assistant Professor in the Department of Chemical Biology at the Ernest Mario School of Pharmacy of Rutgers University and the Department of Pediatrics at Rutgers Robert Wood Johnson Medical School. She is a member of Cancer Metabolism & Immunology and the Cancer Pharmacology Programs, at the Cancer Institute of New Jersey. Dr. Glytsou’s laboratory aims to address fundamental questions unravelling the role of mitochondrial biology in blood malignancies’ progression and drug resistance.

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there's been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we're now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Thank you for your attention. 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. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

A new research paper was published in Aging (Aging-US) Volume 15, Issue 7, entitled, “Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.” The accumulation of senescent cells has an important role in the phenotypical changes observed in aging and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, researchers Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip from the University of Leicester, Najran University and Universitat Oberta de Catalunya hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. “Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.” Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Their results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, their results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved. “According to our results, CUDC-907 could be an interesting drug to be used as a senolytic, alone or as part of a targeted approach.” DOI: https://doi.org/10.18632/aging.204616 Corresponding author - Salvador Macip - sm460@le.ac.uk Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204616 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, senescence, senolytics, HDAC, PI3K, CUDC-907 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.02.535249v1?rss=1 Authors: Pemberton, J. M., Osterlund, E. J., Schoormann, W., Pogmore, J., Nguyen, D., Leber, B., Andrews, D. Abstract: Anti-apoptotic proteins such as BCL-XL promote cell survival by sequestering pro-apoptotic BCL-2 family members, an activity that frequently contributes to tumorigenesis. Thus, the development of small-molecule inhibitors for anti-apoptotic proteins, termed BH3-mimetics, is revolutionizing how we treat cancer. BH3 mimetics kill cells by displacing sequestered pro-apoptotic proteins to initiate tumor-cell death. Recent evidence has demonstrated that in live cells the BH3-only proteins PUMA and BIM resist displacement by BH3-mimetics, while others like tBID do not. Analysis of the molecular mechanism by which PUMA resists BH3-mimetic mediated displacement from full-length anti-apoptotic proteins (BCL-XL, BCL-2, BCL-W and MCL-1) reveals that both the BH3-motif and a novel binding site within the carboxyl-terminal sequence (CTS) of PUMA contribute to binding. Together these sequences bind to anti-apoptotic proteins, which effectively "double-bolt locks" the proteins to resist BH3-mimetic displacement. The pro-apoptotic protein BIM has also been shown to double-bolt lock to anti-apoptotic proteins however, the novel binding sequence in PUMA is unrelated to that in the CTS of BIM and functions independent of PUMA binding to membranes. Moreover, contrary to previous reports, we find that when exogenously expressed, the CTS of PUMA directs the protein primarily to the endoplasmic reticulum (ER) rather than mitochondria and that residues I175 and P180 within the CTS are required for both ER localization and BH3-mimetic resistance. Understanding how PUMA resists BH3-mimetic displacement will be useful in designing more efficacious small-molecule inhibitors of anti-apoptotic BCL-2 proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.534530v1?rss=1 Authors: Sun, X.-M., Miles, G. J., Craxton, A., Powley, I. R., Galavotti, S., Chernova, T., Dawson, A., Nakas, A., Willis, A. E., Cain, K., MacFarlane, M. Abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure and highly resistant to chemotherapy, potentially due to upregulated expression of the pro-survival proteins, BCL2/BCL-XL/MCL-1. Using clinically-relevant models of MPM we show that patient-derived primary MPM cell lines and ex-vivo 3D tumour explants are highly resistant to apoptosis induced by the BCL2/BCL-XL inhibitor, ABT-737. Importantly, we discover that 2-deoxyglucose (2DG), a glycolytic inhibitor, can sensitize MPM cells to ABT-737 and show this correlates with loss of the pro-survival protein, MCL-1. siRNA knockdown of MCL-1 (MCL-1 KD) combined with ABT-737 induced BAX/BAK-dependent, but BIM/PUMA-independent apoptosis, mimicking 2DG/ABT-737 treatment. MCL-1 KD/ABT-737 induced mitochondrial cytochrome c release and caspase-independent inhibition of mitochondrial respiration. Moreover, we observed a hitherto unreported caspase-dependent cleavage of glycolytic enzymes and subsequent inhibition of glycolysis. 2DG inhibited ERK/STAT3 activity, decreased MCL-1 mRNA and protein levels, with concurrent activation of AKT, which limited loss of MCL-1 protein. However, co-treatment with a specific AKT inhibitor, AZD5363, and 2DG/ABT-737 potently induced cell death and inhibited clonogenic cell survival, while in MPM 3D tumour explants MCL-1 protein expression decreased significantly following 2DG or 2DG/AZD5363 treatment. Notably, a similar synergy was observed in MPM cell lines and MPM 3D tumour explants using ABT-737 in combination with the recently developed MCL-1 inhibitor, S63845. Importantly, our study provides a mechanistic explanation for the chemoresistance of MPM and highlights how this can be overcome by a combination of metabolic reprogramming and/or simultaneous targeting of MCL-1 and BCL-2/BCL-XL using BH3-mimetics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.23.533672v1?rss=1 Authors: Buckley, N., Craxton, A., Sun, X.-M., Panatta, E., Pinon, L., Llodra, J., Morone, N., Amelio, I., Melino, G., Martins, L. M., MacFarlane, M. Abstract: Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic atrophy 1, a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells also display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We also show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 KO) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 expression is decreased in COPD patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. This work also adds to the growing body of evidence for growth-promoting roles of TAp73 isoforms. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week we are joined by a legend of the game, one of the best players in the world in the 1970s and 1980s, Swedish champion, and legendary positional player, GM Ulf Andersson. Ulf doesn't play as much as he did at his peak, but he still exudes passion for chess, and has accumulated a litany of stories about his games with fellow legends. Ulf regales us with stories about his clashes with Garry Kasparov, Bobby Fischer, Viktor Korchnoi, Bent Larsen, and so many others. At the age of 71, his memory for these encounters is flawless, and he shares many details about these memorable encounters. Ulf still follows modern chess closely, and also discusses his favorite modern players and games, and describes his daily life today.  He splits time between Germany and Sweden. It was quite an honor to hear a lifetime's worth of chess stories as they happened to ULF.  Timestamps of people and topics discussed can be found below.  0:03- Ulf joined me from his part-time home near Cologne, Germany, how does he spend his time there?  0:05- How does Ulf keep up with the chess world? How did he approach chess improvement in his earlier years?  0:09- Question from Chess Historian and Blogger Douglas Griffin: Does Ullf think that faster time controls have decreased the quality of endgame play? How have increments affected chess overall?  13:30- Who are GM Ulf Andersson's favorite modern players? 15:30- What did Ulf think of Magnus' decision not to defend his title?  16:45- Perpetual Chess is brought to you in part by Chessable.com. You can check out all of their latest offerings here:  https://www.chessable.com/courses/all/new/ 18:00- What are Ulf's memories of GM Mikhail Tal?  22:00- Ulf mentions that he finds tournament chess more stressful than he used to it? When did he start to feel this way? 24:00- What was it like to play Fischer at the peak of his power?    28:00- What were GM Ulf Andersson's impressions of Korchnoi? 32:00- Ulf describes his matches with legendary Danish GM Bent Larsen.  37:00- What were Ulf's interactions with Kasparov like? What was the difference between Kasparov and Karpov in personality?  43:00- Perpetual Chess is brought to you in part by Aimchess.com. Aimchess' algorithm reviews your games and gives you actionable advice on how to improve your game. Check it out for free, and if you choose to subscribe you can use the code Perpetual30 to save 30%. Or use this link for the same discount: https://aimchess.com/try?ref=benjohnson12 44:00- What was it like to meet and play Soviet legend GM David Bronstein? What about his friend GM Jan Timman?  48:00- Ulf discusses an infamous loss of his against IM Michael Basman, sometimes called, “The Immortal Waiting Game.” 50:00- Ulf discusses the 15 hour, 300 plus board simul he played in 1996.  57:00- Uf gives his perspective on the epic clash between Gukesh and Abdussatorov at this year's Olympiad.  59:00- Ulf discusses some of the top current Swedish player's approaches to maintaining their nerves and playing fighting chess.  1:09:00- Ulf discusses his interactions with GM Viswanathan Anand  1:13:00- Shirov's famous move Bh3! Wwas inspired by a game Alexei played against Ulf. Does Ulf know this story?  1:16:00- How did Ulf achieve his peak rating in his 40s? Ulf also discusses the differences between open and closed tournaments.  1:20:00- Ulf discusses his correspondence chess career. 1:28:00- Ulf describes his life in Germany, and also back in Arboga, Sweden, where he does not even have a computer! Mentioned: GM Robert Hungaski, GM Sandra Mareco 1:35:00- Ulf discusses coaching the Argentinian Olympiad team in 2014.  1:41:00- Does Ulf do any coaching? 1:47:00- Ulf's favorite games 1:51:00- What are Ulf's favorite chess memories?  1:55:00- Kasparov-Karpov Seville 1987 1:56:00- Thanks so much to Ulf for sharing his passion to a lifetime devoted to chess!    Learn more about your ad choices. Visit podcastchoices.com/adchoices

A new research paper was published in Aging (“Aging (Albany NY)” by Medline/PubMed, “Aging-US” by Web of Science) on the cover of Volume 14, Issue 16, entitled, “Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells.” Cellular senescence, a complex cellular response to stress characterized by a halt of cell cycle progression, is one factor contributing to aging. Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system response contribute to the accumulation of senescent cells and their adverse effects in tissues. Inhibition of antiapoptotic machinery, augmented in senescent cells, by BCL-2 protein family inhibitors represents a promising approach to eliminate senescent cells from tissues. “In this study, with the goal of decreasing the toxicity and potential onset of resistance to senolytic BCL-2 inhibitor monotherapy, we explored the effects of combined treatment covering both BCL-2 and MCL-1 anti-apoptotic factors in human cells.” Researchers David Rysanek, Pavla Vasicova, Jayaprakash Narayana Kolla, David Sedlak, Ladislav Andera, Jiri Bartek, and Zdenek Hodny from the Czech Academy of Sciences and the Danish Cancer Society Research Center aimed to explore synergistic and selective senolytic effects of anti-apoptotic BCL-2 family targeting compounds, particularly BH3 mimetics. “Using human non-transformed cells RPE-1, BJ, and MRC-5 brought to ionizing radiation-, oncogene-, drug-induced and replicative senescence, we found synergy in combining MCL-1 selective inhibitors with other BH3 mimetics.” In an attempt to uncover the mechanism of such synergy, the team revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, the researchers found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy. DOI: https://doi.org/10.18632/aging.204207 Corresponding Author: Jiri Bartek, Zdenek Hodny – Email: jb@cancer.dk, hodny@img.cas.cz Keywords: homoharringtonine, cellular senescence, BCL-2, MCL-1, senolytics Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204207 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/

After a one month hiatus, Chess Books Recaptured returns to discuss another classic chess book- GM Alexei Shirov's Fire on Board. This 1997 game collection book shows the games of one of the world's best attacking players at the peak of his powers. Joining me to discuss the book is Mitchell Fabian. Mitch is a 26 year old dad, actuary and avid chess student who suggested this book because he felt that it helped his chess tremendously. In addition to many wild slugfest games and creative ideas, the book covers an interesting time in chess history, when the World Championship Title was disputed by different organizations. We cover all of this in a fun conversation about a challenging, but informative book. More details and timestamps below:  0:00- We welcome Mitch Fabian to the show and he discusses why he chose Shirov's Fire on Board.  Mentioned: IM Kostya Kavutskiiy  6:00- For what rating is Fire on Board best suited? Mentioned: Seirawan's Play Winning Chess  12:30- Perpetual Chess is brought to you by Chessable.com, the premier chess education website. Check out their latest offerings here: New Chess Courses Online - For All Levels - Chessable.com 13:00- Patreon mailbag question: Any hot takes on the Shirov-Kasparov World Championship match that was supposed to take place in the late 1990's but never did?  Mentioned: Fire on Board 2, Luis Rentero Suarez  24:00- Back to the book! We discuss the book's structure and share some quotes from a great foreword by GM Jon Speelman  Mentioned: Topalov-Shirov 2004 with 47… Bh3!!! 36:00- Perpetual Chess is brought to you in part by Aimchess.com. Aimchess' algorithm reviews your games and gives you actionable advice of how to improve your game. Check it out for free and if you choose to subscribe you can use the code Perpetual30 to save 30%.  37:00- We share a few of things that struck us about Fire on Board  Mentioned: Attack with Mikhail Tal, Episode 273 with GM Johan Hellsten, GM Vasilios Kotronios, Lifetime Repertoires: Jan Gustaffson 1. E4 e5 , Everyman Chess “E Book” of Fire on Board  48:00- Should we be concerned about some errors in the book that modern engines identify?  Mentioned: GM Samuel Sevian, Shirov-Kramnik 1994  51:00- Mitch and I share a few other things we like about Fire on the Board.  Mentioned: Book Recap #1- The Life and Games of Mikhail Tal, Chess Structures by GM Mauricio Flores Rios 1:04:00- We wrap the book discussion before segueing to some adult improvement discussion with Mitch. In Mitch's honor I will be making a modest donation to The US Chess School.  1:05:00- Mitch is quite an accomplished adult improver so before we wrap up he shares some improvement recs.  Mentioned: Chess Dojo Discord, GM Eugene Perelshteyn  1:16:00- Thanks so much to Mitch for joining us! Here is where you can find him: Chess Dojo Discord Twitter Chess.com Lichess   Learn more about your ad choices. Visit podcastchoices.com/adchoices

1.e4 e5 2.d4 exd4 3.Qxd4 Nc6 4.Qd1 Nf6 5.Nc3 Bb4 6.Bd3 O-O 7.Bg5 Re8 8.Nf3 Nxe4 9.Bxe4 Bxc3+ 10.Kf1 Bf6 11.Bxf6 Qxf6 12.Qd3 Nb4 13.Qc4 d5 14.Bxh7+ Kxh7 15.Qxb4 c5 16.Qxc5 {Diagram} 16...Qxf3 17.gxf3 Bh3+ 18.Kg1 Re6 19.Qc7 Rae8 20.Rf1 Re1 {White resigns} 0-1

While it would be true to say that Billy Hurley III’s win on the PGA Tour put him on a very short list of winners at the highest level of golf from the capital region, that fact is hardly what makes that win & his career so unique.  Having served 5 years in active service […]

Acute myeloid leukemia (AML) is a cancer of the blood that begins in the bone marrow and progresses quickly if left untreated. AML can occur both in adults and children and is often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT is a procedure that replaces stem cells that were damaged or destroyed after radiation and/or chemotherapy treatment with stem cells from healthy donors. While allo-HSCT provides a high rate of curability in AML patients, the success of this procedure is partially dependent on the efficacy of pre-transplant treatment regimens. Researchers have identified an urgent need to determine new therapeutic approaches that provide better cytotoxicity in AML cells, without jeopardizing patient safety. To improve AML patient outcomes after allo-HSCT, researchers from the University of Texas MD Anderson Cancer Center and the University of Alberta's Cross Cancer Institute conducted a new study investigating the combinations of the BCL-inhibitor ABT199/venetoclax with two alkylating agents and a nucleoside analog. Their trending research paper was published by Oncotarget on February 10, 2022, and entitled, “ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.” “One such candidate drug is ABT199/venetoclax, a BH3-mimetic small molecule that binds to and inhibits the anti-apoptotic B-cell lymphoma 2 (BCL2) protein, preferentially causing malignant cells to undergo apoptosis.” Full blog - https://www.oncotarget.org/2022/02/17/trending-with-impact-new-pre-transplant-aml-treatment-combinations/ DOI - https://doi.org/10.18632/oncotarget.28193 Correspondence to - Benigno C. Valdez - bvaldez@mdanderson.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28193 Keywords - ABT199/venetoclax, busulfan, cyclophosphamide, fludarabine, acute myeloid leukemia About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

This is an awesome show! We sit down with Dan Lebensohn to talk about how he went from a high power real estate attorney in New York to becoming an active investor and developer of CRE. We talk about some of his war stories and lessons he has learned over the course of his career. With an expertise in complex distressed and workout scenarios, Mr. Lebensohn oversees the Deal Sourcing, Legal and Structuring components of BH3's acquisitions. Prior to cofounding BH3, Mr. Lebensohn served as in-house counsel to a Manhattan owner, operator and developer for several years and has more than 20 years of investment and operational experience, including acquisitions and management of multifamily and commercial projects in NYC through his first company Wilder Realty LLC. Mr. Lebensohn holds a juris doctorate from the prestigious New York Law School and practiced law in New York City for more than 12 years, during which he was actively acquiring and turning around assets in the Tri-State region. Daniel also serves as Co-Portfolio Manager of the BH3 Debt Opportunity Fund I, L.P. where in that capacity he is jointly responsible for all major decisions including investment decisions, legal strategy and asset dispositions. Mr. Lebensohn also serves as Co-CEO, Investment Committee Member and Board Member for Crixus BH3 Acquisition Company (Nasdaq: BHAC), a special purpose acquisition company focused on real estate, construction and infrastructure.

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Arin & Kristen from BH3 join Jami and I to wrap up (for now) my mini series surrounding love, relationships, and couples. This episode is authentic, raw, unadulterated ABA and positive psychology. We step into a place of bravery and discuss our relationships and how we first show up every day as humble and kind individuals, and then how we choose to show up every day for each other.

Happy Pride Month! In this episode we uplift the stories from the LGBTQIA+ community in all unique forms they take. You will hear the themes of self-discovery, pain, isolation, joy and the relentless pursuit of unapologetic self-love. We are grateful for all the courageous humans who were willing to share their stories with the world. About our guests: Beautiful Human Number 1: Akanksha Chhettri (she/her) Akanksha's Bio: I was born and brought up in India. I have lived in Ghana for the past 2 years. Potterhead (Gryffindor!), brown unicorn, proud feminist, autism advocate and social justice warrior. You can find Akanksha at: akankshachhettri4@gmail.com Instagram @orangedot7 Beautiful Human Number 2: Barb Gross (she/her/hers) Barbara Gross (she/her/hers) is a Board Certified Behavior Analyst and AASECT Certified Sexuality Educator. She specializes in staff and caregiver training and development of sexual behavior intervention plans for people with intellectual and developmental disabilities (I/DD), including autism spectrum disorder. She also works to coordinate with educators and other helping professionals to promote equity in access to comprehensive sexuality education for people with disabilities. Other areas of practice and research interests include pornography literacy, abuse prevention for children and adults with disabilities, and dissemination of behavior analysis and the potential it offers to promote healthy sexuality for people of all abilities. You can find Barb at: barb.gross@empoweredcenter.com Beautiful Human Number 3: Brea Baker (she/her/hers) Brea Baker is a queer Black millennial woman working at the intersections of race, gender identity, public safety, and community. Currently working as Director of Programs at Inspire Justice, Brea understands that we need a multi-pronged approach to the complex problems facing society. Working across fields and industries from activism to the entertainment industry to electoral work and politics, she believes in the need for progressive policy along with a culture that reflects and affirms everyone’s right to thrive. You can find Brea at: Instagram @FreckledWhileBlack Beautiful Human Number 4: Devin Ariel (Mahogany) Proud, melanated woman of the trans experience with a passion for attaining knowledge of different cultures and spreading consciousness within her respective communities. You can find Mahogany at: Instagram- @Mahogany_Gyal and YouTube: Mahogany Gyal Beautiful Human Number 5: Elliot White queer trans*person committed to anti-racism, life-long learning, and behavior analysis You can find Elliot: Contact info upon request - happy for either of you to share email if anyone wants to chat/collaborate Beautiful Human Number 6: Arin Donovan(They, Their, Theirs) Arin Donovan is a BCBA, adjunct faculty member at Capella University and co-owner of BH3, Inc, an organization that provides training, webinars and talks on gender diversity and inclusive practices, BACB supervision with a values-centered approach, and organizational consultation services to cultivate inclusive and affirming environments. Arin is also the co-creator of Beautiful Humans Change! You can find Arin: Right here! As always, we hope that you enjoy the conversation, as much as we enjoyed recording it. Please follow us on FB @BeautifulHumansCast or IG @BeautifulHumansChange

1. e4 d6 2. d4 Nf6 3. Nc3 g6 4. Be3 Bg7 5. Qd2 c6 6. f3 b5 7. Nge2 Nbd7 8. Bh6 Bh6 9. Qh6 Bb7 10. a3 e5 11. O-O-O Qe7 12. Kb1 a6 13. Nc1 O-O-O 14. Nb3 ed4 15. Rd4 c5 16. Rd1 Nb6 17. g3 Kb8 18. Na5 Ba8 19. Bh3 d5 20. Qf4 Ka7 21. Rhe1 d4 22. Nd5 Nbd5 23. ed5 Qd6 24. Rd4 cd4 25. Re7 Kb6 26. Qd4 Ka5 27. b4 Ka4 28. Qc3 Qd5 29. Ra7 Bb7 30. Rb7 Qc4 31. Qf6 Ka3 32. Qa6 Kb4 33. c3 Kc3 34. Qa1 Kd2 35. Qb2 Kd1 36. Bf1 Rd2 37. Rd7 Rd7 38. Bc4 bc4 39. Qh8 Rd3 40. Qa8 c3 41. Qa4 Ke1 42. f4 f5 43. Kc1 Rd2 44. Qa7 Download the mp3 file Subscribe in iTunes >>> From recent débuts to classics, fiction to non-fiction, memoirs, philosophy, science, history and journalism, Burning Books separates the smoking from the singeworthy, looking at the pleasures (and pains) of reading, the craft of writing, the ideas that are at the heart of great novels as well as novels that try to be great, but don’t quite make it. http://litopia.com/shows/burn/

1. e4 d6 2. d4 Nf6 3. Nc3 g6 4. Be3 Bg7 5. Qd2 c6 6. f3 b5 7. Nge2 Nbd7 8. Bh6 Bh6 9. Qh6 Bb7 10. a3 e5 11. O-O-O Qe7 12. Kb1 a6 13. Nc1 O-O-O 14. Nb3 ed4 15. Rd4 c5 16. Rd1 Nb6 17. g3 Kb8 18. Na5 Ba8 19. Bh3 d5 20. Qf4 Ka7 21. Rhe1 d4 22. Nd5 Nbd5 23. ed5 Qd6 24. Rd4 cd4 25. Re7 Kb6 26. Qd4 Ka5 27. b4 Ka4 28. Qc3 Qd5 29. Ra7 Bb7 30. Rb7 Qc4 31. Qf6 Ka3 32. Qa6 Kb4 33. c3 Kc3 34. Qa1 Kd2 35. Qb2 Kd1 36. Bf1 Rd2 37. Rd7 Rd7 38. Bc4 bc4 39. Qh8 Rd3 40. Qa8 c3 41. Qa4 Ke1 42. f4 f5 43. Kc1 Rd2 44. Qa7 Download the mp3 file Subscribe in iTunes >>> From recent débuts to classics, fiction to non-fiction, memoirs, philosophy, science, history and journalism, Burning Books separates the smoking from the singeworthy, looking at the pleasures (and pains) of reading, the craft of writing, the ideas that are at the heart of great novels as well as novels that try to be great, but don’t quite make it. https://litopia.com/shows/burn/

Dr Seymour talks to ecancertv at EHA 2014 about a new oral drug, ABT-199/GDC-0199, which was designed to exclusively mimic the binding of the “BH3” structural element of the BCL-2 protein in CLL, to restore the regulatory process that tells cancer cells to self-destruct.

Der programmierte Zelltod (Apoptose), ist ein evolutiv konserviertes Selbstmordprogramm der Zelle, um auf äußere oder endogene Signale zu reagieren. Es dient dazu, überflüssige und/oder geschädigte Zellen zu entfernen. Dieser Prozess ist bei Krankheiten wie z.B. Krebs teilweise außer Kraft gesetzt, und bei Parkinson- oder Alzheimer-Erkrankung zu stark ausgeprägt. Im Rahmen dieser Arbeit wurden zwei Gene biochemisch und molekularbiologisch näher charakterisiert. Bei diesen zwei Genen, die mit Hilfe eines speziell zur Identifikation dominanter, Apoptose–induzierender Gene entwickelten Screnningsverfahrens identifiziert wurden, handelt es sich um CybL, eine Komponente von Komplex II der Atmungskette, und um Saip (Small apoptosis inducing protein) einem Protein, das am endoplasmatischen Retikulum (ER) lokalisiert ist. Bisher war bekannt, daß die Atmungskettenkomplexe I und III bei der Fas-Ligand und der Ceramid-vermittelten Apoptose beteiligt sind. Über einen Zusammenhang von Komplex II und Apoptose-Induktion war zu Beginn dieser Arbeit nichts beschrieben. Im Rahmen dieser Arbeit wurde entdeckt, daß neben CybL kann auch noch die kleine Untereinheit von Komplex II (CybS) Apoptose auslösen kann, wohingegen die übrigen Komponenten von Komplex II, das Flavinprotein (FAD) und das Eisen–Schwefelprotein (FeS), nicht in der Lage sind, Apoptose zu induzieren. Die laut Datenbank vorhergesagten vier Transmembrandomänen von CybL sind für die apoptoseinduzierende Eigenschaft notwendig. Darüber hinaus führt nur eine 3,8–fache Induktion von CybL über dem endogenen CybL zu Apoptose in Säugetierzellen. In der vorliegenden Arbeit konnte auch gezeigt werden, daß CybL einerseits bei Überexpression Apoptose induzieren kann, und andererseits Apoptose durch seine Inaktivierung reduziert wird. Daß CybL damit ein spezifischer Sensor für Apoptose ist, konnte dadurch ermittelt werden, daß eine Reihe verschiedener Apoptosestimuli (Doxorubicin, Etoposid, Menadion, Cisplatin, Taxol) und der Fas-Rezeptor einen intakten Komplex II zur Signalvermittlung benötigen. Dazu wurde mit sogenannten B9/B30 Zellen gearbeitet. B9/B30-Zellen sind Lungenfibroblasten aus Hamsterzellen, in denen CybL inaktiv ist (B9), wohingegen die B30-Zellen ein Fusionsprotein zwischen CybL und GFP enthalten, welches die physiologische Aktivität von Komplex II wiederherstellt. In den B9-Zellen ist die Apoptoseinduktion durch Cytostatika (Ausnahme Arsentrioxid) bzw. durch den Fas-Rezeptor reduziert, verglichen mit den B30-Zellen. Auch Untersuchungen an HeLa WT- bzw. HeLa 0-Zellen (die keine intakte Atmungskette besitzen) zeigten, daß für die Apoptoseinduktion mit den oben genannten Reagenzien eine intakte Atmungskette benötigt wird. Im Jahre 2000 wurde CybL als Tumosupressor beschrieben. Es ist daher zu vermuten, daß die Tumorsuppressor-Eigenschaften von CybL auf der Fähigkeit von Komplex II beruhen, proapoptotische Signale aufzunehmen und weiterleiten zu können. Bisher war bekannt, daß eine transiente Inhibition einiger Atmungskettenkomplexe (Komplex I, II, III) zur Bildung von reaktiven Sauerstoffintermediaten (ROI) führt. Es konnte gezeigt werden, daß auch CybL bei Überexpression reaktive Sauerstoffintermediate produziert, und daß viele proapoptotische Signale zur spezifischen Inhibition von Komplex II führt. Da bereits eine geringe Expression von CybL ausreichend ist, um Komplex II zu inhibieren, und dadurch Apoptose ausgelöst wird, kann Komplex II als spezifischer Sensor für Apoptose angesehen werden. Das bisher unbekannte Gen mit dem Namen Saip löst dominant Apoptose in Säugetierzellen aus. Die proapoptotische Eigenschaft von Saip ist vermutlich auf einen evolutiv konservierten Mechanismus zurückzuführen, da auch ein Homolog aus C.elegans nach transienter Transfektion in Säugerzellen Apoptose auslöst. Dabei induziert Saip Caspase-abhängige Apoptosewege, die zur Apoptose-typischen DNA–Fragmentierung und Bildung von apoptotischen Körperchen (Membran blebbing) führt. Es konnte auch eine physikalische Protein-Proteininteraktion (mittels Co-Immunpräzipitation) mit Bap31 gefunden werden. Dieses Protein ist ebenfalls am ER lokalisiert und Bestandteil eines lokalen Apoptose-Sensors, der einen Proteinkomplex mit Procaspase-8L sowie antiapoptotischen Mitgliedern der Bcl-2-Familie (Bcl-2 bzw. Bcl-XL) bildet. Des weiteren interagiert Saip auch mit einer Deletionsmutante von Spike (Small protein with inherent killing effect-SpikeN19), einem neuen proapoptotischen BH3-only Protein, das ebenfalls am ER lokalisiert ist, und an Bap31 bindet. Saip ist ein ubiquitäres Protein und wird in sehr vielen der getesteten Gewebe und Zelltypen exprimiert. Im Northern-Blot-Verfahren konnte vergleichsweise eine hohe Expression an humaner Saip-mRNA in Niere, Placenta, Herz, Leber, Dünndarm und Skelettmuskulatur detektiert werden. Mit Hilfe von weiteren Northern-Blots wurde herausgefunden, daß Saip durch diverse Reagenzien, die bekanntermaßen Apoptose induzieren können, transkriptionell hochreguliert wird. So ist zum Beispiel das Signal von Saip nach 5-Fluorouracil-Behandlung (5FU), um das 80-fache gegenüber der Kontrolle erhöht. 5FU ist ein sehr effektives und bekanntes Zytostatikum, das in der Klinik zur Behandlung von Colon- und Mammakarzinomen erfolgreich eingesetzt wird. Wird Saip mittels der RNAi–Methode deaktiviert, wird die 5FU-induzierte Apoptose um 1/3 reduziert. Saip könnte somit eine wichtige Rolle in der Behandlung von Tumoren spielen, die mit 5FU therapiert werden.

During my PhD thesis I was working on the identification of novel apoptosis-inducing genes by using a novel genetic expression screen (Grimm and Leder, 1997). One of the identified genes turned out to be a evolutionary conserved cDNA that codes for a novel BH3-only protein of 219 amino acid residues which was named Spike, for Small protein with inherent killing effect. Spike was then in the course of my PhD thesis extensively characterised, molecularly and biochemically. In summary, upon overexpression in mammalian cells Spike efficiently leads to all features of apoptosis, such as phenotypic alterations, cytochrome c release, caspase activation and DNA degradation. It was shown that Spike localised to the endoplasmic reticulum, where it interacts with a recently identified apoptosis regulating protein complex, consisting of Bap31, Bcl-2, Bcl-XL and an ER-specific isoform of caspase-8: pro-caspase 8L (Breckenridge et al. 2002). Although no direct interaction with anti-apoptotic members of the Bcl2-family could be observed, the importance of the BH3-like sequence for the apoptosis-inducing activity of Spike was demonstrated by using point mutations of conserved amino acid residues of this motif (Mund et al. 2003). Instead of directly interacting with anti-apoptotic members of the Bcl-2 family Spike is able to interfere with the complex formation between Bap31 and Bcl-XL. Based on these data I proposed a model according to which the complex on Bap31 is controlled by Bcl-2/Bcl-XL as long as they are associated. Displacement of Bcl-2/Bcl-XL from Bap31 by Spike leads to the formation of a pro-apoptotic complex. In addition, Spike appears to be implicated in the cell death signal of the Fas receptor. I observed that a dominant-negative version of Spike and a highly effective anti-sense oligonucleotide significantly reduced Fas-mediated DNA fragmentation whereas no reduction was detected in TNFa-induced cell death (Mund et al. 2003).

Durch die systematische Umsetzung von Lithiumtetrahydroboraten mit verschieden substituierten Pyridin-Liganden gelingt es, Regelmäßigkeiten in den erhaltenen Strukturen zu erkennen. Bei Substitution an der para-Stellung der Pyridinringe ändert sich die Zusammensetzung der Verbindung im Vergleich zu LiBH4ž3 py (1) nicht. Das Tetrahydroborat zeigt m2- oder m3-Koordination zum Lithiumion. Bei einfacher ortho-Substitution der Pyridinringe wird eine Verbindung der Zusammensetzung (LiBH4ž2 L)2 erhalten, in der das Tetrahydroborat über ein 2m1 1, m1 2-Koordinationschema zwei Lithiumatome verbrückt. DFT-Rechnungen bestätigen, dass dieses Dimere sich durch besondere Stabilität auszeichnet. Hingegen wird bei zweifacher ortho-Substitution eine monomere Verbindung der Zusammensetzung LiBH4ž2 L erhalten. Durch die Verwendung von Pyridin als Lösemittel gelingt es, Solvate von Lithiumtetrahydroborat mit den Liganden Ethylendiamin und Diethylentriamin darzustellen. Der Vergleich zwischen den Solvaten des Lithiumtetrahydroborates und Lithiumhalogeniden zeigt, dass nur bei guter Solvatation des Lithiumkations analoge Strukturen vorliegen. Pyridin als Lösemittel eignet sich auch zur Darstellung der Kronenether-Solvate von Natrium- und Kaliumtetrahydroborat. Mit KBH4ž18-Krone-6 (24) gelingt erstmalig eine Einkristallstrukturanalyse eines KBH4-Solvates. Durch Verwendung von 18-Krone-6 kann die Struktur des Kaliumborinats KH2BC5H10 (25) aufgeklärt werden. Da zwischen dem Borinat und dem Kaliumion hauptsächlich ionische Wechselwirkungen auftreten, zeigt es deutlich andere Bindungsparameter als die analoge Zirkonverbindung. Insbesondere ist der Bor-Kohlenstoff-Abstand signifikant länger. Ferner gelangt es, Strukturen von vier Amin-Solvaten des Magnesiumtetrahydroborates zu bestimmen. Dabei zeigt sich, dass das Tetrahydroborat-Ion durch Liganden vom Magnesiumatom verdrängt werden kann. Während in Mg(BH4)2ž3 tBuNH2 (28) der durchschnittliche Magnesium-Bor-Abstand 2.537(2) Å beträgt, wird in Mg(BH4)2ž4 py (30) ein Abstand von 2.988(4) Å gefunden. In [Mg(BzlNH2)6](BH4)2 (31) wird das Tetrahydroborat vollständig von dem Magnesium-Ion verdrängt. Durch den Zusatz von einem Äquivalent Wasser gelingt es, Pyridin mit LiBH4 zu Dihydropyridin zu reduzieren. Ohne Wasserzusatz verhält sich LiBH4 gegenüber Pyridin inert. Das Produkt Lithiumtetrakis(1,4-dihydropyridyl)boratž4 py (32) konnte durch Röntgenstrukturanalyse charakterisiert werden. Es handelt sich um das Bor-Analoge des Landsbury-Reagenz, das Aluminium als Zentralatom enthält. Nach Hydrolyse wird 1,4-Dihydropyridin erhalten. Die Umsetzung von Tetrahydroboraten mit Alkoholen und Carbonsäuren eignet sich nur in wenigen Fällen zur Darstellung substituierter Hydroboraten HnB(OR)4-n - bzw. HnB(O2CR)4-n -. Durch die Reaktion von LiBH4 mit 2,2´-Dihydroxybiphenyl in den sekundären Aminen Piperidin, Morpholin und Pyrrolidin als Lösemittel (Gleichung 35) werden gemischte Borate leicht erhalten. Auch bei der Umsetzung von Alkoholaten mit BH3žthf werden verschiedene, von dem eingesetzten Alkoholat abhängige, Reaktionsprodukte erhalten. Auf diesem Weg gelang es NaBH3NCS darzustellen. Mit NaBH3NCSž15-Krone-5 thf (37) war es erstmals möglich, eine nicht fehlgeordnete Struktur mit dem Anion BH3NCS- zu untersuchen. Wie durch IR- und 14N-NMR-Spektroskopie vorhergesagt, liegt 37 als Isothiocyanato-Komplex vor. Der B-NAbstand wird zu 1.575(5) Å bestimmt. Die durch DFT-Rechnung für das Anion BH3NCS- vorhergesagten Bindungsparameter stimmen gut mit den experimentell erhaltenen überein. Phthalsäure reagiert mit BH3žthf unter Bildung von Phthalatohydroborat. Dies kann als Edukt für die Synthese von Monohydroboraten HBR3 - mit sterisch anspruchsvollen Resten R verwendet werden. Deren Darstellung gelingt für R = tBu, OtBu und NMePh. Doch nur für R = tBu wurden Einkristalle erhalten. Für R = OtBu konnten Kristalle isoliert werden, die neben zwei Zersetzungsprodukten auch NaHB(OtBu)3 enthalten. Die Umsetzung von Nukleophilen mit Catecholboran führte in keinem Fall zu dem erwarteten Monohydroborat. Wird Lithiumpiperidid als Nukleophil verwendet, so gelingt es Li2Cat2BHždmežthf (43) zu isolieren. 43 ist formal als Additionsprodukt des bislithiiertem Catechols mit Catecholboran aufzufassen. Das Auftreten von 43 gibt wertvolle Einblicke in den Mechanismus des Ligandenaustausches. Neben NaHB(OtBu)3 (40) ist 43 bisher das einzige durch Röntgenstrukturanalyse charakterisierte Trialkoholatohydroborat. Die Verbindung Na[CatB(NCS)2] (42), die bei der Umsetzung von Catecholboran mit Natriumthiocyanat als Nebenprodukt auftritt, zeigt ein außergewöhnliches NMR-Spektrum. Sowohl im 11B- als auch im 14N-NMR-Spektrum ist die 1J(11B-14N)-Kopplung aufgelöst. Sie beträgt 24 Hz. Mit 42 gelang es zu erstem mal, eine Verbindung, die diese Kopplung zeigt, zu isolieren und in ihrer Struktur aufzuklären. Die Zusammensetzung des Reagenz BBN-CN, das durch Umsetzung von 9-BBN-H mit Natriumcyanid entsteht, wurde durch 11B-, 13C-NMR-Spektroskopie und Einkristallstrukturanalyse aufgeklärt. Es handelt sich bei 44 um das doppelte Addukt von 9-BBN-H an CN-. Die Umsetzung von Thiocyanat mit 9-BBN-H führt zu dem 1:1 Isothiocyanato-Addukt 45. Die experimentellen Befunde, dass Amide und Alkoholate zur Destabilisierung von substituierten Hydroboraten HnBR4-n - führen, wohingegen Cyanid und Thiocyanat diese stabilisieren, wird durch DFT-Rechnungen bestätigt.