Podcasts about CD8

 | Artist  | Title  | Album Name  | Album Copyright  | Alger "Texas" Alexander  | Bantam Rooster Blues (1927)  | Complete Recorded Works, Vol. 1 (1927 - 1928)  | Roy Bookbinder  | Travelin' Man  |   |   | Jake Leg Jug Band  | Kitchen Man  | LIve At The Audley Theatre   | Tight Like That  | How You Want Your Rolling Done  | Shake That Thing [The Blues In Britain 1963-1973]  | Snooks Eaglin  | Mailman Passed  | That's Alright  |   | Chris Kramer & Paddy Boy Zimmermann  | The Duck Yas Yas Yas  | Tales of Tampa  |   | Blind Willie Johnson  | Dark Was The Night (Cold Was The Ground)  | Satan's Blues  |   | Big Bill Broonzy  | Border Blues  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Johan 'Bottleneck John' Eliasson  | Broken  | Road Worn  |   | Geiger von Muller  | Cosmic Cruiser  | Slide Sonatas II  | Lightnin' Hopkins  | Whiskey Headed Woman  | Blues Master Works: Lightnin' Hopkins  | Robert Lockwood Jr.  | Take A Little Walk With Me  | I Got To Find Me A Woman  | Scott Low  | Gamblin' Man  | Appalachian Blues  |   | Etta Baker  | Talks About The Banjo  | Sisters Of The South (Cd2)  | Blind Blake  | West Coast Blues  | All the Published Sides  | Son House  | Special Rider Blues  | The Delta Blues Of Son House  | Bessie Jones & with the Georgia Sea Island Singers  | There Was An Old Lady from Brewster  | Get In Union  | Alan Lomax Archives/Association For Cultural Equity

 | Artist  | Title  | Album Name  | Album Copyright  | Rory Block  | Death Don't Have No Mercy  | I Belong To The Band  | Tom Doughty  | Girl from the North Country  | You Can't Teach An Old Dog  | Charles -Cow Cow- Davenport  | Back in the Alley  | Complete Recorded Works, Vol. 1  | Big Bill Broonzy  | I'll Start Cutting On You  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Mike Ross  | Don't Say A Word  | Tennessee Transition  | The Jake Leg Jug Band  | Your Feet's Too Big  | Fifth Avenue  |   | Adam Franklin  | Falling Rain Blues  | England's Newest Hit Maker - The Best Of Adam Franklin  | Hans Theessink  | Early This Morning Blues [WISHING WELL]  | Wishing Well  |   | Michael Messer  | The Rising Sun  | Rhythm Oil 1993  |   | The Curse of K.K. Hammond  | Death Roll Blues  | Death Roll Blues  |   | Half Deaf Clatch  | A Road Less Travelled  | A Road Less Travelled  | Seasick Steve  | Happy (To Have A Job)  | Man From Another Time  | Stompin' Dave  | Supposed To Do  | Acoustic Blues  |   | Gary Grainger  | Nobody's Fault But Mine  | Mistakes and Out-takes  | Jimmy Womack  | Talking Blues  | Playing for the Man at the Door Disc 3  | Furry Lewis  | Cannonball Blues  | In His Prime 1927-1928

Dr. Tara Reid from the University of Washington Division of Allergy & Infectious Diseases and Dr. Meena Ramchandani discuss Dr. Reid's recent study to identify key T. pallidum proteins which stimulate CD4 T cell response to syphilis. View episode transcript and reference at www.std.uw.edu.This podcast is dedicated to an STD [sexually transmitted disease] review for health care professionals who are interested in remaining up-to-date on the diagnosis, management, and prevention of STDs. Editor and host Dr. Meena Ramchandani is an Assistant Professor of Medicine at the University of Washington (UW) and Program Director of the UW Infectious Diseases Fellowship Program. 

The body's immune response to syphilis and how the response impacts the development of a vaccine is complex. Dr. Tara Reid from the University of Washington Division of Allergy & Infectious Diseases delves into the various responses and the difficulties of vaccine development with Dr. Meena Ramchandani. View episode transcript at www.std.uw.edu.This podcast is dedicated to an STD [sexually transmitted disease] review for health care professionals who are interested in remaining up-to-date on the diagnosis, management, and prevention of STDs. Editor and host Dr. Meena Ramchandani is an Assistant Professor of Medicine at the University of Washington (UW) and Program Director of the UW Infectious Diseases Fellowship Program. 

Featuring an interview with Dr Steven Horwitz, including the following topics: Overview of peripheral T-cell lymphomas (PTCLs) (0:00) Efficacy and safety of brentuximab vedotin in the management of treatment-naïve and relapsed PTCLs (9:57) Emerging therapeutic strategies for PTCLs (19:48) Case: A man in his early 50s with CD30-positive anaplastic large cell lymphoma who experienced complete response (CR) to BV-CHP and continued remission after consolidation with autologous stem cell transplant (ASCT) (25:53) Management of ALK-positive anaplastic large cell lymphoma (32:14) Case: A man in his late 50s with CD8-positive PTCL not otherwise specified who achieved CR with CHOEP and experienced relapse after ASCT (34:33) Case: A woman in her early 70s with chemorefractory CD30-positive angioimmunoblastic T-cell lymphoma (38:26) Ongoing first-line studies for T-cell lymphomas; association of CAR T-cell therapy with T-cell malignancies (42:18) CME information and select publications  

Matt was joined by Jen Schultz, who is the DFL nominee in the 8th Congressional district against Republican incumbent Pete Stauber. CD8 includes Duluth, the Iron Range and other areas in northeast Minnesota.

Matt was joined by Jen Schultz, who is the DFL nominee in the 8th Congressional district against Republican incumbent Pete Stauber. CD8 includes Duluth, the Iron Range and other areas in northeast Minnesota.

0:00 Republicans and Democrats agree with Prop 140 groundswell opposition. Angela breaks down the dishonest “end the ban” campaign pro abortion prop 139'ers are running. Every time she talks, Kamala Harris is massively annoying the male demo and they're running away to Trump!  24:24 PROP 487, BBB tax discussion with Heidi Hansen, Director of the Economic Vitality Department of the City of Flagstaff. 38:30 HOW to CHECK the status of your ballot! www.My.Arizona.Vote  43:00 Abe Hamadeh talks about the border and the drug cartels and the need to “go to war against these barbarians”. We also hit on the election system and what the country looks like after November 5th.  Abe is a candidate for CD8. https://www.abeforaz.com 63:00 NAZ and its TWO Seasons.  67:00 I answer listener questions (talkwithjeff@icloud.com) mostly asking me to answer specific election issues.  83:20 Is there a new danger on NAZ roads? Olivia sheds light on it!     https://talkwithjeff.podbean.com/e/abe-hamadeh-is-a-cartel-war-coming-ep-1996/   —————————————— Please FOLLOW or SUBSCRIBE to the Jeff Oravits Show! RUMBLE   YouTube   ApplePodCasts   AmazonMusic   Spotify        Also on Twitter and www.TalkWithJeff.com   Disclaimer: The information provided on the Jeff Oravits Show does not constitute legal, medical, financial or tax advice.  All information is the opinions of the host's and his guests.  You should always seek the advice of a professional regarding any of these complex issues to make sure all circumstances of your situation are properly considered.   ——————————————

 | Artist  | Title  | Album Name  | Album Copyright  |  | Seasick Steve  | Just Because I Can  | Man From Another Time  |   | Amedie Ardoin & Dennis McGee  | Two Step De La Prairie Soileau  | The Stuff that Dreams are Made Of (disc 1)  | Pink Anderson  | In The Jailhouse Now  | Blues Legend  |   |   | Charles -Cow Cow- Davenport  | Alabama Strut  | Complete Recorded Works, Vol. 1  | Guy Davis  | Ramblin' All Over  | The Adventures Of Fishy Waters In Bed With The Blues (2012)  -   | Ma Rainey  | Little Low Mama Blues  | Classic Blues Artwork From  the 1920's  | Gary Fletcher.  | It's Just Feel.  | River Keeps Flowing'  |   |   | Seasick Steve & The Level Devils  | Cheap  | Cheap  |   |   |   | Big Bill Broonzy  | Why Do You Do That To Me  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | The Jake Leg Jug Band  | Your Feet's Too Big  | Fifth Avenue  |   |   | Arthur Montana Taylor  | Five O' Clocks (NYC 28/6/47)  | Montana Taylor  |   |   | Bukka White  | The Promise True And Grand  | The Vintage Recordings 1930 -1940  | Gladys Bentley  | Ground Hog Blues (1928)  | Broadcasting the Blues, volume 2  | Merle Travis  | Louisiana Boogie  |   |   |   | Blind Willie McTell  | That Will Never Happen No More (Remastered 2018)  | Last Session - Remastered  | Prestige/Bluesville Records  | J.B. Lenoir  | If I Get Lucky  | American Folk Blues Festival 1962-1965  CD5  |  

Dr. John Lewis earned his BS in Business Administration from University of Tennessee, his MS in Exercise Physiology also from the University of Tennessee and then his PhD in Education and Psychological Studies from University of Miami in Coral Gables, Florida. In the 90's and early 2000's he grew in rank at the University of Miami Miller School of Medicine in various areas of research. I tracked him down in 2014 to find out more about his study titled “The Effect of an Aloe Polymannose Multinutrient Complex on Cognitive and Immune Functioning in Alzheimer's Disease”.RESOURCES:Get Daily Brain Care:https://drlewisnutrition.com/Visit the Show Blog Page:https://drhaley.com/reversing-alzheimers-diseaseSubscribe to Dr. Lewis on YouTube:https://www.youtube.com/channel/UC5xvuUBaSGsAuSo4ZxhNR0AGet Aloe from Haley Nutrition:https://haleynutrition.com/Who is Dr. Reg McDaniel:https://www.drreg.net/about/TIMESTAMPS:00:00 Intro Snip00:41 Introduce Dr. John Lewis01:40 How is it possible "Sugar Is Good For You"?04:07 What was the study "The effect of an aloe poly mannose multi nutrient complex on cognitive and immune functioning in Alzheimer's disease" about?04:25 Why aren't studies of this nature typically financed through organizations like NIH and Alzheimer's Association?10:33 Why a couple was willing to donate so much money to study nutrition for a disease process when even positive results would only amount to dietary recommendations11:25 A psychiatrists perspective that food could never help - only drugs work. (He was wrong!)12:10 Why doctors are so blind to the fact that nutrition plays such a large role in the allowance of and recovery from disease.13:00 Dr. Reg McDaniel's ("Reg") story about realizing how nutrition plays a role in disease and may even make the HIV viral load undetectable.16:50 How Dr. Wesley Calvin, a naturopath, had patients with HIV that became "HIV undetectable" by consuming aloe vera.20:30 How the psychiatrist that was part of the aloe multi-nutrient study came to realize that nutrition could make a difference.22:19 What was the product used in the study on cognitive health and Alzheimer's disease?23:37 how positive were the results of this study?23:56 What is the "ADAS-Cog"?24:55 What is the difference between clinically and statistically significant?28:41 What is the amount of product people had to have to get these positive results and is more better?29:53 Can you consumer more than is recommended?30:27 What is your theory on how the mechanism of the benefit was?31:07 What is the CD4 to CD8 ratio and how was it affected by the multi-nutrient complex used in your study?33:20 How did the polymannose multi-nutrient product affect stem cell production?35:10 What is neuroplasticity?37:10 What is the summary of benefits shown by this study?39:40 Product Reveal "Daily Brain Care" in the canister and capsules44:49 What are the special sugar molecules found in the "Daily Brain Care" products?52:00 The study done in the 30's showing mannose when given to rats that were in ketosis53:27 Dr. Robert LoPinto who mentioned Dr. John Lewis and his lecture at the FCA55:08 What is the principle investigator?55:43 What does "peer reviewed" mean?

Jen Schultz, Congressional candidate for CD8 joins the show; Matt discusses her opponent Pete Stauber; more fallout from Trump campaign violations at Arlington National Cemetery; Republican racism in money allocations; right-wing media goes after Democratic-donating State Fair donut stand; Bloomington Kennedy will drop hockey; disappointing test results; Michael Brodkorb makes a visit.

Kari Lake advances to face far left Democrat, who now plays the part of centrist, Rubin Gallego. No surprise! But what were the surprises Tuesday night in the Arizona Primary? Rob Wilson joins me to break down the BIG results in LD1 between Ken Bennett & Mark Finchem, LD7 and the controversial race for the AZ House as well as the slugfest between Wendy Rogers and David Cook in the LD7 senate race. We'll also hit on the CD2 and CD8 congressional races and several mayoral elections. We'll also analyze and guess as to what this all means going into the general election in November.    Rob and I also discuss an attempt to block uranium ore transport in NAZ, another grilling of the Secret Service by Congress, the Middle East flaring up even more and a windmill story.    —————————————— Please FOLLOW or SUBSCRIBE to the Jeff Oravits Show! RUMBLE   YouTube   ApplePodCasts   AmazonMusic   Spotify        Also on Twitter and www.TalkWithJeff.com   Disclaimer: The information provided on the Jeff Oravits Show does not constitute legal, medical, financial or tax advice.  All information is the opinions of the host's and his guests.  You should always seek the advice of a professional regarding any of these complex issues to make sure all circumstances of your situation are properly considered.   ——————————————

A video snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Shane Crotty: A Landmark Study on Upper Airway Mucosal ImmunityTranscriptThis is the first time a Ground Truths podcast is being posted simultaneous with a new publication, this one in Nature, by Professor Shane Crotty and his colleagues at La Jolla Institute for Immunology. Shane is one of the leading immunologists and virologists in the country; he and his group published in 2020 the first detailed analysis for how our immune system responds to SARS-CoV-2. Shane also, among many other notable contributions during COVID, illuminated the role of hybrid immunity vs COVID, the differences between and additivity of vaccination and infection.Today's paper in Nature is indeed a landmark contribution doing something that hasn't been done before—to understand the underpinnings of mucosal immunity of the upper airway. 100 participants had monthly nasal and nasopharyngeal swabs throughout the pandemic. With a median of >100,000 cells per swab recovered, they undertook single-cell sequencing and full characterization of the cells (tissue-resident memory B cells, CD4+ and CD8+ T cells, germinal center follicular helper T cells and B cells, etc.) to determine optimal immune protection of the upper airway, the effect of infections by different variants, breakthrough infections, vaccination, and age.Here is the transcript of our conversation about the new report with links to the audio:Eric Topol (00:06):Hello, it's Eric Topol with Ground Truths, and with me today is Professor Shane Crotty from the La Jolla Institute of Immunology (LJI), not too far away from where I work at Scripps. And Shane has been a go-to immunologist colleague here in the Mesa, and he and his colleagues were the ones that really first published the response to SARS-CoV-2 as far as the immunologic response. And today we're doing something very unique. We're going to go over for the first time in the two year plus history of Ground Truths, going to have a publication with at least simultaneous or near simultaneous podcast. Shane, welcome and congratulations on this really important paper in Nature.Shane Crotty (00:57):Thanks, Eric. Thanks for having me. Yeah, somebody asked if I was going to go over to Scripps for the podcast and I was like, yeah, we could.Eric Topol (01:06):You could. You could. But no, it's good. And it's nice having the logo of this great institute you work at right in the right corner. And you've done so many contributions with your colleagues at La Jolla Institute. It's really a privilege to have a chance to learn from you and particularly about what we're going to talk about today, which is mucosal immunity to upper airway infections, which is especially germane to COVID. And we're actually in the middle of a significant wave of COVID right now. And I guess it would maybe be fair to say, Shane, that we've never truly understood the underpinnings, the real details of upper airway mucosal immunity. Is that a fair statement?Shane Crotty (01:53):Yeah, it is a fair statement.Eric Topol (01:56):Okay. So today we're going to crack the case. This paper from you and your colleagues, of course, you're the senior author and first author, Sydney Ramirez did a remarkable study. I mean, just extraordinary. This is why we're doing a special podcast about it. Maybe you could just kind of give us the overview of the design because you were doing things that haven't been done before.Shane Crotty (02:24):Sure. And, I would say the genesis even of it goes back to what you were introducing. I mean, during the pandemic, we like a lot of scientists spent a lot of time and energy trying to help understanding immune responses to this virus, and immune memory to this virus, and what was involved in protective immunity. And we're certainly proud of the work that we did. And it was hard work. And after a while we were exhausted and we stopped.Shane Crotty (02:59):And then we came back to it after a while and said, well, the virus is still here. And so many people have contributed so much to better understanding the virus and creating vaccines. But there are clearly still things we don't understand. What are those biggest knowledge gaps and where might we be able to contribute? And really to me the biggest one was location, location, location. This is a virus that infects your nose, infects your upper airway—your nose, and throat, and oral cavity. And then obviously if you get severe disease, the severe disease and death are from the lungs. And it's just been a big knowledge gap in terms of understanding what actually occurs in those tissues immunologically and what is associated with protective immunity or what could be associated with protective immunity. And sort of looking forward what might be helpful for mucosal vaccine development from things that we could learn.Shane Crotty (04:12):So we started from what we would call the basics, and what does immune memory look like in the upper airways in normal people? And that hasn't been available really even in, and we started this two years ago, even in the biggest atlases published of the human body. There was no upper airway tissue representation at all. And that's because technically it's just tough to access and difficult to reproducibly get at. And so, we recruited people to a group of 20 to 30 people to come to LJI once a month, and just started testing out, published and unpublished sampling techniques to see were there ways where we could reproducibly sample immune cells in the upper airways from people. And once we got things, so the keys for us were you got to have enough cells that you can collect to learn something from. And luckily with modern techniques of flow cytometry and single cell sequencing, you don't need that many cells. And so, we could get a hundred thousand cells on a swab and that's enough to do a lot with. And second, how reproducible was it? So we showed, we had people come in every month for a year and we could reproducibly find the same things in their swab; same cell types in their swabs. And the third thing was that people would come back.Shane Crotty (06:05):We found that if you have good nurses doing the techniques, we could find ways that this would be a sampling approach that was tolerable and people would come back for repeat measures, which is really valuable to see what's happening in people over time. So that was what we started from in the study and built from.Eric Topol (06:27):And if I am correct, you sampled two places with the swabs, one in the nose and one of the throat. Or, I think one which you have in the paper as the MT for something about the median nasal turbinate and the other adenoid in the back of the throat. Is that right?Shane Crotty (06:50):So all the sampling is a swab into your nose. And when we were doing that, we were really excited to see the diversity of immune cells, particularly T cells and B cells, memory T cells and B cells that we isolated. They're like, wow, there's actually a lot of interesting immune memory up in there. And the lab said, oh, by the way, we're seeing T follicular helper cells (TFH). Now that happens to be my favorite cell type.Eric Topol (07:22):Why is that, Shane? Of all the cells, why do you say that's your favorite? I know you publish a lot on it.Shane Crotty (07:31):Because those are the T cells that are required for basically all neutralizing antibody responses. All high-quality antibody responses depend on—almost all high-quality antibody responses depend on—T cell help. That T cell help comes from T follicular helper cells. Antibody evolution is certainly one of the coolest processes of the immune system. And all of that depends on T follicular helper cells. So the fact that for example, you could get Omicron neutralizing antibodies even after only being vaccinated with ancestral vaccine, that's the immune system making guesses of what variants would look like. And those guesses come about through this antibody evolution that's driven by T follicular helper cells. So, it's really one of the most brilliant things the immune system does, and that's a cell type that's really key, but those processes happen in lymphoid tissue. That's what happens in lymph nodes and spleen. And here we were sampling epithelium, your nasal epithelium, so the cells didn't really belong there.Shane Crotty (08:37):And so, that's what turned the study in another direction. And we said, okay, let's figure out why is it that these cells are present in these swabs? And we had a couple of possibilities. One possibility was that the swab was going all the way back to the posterior wall of your nasopharynx, your top of your throat and sampling adenoid tissue. So adenoid tonsils and adenoids are a true lymphoid tissue and they're a mucosal lymphoid tissue. And so, we came up with multiple ways to validate that that's what we were testing. And in fact, it was the Sydney Ramirez, a clinician, and the ENTs involved who said, well, let's just look. And so, they actually did endoscopies with the swab to actually see where the swab went. We've got videos of the swabs going into the adenoid crypt in the back, and then we've got measurements of here are the cells that you find on those swabs.Shane Crotty (09:58):And what's cool about it is that, yes, so we did studies with two sets. We then shifted to doing studies with two sets of swabs. One where we essentially went “halfway back” where we were detecting that epithelium of your nasal passages and then one where it was all the way back and detecting the adenoid lymphoid tissue. So here we've got two different sites in your upper airways that are about an inch apart, and we're detecting essentially completely different cells of the immune system at those two places. And we tend to think of the cells present in that epithelial tissue as probably the sentinels, the cells that are sitting there that can potentially immediately react and try and protect you against a viral or bacterial infection. Whereas the lymphoid tissue, the adenoids, is really about generating the immune responses in the first place and priming immune responses. And that's where these germinal centers can occur, which are where the TFH are where you can get antibody evolution. And so, we found in the course of the study that with this non-invasive technique that we can.Eric Topol (11:14):By the way, I don't want to be signing up for the one way up there because I mean just a mid-nose enough for me. So wow, I got to give credit to your study participants for coming back every month for a year to have that. Some people call it a brain biopsy.Video of swab of nasopharyngeal tissueShane Crotty (11:33):Right. So I will tell you, it is a different experience than the COVID nasopharyngeal swab might've gotten through your car window. If you're actually sitting down in a comfortable space and there's a nurse doing it with these particular goals. We really found, we had a hundred people in the study and a total of 300 swabs, and the vast majority of people came back if we asked them to.Eric Topol (12:06):That's great.Shane Crotty (12:07):And we're certainly very thankful for the volunteers. Obviously they were volunteering in the first place to participate. So I'm a little hesitant about the video because I've told people to not show it to potential volunteers because it definitely doesn't encourage you to volunteer. You're like, wait, that's what's happening? But actually, I've had it done on me.Video of the swab to the nasopharynx for adenoid (lymphoid tissue) access.Eric Topol (12:37):Not that bad.Shane Crotty (12:39):It's really pretty compelling. And by doing these repeated samples, we actually now have the capacity to look at ongoing immune responses like after an infection or vaccination in people and see how that results in the immune system changing and what might be the source of the protective immunity that comes up. So we've actually got data in the paper looking at this antibody evolution in real time. So we've got affinity maturation of B cells occurring in just normal healthy adults of mucosal B cells against COVID. And so, that's really helping us learn what's possible, basically to figure out, okay, if you're going to try and make a vaccine, what types of immune cells are even possible to generate in this tissue? And where might you try and generate them? Or if you're trying to study some disease state, what are types of cells that might be problematic?Eric Topol (13:45):Yeah, I mean, I think the idea that so many of us have been pushing for a nasal vaccine to induce mucosal immunity because, as you know very well, the current shots are not very good at any durable or substantial protection from upper airway infections of COVID or SARS-CoV-2 and other infections. So I think one of the most important parts of this report is that it lends itself well to helping towards artificially, if you will, make a vaccine to get the protective features that you were able to identify. Maybe you could just [speculate], if you had the ideal nasal airway, what would the cellular profile look like?Shane Crotty (14:44):Ah, I see. Yeah, great question. So, first of all, antibodies are great. So most of my career has been dedicated to most licensed vaccines. The correlate of protection is antibodies. Antibodies clearly can be protective, and if you can get them that's excellent, so certainly I would want, in terms of the non-cellular component, I would want antibodies present, neutralizing antibodies present in it.Eric Topol (15:26):Are these IgA or IgG?Shane Crotty (15:31):Yeah, in an ideal situation, what would I want? I'd want a mix of both, basically. The IgAs look like they have a little more protective efficacy, but the IgGs, just at a molecular level have a longer half-life, stick around a little. So yeah, I'd want both. And then really the premise for most of what we do is saying, in situations where antibody isn't enough or the antibodies don't stay around long enough, or you've got a variant that now obviates the protective efficacy of that particular antibody, are there other types of protective immunity you can have? And the immune system has other stuff besides antibodies for a reason. Of the lymphocytes in your blood, most of them aren't antibody producing cells. Most of them are other things. And so, well sticking with adjacent to antibodies, those antibodies in the mucosa, I'd want them to be made by cells that were literally right there. So plasma cells living in that site so that you've got basically the highest concentration of antibodies you can get because they're not having to diffuse through the whole body. They're just already at their highest concentration right there. Now antibodies come from B cells, that's what encodes the antibodies.Shane Crotty (17:03):And so, the B cells can make neutralizing antibodies if it turns out that you haven't made enough neutralizing antibodies, or if there's a variant that escapes those, maybe there are other B cells that could make, once you get infected, more B cells that could make more antibody rapidly infection, or B cells that recognize this variant that is mismatched to the current antibodies you have. But memory B cells are basically a library of different antibody specificities representing different guesses about what viral variants or structures might look like. And so, I would want memory B cells in that upper airway tissue that could reactivate quickly. There are memory B cells in your blood and we don't know how long it takes. And that's one of the reasons we're hoping we and others build upon this study. But it might take, let's say five days for memory B cells to go from your blood into your upper airway.Eric Topol (18:06):Oh, right.Shane Crotty (18:08):That's right, you were already quite sick by that point. Instead, if memory B cells are right there, as soon as virus showed up, they got activated. Now maybe after (we're not sure yet), but maybe after 48 hours those cells are now activated and doing something useful. That would be optimal. So then we can pivot to the T cell side. So there's a fantastic recognition that T cells being physically present in tissues, tissue resident memory cells, as they're most often called, can really have fantastic protective capacities. From a lot of mouse model systems where you can see T cells are in the skin or the liver, or whatever [tissue] are already there, they're more protective than if the cells are in the blood. So if you could also have T cells essentially permanently parked in the epithelium of your nasal passages and in the adenoid, hopefully those could essentially be sentinels for protective immunity, and as soon as you get infected, those T cells would reactivate and start killing off infected cells. 'That's the mix that I would want to see. And I think there's at least some reasonable evidence in the context of COVID that people who have T cells in their upper airways maybe manage to control the virus so quickly that it's a subclinical infection; they never notice when they get infected. And so, building on those types of observations, that's what I would want.Eric Topol (19:56):That sounds good. I like that. I'd like to have that in my nasal airway. Now, just to make sure I've got this, what you found, of course, the memory B cells, the T cell memory, CD8+, that is the cell-killing T cells that you mentioned, the resident T cells. One clarification on that, they are not really going to do much until there's been some cells that have been infected with the virus, right? Then they come alive and kill those cells. So they're not immediate, but they can work pretty quickly still though, right? If they're resident T cells?Shane Crotty (20:45):Yeah, in theory it might take as little as 12 hours for a virus to infect a cell, and then you get some antigen presentation on that cell that could activate the T cell.Eric Topol (20:58):And that's all happening perhaps within the incubation phase of the virus, right?Shane Crotty (21:07):Correct. That's a tough thing to study, but conceptually that's the way people tend to sketch it out.Eric Topol (21:13):Right. Now the other part of the story is, and you alluded to it earlier, is the lymphoid tissue up there, higher up where there are these germinal centers; is there anything different you want in these germinal centers? Do they contribute to mucosal immunity that you haven't already mentioned?Shane Crotty (21:36):So they really contribute in this forward looking sense or really in the classroom kind of sense. The germinal centers are where you're basically teaching the B cells in advance of seeing the infection either with your vaccine or with your previous infection, evolving better B cells and better antibodies and hopefully instructing them where to go reside to then be ready for the next infection. If you get really great protection that next time, hopefully then you don't need to start.Eric Topol (22:14):Right. So it's like the training grounds for this coordinated response, I guess. Now you also noted this, I mean this is a rich paper, which is we're illuminating something that's never been done before in human beings. I mean it's pretty damn important and impressive. But you also found that you had an age relationship. Can you tell us about that?Shane Crotty (22:39):Sure. This is one of our favorite parts of the study. I'd say in particular for several of the clinicians who were involved, because the general conversations people have about upper airway lymphoid tissue, like your tonsils and including your adenoids, is that adults don't really have functional lymphoid tissue in the upper airway that your tonsils atrophy by the time maybe you're 20 or something. So, immunologically, functionally, what that means is if you have let's say an intranasal vaccine or you get infected with a new [virus] like SARS-CoV-2, if those would normally be the sites that start your immune response, where does it now happen? And instead what we saw was, we had such a diverse group of people in our studies—we realized we had people from age 18 to 68—and so we could directly ask, in normal healthy individuals across a large age span of adulthood is there functional mucosal lymphoid tissue? And the answer was yes, it was there. But it definitely declines over time, and it's declining on a log scale. Our simplest statement was that 75% of everybody we sampled still had functional tissue, but the younger the people were, the more functional it was, and the more germinal centers actually we saw; again these training grounds.Eric Topol (24:35):So this is really important because we know for COVID and obviously for influenza and other respiratory infections that people of advanced age are much more susceptible. And here you are finding something that supports that ,and it's almost like, the thymus, it involutes. After that, what age 20, and our lymphoid tissue [involutes]. We're just set up to fail. Old codgers, like me we're defenseless, I guess, right?Shane Crotty (25:12):So what I've liked about that in a positive sense is that it's not that all of these things go to zero. Like for example, naive T cells are definitely less abundant in people over the age of 60 than under, but they're not zero. And the mucosal lymphoid tissue is definitely less abundant in people over the age of 60, but in most people it still wasn't zero. And I always think about these things from a vaccine immunology perspective, and fundamentally the difference between getting vaccinated and infected frequently is that the whole point of the vaccine is you get to generate the immune response on your own time. And so, even if you're starting with five times fewer T cells or five times fewer germinal centers, if you're getting to do all that training ground in advance, you can end up with just as many bispecific T cells as a 20-year-old or just as many memory B cells as a 20-year-old because these things occur on an exponential scale because of the cell divisions. And so, it might take you three extra days, for example, to get to the same level, which again, if you're racing a virus, can be the difference between life and death. But if it's not a race and if you're doing it in the context of a vaccine, it's a much smaller factor. And that's some of what we've been trying to learn.Eric Topol (26:42):Now we only have started to scratch the surface of your findings. One of the things that drives me nutty in reading papers, especially from great immunologists like you, is that in each figure there's like 20 different panels. We get to one of the figures, figure three is all the way to panel W. I mean that starts with A. That gives you a little impression of the data. It's rich, another one goes to N or R. I mean we're talking about a lot of data. So I've only started to really deconvolute what you've done here, which is just an amazing study. But what are some other things that we should touch on before wrapping up?Shane Crotty (27:35):A lot of the goal in this study was to establish baselines of what is normal in humans in the upper airways. And that's one reason why in this case there actually are a lot of figure panels because we could work out a bunch of individual parts of the immune system that really hadn't been characterized in this way before. And something we really cared about was durability of immune memory. It's often talked about, well, mucosal responses are inherently short-lived. And we're like, well, what does that mean? Does that mean there's just no memory? Is it different kinds of memory? And so, this is the first measurement of memory B cells in this tissue in an antigen specific way. And we were doing it in people who had had recent COVID breakthrough infections. And we saw really the mucosal memory was stable for six months. And so, to me that's quite encouraging that it's not one month and it's gone, at least with an infection, it's at least six months and it looks like it'll project out for substantially longer.Shane Crotty (28:53):Amongst those cells, many of them are IgA. IgA is this antibody isotype that's particularly mucosal associated. And only 5% of the memory B cells circulating in blood were IgA. Whereas many of the memory B cells in the local tissue were IgA, which we think is also telling us that there's a lot of immune memory and the immune system in this tissue that we're probably not sampling in the blood. And so, sampling blood's great, right? It's accessible and we can learn a lot from it, but it does look like there is some tissue compartmentalization.Eric Topol (29:37):Oh, not a question. And the findings you had of the resident T cell is so indicative of that. And what's really striking, of course Shane, is that as we assess the immune system in people at large, we look at a lymphocyte neutrophil ratio [in the blood], we get almost nothing. And then in the course of the pandemic, you and your colleagues there provided such granular data on B and T cells, CD4 and CD8 T cells, and that you illuminated things that are not done ever clinically. These are research, high tier research labs like yours. The only question I have on before I just wrap up with the nasal vaccine story, interferon wasn't really part of this. As we know SARS-CoV-2 can shut down the interferon response, it's considered a frontline part of the defense. Where does that fit into the mucosal immunity of the upper airway?Shane Crotty (30:46):Yeah, it's really important. And that's in this basic divide we do in the immune system, the innate immune system and the adaptive immune system. So everything I was talking about is the B cells, the T cells, and antibodies. That's all the adaptive immune system. That's all virus specific. And then the innate immune system is the generalists, and really sort of the fire alarm, just sensing some danger. And definitely in COVID interferon is very important. I'm quite intrigued to see if using these techniques. I'm curious to see if some of these other aspects of the immune system can compensate somewhat for the fact that this virus. To me, if this virus has one superpower, it's its incredible ability to evade triggering interferon for as long as it does. And that has this massive cascading effect to almost everything about the pandemic essentially. And so, I'm intrigued by whether in people who have immunity are there ways that these other cells of the immune system or even antibodies can do things when a viral infection occurs, that helps trigger the overall immune system to recognize that something's there, even in the absence of type 1 interferons. That's where I think for now it fits in.Eric Topol (32:14):Well. I think you've so aptly described, not surprisingly, the superpower of SARS-CoV-2, which I think a lot of people haven't realized that it's so good at shutting down that defense system. Now on the basis of you having really gotten this understanding of the mucosal immunity in the upper airway, does this make you think that the nasal vaccine that we aspire to have is more of a reality? Do you kind of know what the ideal profile might look like to keep people healthy and resist infections? Do you think this is achievable in any durable sense at high level success with a nasal spray vaccine?Shane Crotty (33:04):I'm optimistic for several reasons. One is we really saw a lot of different immune memory cell types that were present, that was encouraging and seeing the B cell memory durability for at least six months—pretty flat line for that six months—was encouraging. It looks like the immune system knows how to keep these cells around if it wants to for a significant period of time. We'll have to do more in follow up. But again, it was encouraging. Third, we had some people who were vaccinated only and some people who had breakthrough infections. And really in the vaccinated only, we didn't see T cell memory in the upper airways. And I actually consider that encouraging because it suggests local exposure does give you the memory and exposure in your arm really doesn't. So I think there is something to improve upon. It can be improved upon. And lastly, I get asked all the time, I'm sure you get asked all the time: Why aren't there more intranasal vaccines or inhaled vaccines, more mucosal vaccines in some way?Shane Crotty (34:25):And I think there's more than one reason, but I tend to be very practical, and I think one practical reason is there's very little to measure, to guide you in your vaccine development. If you have six ideas or six constructs that you think might work in humans as a nasal vaccine, you basically just have to pick one, try something, and hoping there's not much you can measure it clinical trials for what might be the type of response even. So for example, the FluMist vaccine, it's the only licensed inhaled vaccine, intranasal vaccine. In adults it doesn't have a clear correlate of protection. If you get vaccinated with that, your circulating antibody responses don't increase, but also increases in nasal antibody didn't correlate with protection well. So, what does that mean? That probably means there's other things going on up there that could be indicative of protection but weren't being measured before. So I'm hopeful with these types of approaches. Now, if you're an intranasal vaccine developer, you maybe have 4, 5, 6, 7, 8 ideas or constructs. If you can try those in a few people and make these different measurements and you've got your favorite immune profile that you might, now you have something to, it's more of an engineering problem. It's not a throwing a dart problem. You're like, yeah, this has given me the type of response that I like and I'm going to try and push this into clinical trials. So those are the things that I'm optimistic about moving forward.Eric Topol (36:04):Well, I love it because we really need it. And if anybody's optimistic that means a lot; it's yours. What you've done here has been quite extraordinary because you defined for the first time really the underpinnings of the mucosal immune response, the upper airway, you did it by age, you did it by variant, you did it by vaccine and infection. And most importantly, perhaps for longer term is you established what are the desirable features to have, which didn't exist before. It seemed like whatever I read for nasal vaccines, they were measuring some IgA or IgG, and they didn't get down to the memory B cells and the tissue resident T cells, memory cells, and all these other things that you found. You did all this single cell sequencing and flow cytometry. The work is just really fantastic. So Shane, just in closing, I just want to congratulate you.Eric Topol (37:05):You made seminal findings along the pandemic. You were the one that really illuminated hybrid immunity, the advantage of if you don't want to have an infection of COVID, but if you did have that and a vaccine, you kind of had some extra synergy, if you will. But here you've done something, you and your team. Unique. Congratulations on that. No surprise that it's in Nature this week. I'm sure a lot of people will share your optimism that we will have something beyond just shots in the future because COVID isn't going away. There's other respiratory pathogens. And finally, somebody did the right study, who knows immunology inside and out. So Shane, thanks very much.Shane Crotty (37:52):Thanks Eric. Very much appreciated particularly coming from you.*****************************************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

In this episode, we sit down with Dr. John Lewis, a leading expert in nutritional research and the therapeutic potential of Aloe polysaccharides. Dr. Lewis shares insights from his groundbreaking studies on Alzheimer's disease, multiple sclerosis (MS), and the broader impacts of Aloe polysaccharides on immune function and brain health. Key Topics Discussed Understanding Aloe Polysaccharides What are Aloe polysaccharides? How are they extracted and formulated for nutritional supplements? Research on Alzheimer's Disease and Multiple Sclerosis Overview of Dr. Lewis's studies on Alzheimer's disease and MS. Impact of Aloe polysaccharides on cognitive function and disease progression. Immune System Modulation Effects of Aloe polysaccharides on CD4 to CD8 ratios. Regulation of key cytokines: TNF-alpha, VEGF, and BDNF. Balancing TH1 and TH2 responses. Brain Care Formulation Detailed discussion on the Brain Care formulation developed by Dr. Lewis. Clinical results and patient outcomes. Challenges in Nutritional Research Funding difficulties for nutritional and supplement research. Issues with the pharmacological model of placebo-controlled randomized double-blind trials. Why this model is challenging for evaluating supplements and nutritional interventions. Future Directions and Innovations Potential future applications of Aloe polysaccharides in other health conditions. Innovations in nutritional research methodologies. Key Takeaways Aloe Polysaccharides: Naturally occurring compounds with significant therapeutic potential, particularly in modulating immune function and supporting brain health. Clinical Research: Dr. Lewis's studies highlight the positive effects of Aloe polysaccharides on Alzheimer's disease, MS, and overall immune health. Nutritional Research Challenges: The current pharmacological model of clinical trials poses challenges for the study of supplements, necessitating new research approaches. Research References Studies on Alzheimer's disease and Aloe polysaccharides: Positive impacts on cognitive function and disease markers. Research on MS: Aloe polysaccharides and their role in managing symptoms and progression. Immune modulation: Detailed findings on CD4/CD8 ratios, cytokines (TNF-alpha, VEGF, BDNF), and TH1/TH2 balance. Dr. John Lewis provides compelling evidence on the health benefits of Aloe polysaccharides and underscores the need for innovative research methodologies in nutritional science. This episode offers valuable insights for anyone interested in the intersection of nutrition, immune function, and brain health.Connect with Dr. John Lewis Website: Dr. John Lewis Nutrition If you want to get Daily Brain Care visit our online curated range of cutting edge longevity and anti-aging supplements at  BIO John E. Lewis, Ph.D. is the Founder and President of Dr Lewis Nutrition™. Dr. John E. Lewis has spent most of his career developing a unique approach as someone who "walks the walk" through all of his combined professional and personal experiences to attaining optimal health through nutrition, dietary supplements, and exercise. Throughout his research career, he has evaluated many different nutritional approaches to enhancing well-being, particularly for brain health, immune function, and counteracting aging. He can separate fact from fiction regarding how to utilize nutrition and dietary supplements to help you achieve and maintain optimal health. If you need a trusted source of information, products, and services, then look no further than Dr. Lewis and how he can help you achieve your health-related goals. Professional Career Dr. Lewis is past full-time Associate Professor in the Department of Psychiatry and Behavioral Sciences at the University of Miami Miller School of Medicine and the Founder and President of Dr Lewis Nutrition™. He is a Diplomate, Faculty Member, and Advisor of the Medical Wellness Association. He has been the principal investigator of over 30 different studies on human health in his research career. During that time, he either directly raised or indirectly supported raising over $23 million in grants, gifts, and contracts for research studies and clinical trials and educational programs for medical students. In addition to his research, Dr. Lewis has been an invited national and international lecturer and guest speaker at conferences and as a guest on television shows. He is a well-known author with over 180 peer-reviewed publications in some of the world's leading scientific journals. He has also mentored many different students, from undergraduates to post-doctoral trainees, in not only how to conduct clinical research but to apply the principles of health promotion into daily practice. Research Interests Much of Dr. Lewis's research has focused on evaluating the effects of nutrition, dietary supplements, and exercise on various aspects of human health. He and his colleagues have been continually searching for ways to help people achieve and maintain health through natural treatments that align with our physiology. A primary stimulus for the origin of Dr Lewis Nutrition™ occurred after Dr. Lewis ran his landmark study on how an aloe polysaccharide multi-nutrient complex improved cognitive and immune functioning after 12 months in persons with moderate to severe Alzheimer's disease, leading to the creation of the dietary supplement, Daily Brain Care. Daily Brain Care showed clinically and statistically significant improvements in cognition according to the ADAS-cog cognition score and statistically significant improvements in inflammation (according to TNFα and VEGF), immune function (according to the CD4/CD8 ratio), and adult stem cells (according to CD14+ cells). His seminal publication from the study in the Journal of Alzheimer's Disease not only spurred him to leave academics and pursue a science-based business career, but also enabled him to be selected for a widely-acclaimed TEDxMiami talk. Founding Dr Lewis Nutrition™ While Dr. Lewis still maintains an academic affiliation, he chose to leave a full-time research career to pursue his true passion of helping people achieve health through nutrition, dietary supplements, and exercise. His research in brain health and immune function was key in the creation of Daily Brain Care, but afterward he chose to shift into business where the opportunity to reach a larger audience is greater. Dr Lewis Nutrition™ is the vehicle through which Dr. Lewis leverages his many years of personal and professional work to spread a message of health that is so desperately needed, particularly for those who are afflicted with an all-too-common chronic disease, e.g., neurodegeneration, immune dysfunction, or cardiac and metabolic disorder. Dr. Lewis will continue to be a thought leader to help people utilize the power of nutrition and dietary supplements and learn how to take control of and optimize their health.         Personalised Health Optimisation Consulting with Lisa Tamati Lisa offers solution focused coaching sessions to help you find the right answers to your challenges. Topics Lisa can help with:  Lisa is a Genetics Practitioner, Health Optimisation Coach, High Performance and Mindset Coach. She is a qualified Ph360 Epigenetics coach and a clinician with The DNA Company and has done years of research into brain rehabilitation, neurodegenerative diseases and biohacking. She has extensive knowledge on such therapies as hyperbaric oxygen,  intravenous vitamin C, sports performance, functional genomics, Thyroid, Hormones, Cancer and much more. She can assist with all functional medicine testing. Testing Options Comprehensive Thyroid testing DUTCH Hormone testing Adrenal Testing Organic Acid Testing Microbiome Testing Cell Blueprint Testing Epigenetics Testing DNA testing Basic Blood Test analysis Heavy Metals  Nutristat Omega 3 to 6 status and more  Lisa and her functional medicine colleagues in the practice can help you navigate the confusing world of health and medicine . She can also advise on the latest research and where to get help if mainstream medicine hasn't got the answers you are searching for whatever the  challenge you are facing from cancer to gut issues, from depression and anxiety, weight loss issues, from head injuries to burn out to hormone optimisation to the latest in longevity science. Book your consultation with Lisa    Join our Patron program and support the show Pushing the Limits' has been free to air for over 8 years. Providing leading edge information to anyone who needs it. 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Lisa is constantly researching and interviewing the top scientists and researchers in the world to get you the best cutting edge supplements to optimize your life.   Subscribe to our popular Youtube channel  with over 600 videos, millions of views, a number of full length documentaries, and much more. You don't want to miss out on all the great content on our Lisa's youtube channel. Youtube   Order Lisa's Books Lisa has published 5 books: Running Hot, Running to Extremes, Relentless, What your oncologist isn't telling you and her latest "Thriving on the Edge"  Check them all out at  https://shop.lisatamati.com/collections/books   Perfect Amino Supplement by Dr David Minkoff Introducing PerfectAmino PerfectAmino is an amino acid supplement that is 99% utilized by the body to make protein. PerfectAmino is 3-6x the protein of other sources with almost no calories. 100% vegan and non-GMO. The coated PerfectAmino tablets are a slightly different shape and have a natural, non-GMO, certified organic vegan coating on them so they will glide down your throat easily. Fully absorbed within 20-30 minutes! No other form of protein comes close to PerfectAminos Listen to the episode with Dr Minkoff here:    Use code "tamati" at checkout to get a 10% discount on any of their devices.   Red Light Therapy: Lisa is a huge fan of Red Light Therapy and runs a Hyperbaric and Red Light Therapy clinic. If you are wanting to get the best products try Flexbeam: A wearable Red Light Device https://recharge.health/product/flexbeam-aff/?ref=A9svb6YLz79r38   Or Try Vielights' advanced Photobiomodulation Devices Vielight brain photobiomodulation devices combine electrical engineering and neuroscience. To find out more about photobiomodulation, current studies underway and already completed and for the devices mentioned in this video go to www.vielight.com and use code “tamati” to get 10% off     Enjoyed This Podcast? If you did, subscribe and share it with your friends! If you enjoyed tuning in, then leave us a review and share this with your family and friends. Have any questions? You can contact my team through email (support@lisatamati.com) or find me on Facebook, Twitter, Instagram and YouTube. For more episode updates, visit my website. You may also tune in on Apple Podcasts.  To pushing the limits, Lisa and team

 | Artist  | Title  | Album Name  | Album Copyright  |  | J.D. Harris  | The Grey Eagle  | The Stuff that Dreams are Made Of (disc 1)  | Lonnie Johnson  | Lonesome Road  | Lonnie Johnson Tomorrow Night 1970  | Tampa Red  | Through Train Blues  | Tampa Red Vol. 1 (1928-1929)  |   | Lightnin' Hopkins  | Mean Old Frisco  | The Blues of Lightnin' Hopkins (1967)  | Big Bill Broonzy  | Sad Letter Blues  | Chicago 1937-1938 (CD8)  1937-1940 Part 2  | Leecan and Cooksey  | Dirty Guitar Blues  | A Richer Tradition - Country Blues & String Band Music, 1923-1928  | Corey Harris  | Jack O' Diamonds  | Fish Ain't Bitin'  |   |   | Half Deaf Clatch  | Storm Brewin  | The Blues Continuum  |   | Sonny Terry and Brownie McGhee  | Worried Life Blues (Recorded Live At The Free Trade Hall, Manchester  | Chris Barber Presents The Blues Legacy Lost & Found Series  | Jake Leg Jug Band  | I Love Me  | Break A leg  |   |   | Dik Banovich  | Pay Day  | Run to You  |   |   | Blind Blake  | Fancy Tricks  | All The Recorded Sides  |   | Tom Doughty  | Come Back Baby  | You Can't Teach An Old Dog  |   | Bluesblabber  | The Ballad of Mr. Wright  | Like It Raw  |   |   | Bessie Jones & with the Georgia Sea Island Singers  | That Suits Me  | Get In Union  | Alan Lomax Archives/Association For Cultural Equity  | Peg Leg Howell  | Coal Man Blues  | Country Southern Blues  | 

RINOs slapped down in bid to oust CO GOP Chair Dave Williams.  Grassroots conservative Tim Leonard says they suffer from "Dave derangement syndrome".   With Rep. Brandi Bradley and CD8 candidate Dr. Janak Joshi.

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

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El programa "T'agrada el blues?" d'aquesta setmana t

Drs. Diwakar Davar and Ben Boursi discuss the role of the gut microbiome in the outcome of cancer immunotherapy and the prevention of immunotherapy-related adverse events, as well as compelling research on nutritional interventions to improve response to immune checkpoint inhibitors. TRANSCRIPT   Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar. 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.   Researchers have shown that microorganisms in the gut can impact the effectiveness of immunogenic chemotherapy for patients with cancer. Although microbial therapies for cancer are still at a very early stage of clinical development, compelling research in recent years has shown that changing the gut microbiome can help improve outcomes in patients receiving treatments for cancer enduring immune checkpoint inhibition.  My guest today is Dr. Ben Boursi, a GI medical oncologist at the Sheba Medical Center at Tel Aviv University in Israel. Dr. Boursi is also an adjunct professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He joins me today to discuss his pivotal research on the role of the gut microbiome in mediating its effects on immunotherapy. And again, I want to highlight that we're recording this on October 9th, and as you may well know, many recent events over the last couple of days have happened in Israel, and so Dr. Boursi has joined us at a very difficult time. So, we're very grateful for him taking time out of his suddenly very busy schedule to join us at a time that is fraught for all. You'll find our disclosures in the transcript of this episode. You'll also find the disclosures of all guests on the podcast at asco.org/DNpod. Ben, it's great to have you on the podcast today. Thank you for being here at such a difficult time, sharing what will, I think, be a great episode.  Dr. Ben Boursi: Thanks for having me, Diwakar. Dr. Diwakar Davar: Ben, the gut microbiome and its role in terms of mediating effects and side effects of cancer immunotherapy has gotten a lot of interest recently. You've done some fundamental work in this space. Why don't you briefly summarize for the audience, firstly, what is the gut microbiome and what are the major themes in relation to cancer immunotherapy?  Dr. Ben Boursi: Well, the microbiome is the ecosystem of microorganisms, bacteria, phages, fungi, that are crucial for immunologic, metabolic and hormonal homeostasis of the host. In the last decade, we began to understand the central role of the gut and tumor microbiome in tumorigenesis, metastasis, treatment efficacy and toxicities, and in 2022, polymorphic microbiomes became one of the hallmarks of cancer, in addition to previous hallmarks that focused mainly at the cellular/genetic levels. The initial studies in mice models showed that therapeutic efficacy of immunotherapy depends on both the presence and composition of the microbiota (In germ-free or antibiotic treated mice, immunotherapy is ineffective), and following these studies, three observational studies in human patients showed that the gut microbiome can predict response to immunotherapy and that response to immunotherapy could be transferred to germ-free mice by fecal microbiota transplantation (FMT) from responding patients.  These studies helped us to define three main research questions regarding the possible role of microbial modulation in cancer treatment. First, can microbial modulation overcome resistance to immunotherapy, both primary and secondary resistance? And this question was the focus of the initial proof of concept studies. Second, can microbial modulation improve response to immunotherapy in treatment-naive patients? And third, can microbial modulation prevent or treat immune related adverse events? The initial positive results of clinical trials also led to additional questions. For example, can microbial modulation induce anti-tumor immune response even in non-immunogenic tumors? And it is important to note that there are many ways to modulate the microbiota, but so far, the only reliable way that showed positive results is fecal microbiota transplantation that allows the transfer of the entire microbiota both in terms of composition and relative abundance. Dr. Diwakar Davar: That's great. Essentially with the trials that I think the data sets that you're referencing of course, are papers by Jennifer Wargo, Thomas Gajewski, and Lawrence Zitvogel, looking at the role of gut microbiota in several different cancers, primarily immune checkpoint sensitive tumors such as melanoma, non-small cell lung cancer and kidney cancer. And then the work from several different groups showing that essentially proof of concept experiments can be done to try to change this, certainly preclinically, and now we know that that can be done clinically.   So, I guess the failure rates of immunotherapy in some patients are quite high. And we know that the microbial composition can change the likelihood to respond to immunotherapy based on all these trials. And actually, even going back to 2015, we had two seminal papers that looked at the role of CTLA-4 blockade as well. But subsequently, many years after that, 7 years after 2015, and certainly 3 years after 2018, when the three observational PD-1 papers were published, there were 2 pivotal trials in PD-1 advanced or refractory melanoma. They demonstrated that changing the gut microbiome can reprogram the immune system to attack tumors. So, there were 2 separate trials, both published the same issue of Science. One trial was led by your group at Sheba, and another one's led by us, the University of Pittsburgh. Why don't you summarize both studies for our audience. Dr. Ben Boursi: So, both studies were Phase I clinical trials of FMT in metastatic melanoma patients who failed immunotherapy. Recipients were metastatic melanoma patients that progressed on at least one line of anti PD-1 and in BRAF mutated patients, BRAF inhibitors as well. Donors in the Sheba study were metastatic melanoma patients with durable complete responses to immunotherapy for at least one year, and in the Pittsburgh study, you also included patients with durable partial responses of more than two years as donors. It is important to note that each fecal transplant in both studies was composed of a single donor. Prior to transplantation, we performed a microbiome depletion phase using a combination of two antibiotics, vancomycin and neomycin. The goal of this phase was to assist in engraftment (by avoiding colonization-resistance by recipient bacteria) and to “reset” the immune system, which may remind some people of the logic behind bone marrow transplantation. In the Pittsburgh study, there was no bacterial eradication with antibiotics, mainly because of studies showing that response to immunotherapy is lower following antibiotic treatment.  Both studies performed FMT through colonoscopy. At Sheba, we also performed maintenance FMT using capsules in order to keep the donor's microbial composition. After the initial FMT, both studies reintroduced the same immunotherapy in which the patient progressed in the past. Clinically, we have seen a 30% response rate with durable, complete and partial responses, and in the Pittsburgh study, there was a 20% response rate and 40% disease control rate. Both studies showed following FMT, immune response in the gut and in the tumor, and tumors that were immune deserts prior to FMT became infiltrated with lymphocytes. Interestingly, in our study, there were no moderate to severe immune related adverse events following FMT and reintroduction of immunotherapy. And this is despite the fact that five of the patients had significant side effects during previous rounds of the same immunotherapy.  Dr. Diwakar Davar: So essentially, in these very early proof of concept studies, what I think is pretty remarkable is that obviously the sample sizes were very small, but remarkably, patients that appeared to respond, responded in a setting in which they were not expected to respond. So, the probability of a patient responding to attempt at giving PD-1 in patients who were PD-1 relapse refractory is on the order of about 7%, based on an FDA analysis by Viva et al. And here, two separate studies, two independent studies, investigators had not known that each paper was being published, remarkably similar results clearly demonstrating that this is perhaps one of the best pieces of evidence to suggest that microbiome modulation may actually truly be effective in reversing PD-1 refractoriness.  More recently, our colleague Dr. Bertrand Routy at University of Montreal has done a proof of concept trial in evaluating the use of healthy donor fecal microbiota transplant in addition to anti PD-1 monotherapy in PD-1 naive metastatic melanoma. In this study, published in Nature Medicine a few weeks ago, his group reported an objective response rate of 65%. What are your thoughts about this study? And specifically, what are your thoughts about some of the pharmacodynamic and translational results that were demonstrated?  Dr. Ben Boursi: This is a very interesting question, because in both the Sheba and the University of Pittsburgh studies we chose responding patients as donors. We thought that by using these patients, we provide beneficial bacteria that enhance responses to immunotherapy through several mechanisms (molecular mimicry, immunomodulatory bacterial metabolites, modulation of immune checkpoint expression, and much more), and here in the Routy paper, the researchers used FMT from healthy donors without any selection for specific beneficial bacteria, and they demonstrated a similar effect on overall response rate. So maybe FMT works actually through reducing colonization by deleterious bacteria? Another question that we should ask is whether we need to choose donors differently when we use microbial modulation in treatment resistant patients compared to treatment-naive patients? Moreover, a previous meta-analysis of FMT studies across indications that was conducted by the group of Dr. Nicola Segata, demonstrated that recipients with better engraftment were more likely to experience clinical benefit, and that increased engraftment was mainly observed in individuals receiving FMTs through multiple routes, colonoscopy and capsules, as well as recipients that received antibiotics prior to FMT. But in Routy's trial, they not only used healthy donors, they performed bacterial cleansing only prior to FMT instead of bacterial eradication with antibiotics, and used FMTs through colonoscopy only, and they didn't give maintenance FMT. Of course, such an approach is much more feasible in the clinical setting and is relevant for designing future clinical trials.  Dr. Diwakar Davar: So, many differences, relatively few similarities, but I guess one interesting point is that of engraftment, which is that in your paper, our paper, and certainly in Bertrand's paper, it is very interesting that engraftment appears to be a key pharmacodynamic biomarker of microbiome modulation. And certainly, the analogy that you used earlier, which is that it's very similar to what happens in a stem cell transplant, which is that if there's no take, there's probably not going to be any effect. So that's very interesting that engraftment is emerging as a key PD biomarker of essentially the success of any kind of microbiome modulation across multiple different settings.  Now, we've heard of certainly defined microbial consortia, of cultivated species, as an alternative gut microbiome modulation strategy that balances the benefits of the ecological complexity of FMT with the scalability and practicality of probiotics. Do you think we are ready to design consortia?  Dr. Ben Boursi: So to date there are several probiotics that use a single bacteria and several microbial consortia that were evaluated in clinical trials, and as you mentioned, they may offer more tractable solutions for widespread clinical use. If we begin with the single bacteria probiotics, two phase 2 clinical trials found that administration of the butyrate producing probiotic clostridium butyricum 588 (CBM588) to immunotherapy naive patients with metastatic renal cell carcinoma led to markedly better immunotherapy responses, although the probiotic had a minimal effect on the composition of the microbiota, and the control arm of the trial responded worse than expected. In addition, in preclinical studies, probiotic strains of lactobacillus and bifidobacterium have been shown to enhance immune control of transplanted tumors and to augment anti PD-1 activity. However, a clinical trial in patients with metastatic melanoma found that the use of lactobacillus or bifidobacterium probiotics was associated with reduced microbiota diversity and worse responses to anti PD-1.  So here the conclusion is that when we try to design probiotics, we should not focus only on the composition since other factors, such as the relative abundance also matter. Too much of a beneficial bacterial species may potentially be worse than having a balanced and diverse microbiota. For example, a recent study of patients with non-small cell lung cancer receiving immunotherapy found that patients with a detectable Akkermansia muciniphila in their gut microbiota (this is a beneficial bacteria) responded well to treatment, but those with relative abundance of Akkermansia muciniphila greater than 5% responded worse than patients lacking Akkermansia, and this is due to the mucolytic effect of the bacteria. So, the use of rationally designed consortia may be better than a single probiotic strain.  And there are currently 3 main microbial consortia that are being evaluated: the SER-401, a bacterial consortium enriched with clostridium, led in a randomized controlled trial to reduced response to immunotherapy compared to placebo control in first line metastatic melanoma patients, potentially due to a confounding effect of a vancomycin pretreatment; MET4 is a 30 bacteria consortium that was shown to be safe and to alter the gut microbiota and serum metabolome of immunotherapy naive patients. Here, the initial study was underpowered to determine the effect on treatment efficacy; And finally, VE800 is an immunotherapy enhancing 11-bacterial consortium that is currently being evaluated in phase 1 and 2 clinical trials, and we are looking forward to see the results with this agent. Dr. Diwakar Davar: So I guess where we are right now is that social design is clearly difficult because of all the reasons you've mentioned. The SER-401 data and the MET4-IO trials certainly give us pause for thought. Certainly, no pharmacodynamic changes that were seen with SER-401, MET4-IO did result in pharmacodynamic shifts metagenomically, but neither trial was positive. And certainly, the VE800 trial, which has been ongoing now for several years, and the lack of publicly reported data certainly doesn't suggest that there's a huge efficacy signal. So consortias, at least at this point, certainly do not appear to be having a significant effect, though we don't know what might happen in the future. Data from multiple groups has shown that gut microbial composition influences the development of immune related adverse events (irAEs) in both PD-1 and combination PD-1 and CTLA-4 treated patients. Unsurprisingly, as a result, there have been attempts made at evaluating the role of fecal microbiota transplants to treat refractory immune related adverse events and very specifically immune checkpoint associated colitis or IMC. So, Dr. Yinghong Wang, who is the chair of the Immunotherapy Toxicity Working Group at the University of Texas MD Anderson Cancer Center has been very prominent in this space, and in a recent paper published in Science Translational Medicine, which is a follow up paper to her early work in Nature Medicine, she reported that HDFMT, healthy donor fecal transplantation, was very efficacious in feeding early refractory immune checkpoint colitis. So, what are your thoughts on this approach and how important is this space and where else might it be efficacious?  Dr. Ben Boursi: When I talked about the Sheba clinical study, I mentioned the possible role for microbiota modulation in the prevention of immunotherapy related adverse events in general, not only colitis. But the study by Dr. Yinghong showed that FMT can actually treat immune-related colitis refractory to steroids and anti-TNF. Now, this approach is probably relevant not only for immune related colitis, but also to other immune related adverse events. We can define certain bacterial species that may be associated with different immune related events. For example, streptococci can be associated with immune related arthritis. And maybe in the future we won't need to use FMT, but we will rather be able to target these specific immunogenic strains by narrow spectrum antibiotics or phages. The main challenge would be to develop microbiotic targeting interventions that reduce immune related adverse events without compromising therapeutic efficacy.   Now, is microbial modulation relevant only for toxicity from immune checkpoint inhibitors? So, the answer is ‘no'. We know mainly from animal models of hematopoietic cell transplantation, CAR T, and immune agonist antibodies that antibiotic-treated or germ-free mice have markedly reduced immunotoxicity, such as graft versus host disease, cytokine release syndromes, and more. It is also worth mentioning that microbial modulation is relevant not only for reducing toxicity from immunotherapy, but also from chemotherapy and other anticancer modalities. And the best example is the gastrointestinal toxicity of irinotecan that is mediated by the bacterial beta-glucuronidase. And here the targeting may even be a bit less complex. Dr. Diwakar Davar: So, what we take away from that is that starting with actually your paper originally, and papers to be produced, immune-related adverse events can be prevented using microbiome modulation with FMT, and Dr. Wang's data suggesting that eventually FMT can be used to eradicate highly refractive colitis, again, this is important to keep in mind that this approach is not yet FDA-approved. It's being done under IND. It's not currently something that is a certain standard of care. One interesting area of drug development is that there's a French microbiome company named MaaT Pharma where they have an agent that is a very interestingly a pooled microbiome product from multiple different donors. Again, the trials in both Israel and Pittsburgh used individual donors. This is a pooled donor construct. The lead candidate is actually graft versus host disease. The trial is the ARES trial, A-R-E-S, as in the Roman god of war. This trial is actually ongoing in Europe, and I believe there's some effort to try to see whether or not it's going to be a trial that can be done in the United States as well. So, at this point in time, again, we don't know whether or not there are any developmental approaches from a pharmaceutical company in the United States, but certainly this is definitely an area of interest.  So microbial therapies are still relatively early. It's going to be interesting to see how the advanced field of nutritional interventions provide an appealing method for modulating the gut microbiome due to the excellent safety profile, cost effectiveness and noninvasiveness. And certainly, if you are what you eat and your bacteria are what they eat, which goes down to our diet, there's enough rationale to believe that certain nutritional interventions can have an effect via the intermedial gut microbiota modulation. Holistic dietary changes and or supplementation specific nutrients such as prebiotics could therefore be utilized to specifically shape the population of beneficial microbes and shift the immune microbiota landscape. Now, we have seen in data published by several of our colleagues that in patients with cancer, high fiber intake is associated with greater microbial diversity, greater abundance in fiber fermenting microbes such as members of the Ruminococcaceae family, and these are all associated with the response to checkpoint inhibitor therapy. So, what do you think about nutritional interventions? Do you want us to briefly summarize data regarding nutritional data and where it stands in cancer at his time? And can you speculate as to how effective this might be in the context of patients with cancer? Dr. Ben Boursi: So, let's begin with diet. A growing number of clinical and preclinical studies suggest that specific dietary interventions such as a high fiber diet can not only improve response to immune checkpoint blockers, but also reduce immunotoxicity such as graft versus host disease. And there are many other diets that are being tested such as ketogenic diets and intermittent fasting. And the effects of diet may be mediated by both microbiota-dependent and microbiota-independent mechanisms. The limitation of this approach is that changes to the microbiota induced by diet are generally quite variable between patients and can depend on an individual's microbiota prior to intervention. And patient compliance is also a concern, particularly in the very strict diets.  Now, regarding high fiber diets, several large cohorts of melanoma patients from the US, Australia, and the Netherlands demonstrated how a high fiber diet modulates the microbiome and results in a better response to immunotherapy, better progression-free survival. Additional studies that were presented at AACR in 2023 showed that high fiber dietary interventions, in which patients received a fiber-enriched diet for six weeks, was feasible and that the high fiber diet resulted in a rapid shift in the gut microbiota toward fiber-responsive short chain fatty acid-producing taxa and a shift of the metabolome, with increase in the short chain fatty acid acetate, Omega-3, Omega-6, polyunsaturated fatty acid, and tryptophan metabolites. Prebiotics can also promote the growth of beneficial microbial species in the gut by providing targeted nutrition. And one example of a prebiotic that was shown to enhance immunotherapy efficacy in mouse models is castalagin, which is isolated from the camu-camu berry. Castalagin directly binds the outer membrane of ruminococci and promotes their growth, which has been shown to increase the CD8-positive T-cell activity and anti-PD-1 efficacy. Now, since prebiotics rely on the presence of beneficial taxa already in the host microbiota, symbiotics, which refers to the administration of the appropriate prebiotic and probiotic together, may prove in the future to be more effective than using either separately. Dr. Diwakar Davar: Certainly, these dietary interventions can be very exciting and certainly we do know of several colleagues who are doing these diet interventions, though compliance with any kind of dietary intervention may be a challenge that decides how effective such an approach is going to be. So microbial therapies in general are still at a relatively early stage of development. And it'll be exciting to see how they advance. What approaches are you excited about? What is on your radar?  Dr. Ben Boursi: There are many exciting works that are currently ongoing, and to emphasize just a few: there are many clinical trials in immunogenic tumors, in addition to melanoma, for example, renal cell carcinoma, and non-small cell lung cancer, that also evaluate different modulation protocols. We should remember that one size does not fit all, and different tumors have different microbiomes. We have a project in collaboration with MD Anderson in MSI-high patients with exciting initial results. Another study that was initiated at Sheba is using microbial modulation in order to improve TIL therapy (to overcome resistance to TIL and T-cell exhaustion). There are also studies that try to change the pharmaco-microbiome, for example, to eradicate bacteria that inactivates the chemotherapy agent, gemcitabine, in pancreatic cancer patients. And there are groups that try to identify recipients that will respond to microbial modulation and to generate better donor-recipient matching algorithms. There are already signatures like TOPOSCORE that was presented at ASCO 2023 that try to predict response to immunotherapies through the ratio between harmful and beneficial bacteria. Now, there's also more basic science work, for example, bacterial engineering. There was a wonderful study from the Fischbach group in Stanford that demonstrated how Staphylococcus epidermidis engineered to express melanoma tumor antigens was able to generate a systemic tumor-specific response in mice models when applied topically; functional imaging of the microbiome, for example, FDG uptake in the colon can reflect microbial diversity and response to immunotherapy; works that characterizes other microbiomes such as the urinary and skin microbiomes, and their interaction with the gut microbiome; and studies of the nonbacterial component of the microbiome, mainly phages and fungi. But for me, the most important word should probably be collaboration, because without joining forces internationally, we won't be able to understand the human metaorganism, the variations according to geography, ethnicity, lifestyle, diets, and much more in the microbiome. And this is crucial in order to really understand the complex tumor ecological niche within the human host. Dr. Diwakar Davar: I think one of the key points that you just mentioned is collaboration. That's going to be very, very critical as we move this forward for many reasons, including the unexpected impact of geography upon the composition of the gut microbiome in work that has been published by many groups, but also including ours in a paper that we published about a year ago now.  So, Dr. Boursi, thank you for your great work in this area. Thank you for sharing your insights with us today on the ASCO Daily News Podcast. This is a very difficult time for all of you and your colleagues in Israel, and we thank you so much for taking such a great deal of time out of your busy workday to spend some time with us.  Dr. Ben Boursi: Thank you very much. Dr. Diwakar Davar: Thank you to all our listeners today. This is a very exciting area. This is an area where we are discovering more every day than we knew just up until the day prior. You will find the links to the studies that were discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take the time to rate, review, and subscribe wherever you get your podcast.  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. Guests' 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  Dr. Ben Boursi   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. Ben Boursi: No relationships to disclose.        

Dr. John Lewis discusses The Benefits of Polysaccharides with Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on my WeitzChiro YouTube page.]    Podcast Highlights 13:26  Polysaccharides.  Polysaccharides are complex sugars and some of them have unique health promoting properties, including those that come from aloe vera and from rice bran.  Aloe vera is 99% water, so you have to extract the polysaccharides out of the aloe vera plant and this acetylated polymannose has amazing properties. 20:25  Polymannose.  Dr. Lewis met Dr. Reg McDaniel who had been working on the aloe plant since the 1980s at the Texas A & M vet school, who is still doing research at 87 years of age.  Dr. McDaniel shared studies that these aloe derived polysaccharides were anti-inflammatory, antioxidant, antiproliferative, and have wound healing benefits.  He found that in addition to the wound healing and stem cell production boosting function of aloe vera, this polymannose is a key sugar when the endoplasmic reticulum and the Golgi of the cell are communicating with each other and making other bioactive compounds that you need.  This polymannose is similar to d-mannose, which is often recommended as part of a protocol along with L-carnitine and CoQ10 for supporting the heart muscle in patients with congestive heart failure, though Dr. Lewis's research was more focused on brain health. 25:51  Aloe polymannose multinutrient complex.  In their study on the polysaccharides for Alzheimer's patients, Dr. Lewis and colleagues used an aloe polymannose multinutrient complex, including aloe polymannose, rice bran, larch tree, cysteine, lecithin, tart cherry, inositol hexaphosphate, yam, flax seed, citric acid, and glucosamine.  They gave the patients this nutritional supplement four times per day in a powdered form that put into a liquid to drink. For the Alzheimer's study, they took patients with moderate to severe disease, which means the sickest of the sick and this group is the hardest to see improvements with.  The neuropsychological testing showed a significant improvement at nine and twelve months. 35:06  Alzheimer's study lab results. The lab results showed statistically significant reductions in VEGF and TNF alpha.  There was an improvement in CD4 to CD8 ratio, which obviously is very important for all of us.  They also showed an improvement of just under 300% in CD14 cells, which is a marker of adult stem cells.  And the average age of these patients were 79.9 years of age.  They theorized that these adult stem cells migrated to the brain and created new neurons, new synapses, and repaired damage to neurons.  Also BDNF levels went up by 11%, though this was not considered to be statistically significant.  They did not ask these Alzheimer's patients to change their diet or to exercise or do anything else to improve their lifestyles.  We can only imagine how much more benefit might have been derived if this nutritional intervention were used as part of a Functional Medicine approach that also put them on a healthy diet and had them perform vigorous exercise and do brain stimulating exercises as well, such as the approach used by Dr. Dale Bredesen. [The Effect of an Aloe Polymannose Multinutrient Complex on Cognitive and Immune Functioning in Alzheimer's Disease.] 44:45  MS study. These patients with relapsing remitting MS were placed on a similar aloe polymannose multinutrient complex four times per day for 12 months.  The FAMS (Functional Assessment for MS) questionaire was used for functional assessment and results showed very significant improvements in every scale.  MS patients frequently get infections and these patients who took the nutritional intervention had much fewer infections.  Serum biomarkers, quality of life, symptom severity, and functioning also improved.

 | Artist  | Title  | Album Name  | Album Copyright | Ernie Hawkins  | Sweethearts On Parade (feat. Roger Day, Paul Consentino & Joe D  | Monongahela Rye  |  | Son House  | John The Revelator  | The Delta Blues Of Son House | Big Bill Broonzy  | It's A Low Down Dirty Shame  | Chicago 1937-1938 (CD8)  1937-1940 Part 2 | Tony Joe White  | You Got Me Running  | Baby Please Don't Go | The Georgia Browns  | Who Stole De Lock.  | Curley Weaver (1933-1935) | Pistol Pete Wearn  | Rosalynd  | Blues, Ballads & Barnstormers | Alger ''Texas'' Alexander  | Water Bound Blues (1929)  | Complete Recorded Works, Vol. 2 (1928 - 1930) | Lightnin' Hopkins  | Goin' Away  | Goin' Away (1963)  |  | Pinetop Perkins  | Willow Weep For Me  | Heaven  |   |  | W.C. Handy Preservation Band - Carl Wolfe  | Loveless Love  | W.C. Handy's Beale Street: Where The Blues Began | Guy Davis  | Did You See My Baby  | Juba Dance  |  | Jesse Fuller  | Morning Blues  | San Francisco Bay Blues | Jo Ann Kelly  | Boll Weevil  | Do It and More  |  | Mike Goudreau  | I'm So Glad I Have You  | Acoustic Sessions  |  | Auld Man's Baccie  | Whole Lotta Rosie  | 100% Homage  |  | Half Deaf Clatch  | Tumbledown Blues  | Eat Sleep Stomp Repeat

In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash  from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: “Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium”. The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Davide Soldato: Welcome to this JCO Article Insights episode for the July issues of JCO. This is Davide Soldato and today I will have the pleasure of interviewing Dr. Abdul Rafeh Naqash, the author of the manuscript titled "Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium."  Dr. Naqash is an Assistant Professor of Hematology-Oncology at the University of Oklahoma and a Medical Oncologist working at the Stephenson Cancer Center. His research interests revolve around early-phase clinical trials in solid tumors, lung cancer, and the study of immunotherapy, biomarkers, and resistance.  Welcome, Dr. Naqash, and thank you for accepting our invitation today. Dr. Abdul Rafeh Naqash: Dr. Soldato, thanks so much for having me. I'm really excited to discuss this article with you today. Davide Soldato: So I just wanted to go a little bit over the manuscript with you. So basically, this is a retrospective multicenter study that was conducted across the US, Europe, and Australia by the CATCH-IT Consortium. And so the aim of the study was really to investigate the safety and the activity of immune checkpoint inhibitors among patients diagnosed with cancer and also living with HIV. The article examined two different cohorts, and I just wanted to start with a brief explanation of how the two cohorts were built so that our readers can get a little bit of understanding of what you did then. Dr. Abdul Rafeh Naqash: Sure. Before I take a deep dive into the cohorts, Dr. Soldato, I would definitely like to mention the premise and the background for this paper as to why we did what we did. And one of the primary reasons was that people living with HIV, historically, there have been very limited number of trials that have included these individuals. So it becomes a very important question from a disparity standpoint. And most often we end up, in the real world setting, we end up extrapolating data from clinical trials, but not necessarily know what is the outcome of these individuals in the real world setting.  So there have been some very important studies in the last three years or so in people with HIV as far as clinical trials with checkpoint inhibitors go, but most of those trials have been limited by the number of patients, number of people that have been part of those trials. So we wanted to understand it from a broad perspective, whether it is from a broad geographic perspective or from a heterogeneous patient population perspective, which is why we built this consortium called the CATCH-IT Consortium, which basically stands for Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International Consortium. And this required a lot of effort from a lot of different centers, including those in the US, Europe, and Australia, as you mentioned. And then we ended up having data worth around 400 plus patients, close to 400 patients or so. And then we wanted to look at obviously outcomes, whether it's related to a certain tumor such as lung cancer, which we did in this case, or a pan tumor assessment of toxicities and safeties.  So, to your question, the cohorts that we basically had, we had close to approximately 390 patients that we included in the safety analysis. So first we looked at the safety analysis, which was the entire cohort, and then out of those we excluded around 12 patients or so. Those were patients that were treated in the adjuvant setting. So in the metastatic advanced setting, we had close to 378 individuals that we assessed clinical outcomes for. So, response rates, progression-free survival, and overall survival. And then as far as a separate cohort, we looked at non-small cell lung cancer, which was the most commonly represented tumor type, with approximately 111 patients that had non-small cell lung cancer. We did exclude a certain proportion of those that were earlier stage, stage III.  So in the stage IV, basically we ended up matching in this separate cohort, around 60 odd patients or so of non-small cell lung cancer to 110 stage four, non-small cell lung cancers. So basically it was a one-to-two matching and we chose the same site. So if a site had, let's say, two people with HIV and lung cancer treatment checkpoint, we tried to match it to approximately four to five patients from the same site and we used some variables for matching so that we had some level of homogeneity between the HIV patient population and the non-HIV positive lung cancer individuals. So that's basically cohort A was around 370-something patients, tumor agnostic advanced metastatic setting. Cohort B was lung cancer individuals matched to non-HIV positive lung cancer treatment checkpoint inhibitors. Davide Soldato: Thank you very much. That was very clear. Just to go back to what you were saying before because I think that this is very interesting. You mentioned that patients living with HIV were mostly excluded from clinical trials and in the few that included them, there were some restrictive criteria in terms for example of CD4-positive cells in the blood. And so I was wondering if when you included the patients inside of this cohort, you also had this type of exclusion criteria or you chose a broader population to make the results more generalizable and applicable in clinical practice.  Dr. Abdul Rafeh Naqash: Right, a very important question. Thank you, Dr. Soldato. So yes, previous clinical trials have had some level of restrictions as far as the inclusion of these individuals, but in our study, this was a real-world study, basically, patients whoever presents to the clinic with a history of HIV, they were all included. So we did not restrict it to certain CD4 counts or viral loads because the important thing was we wanted to understand the ground situation of how these individuals do, irrespective of some of these limitations. As far as what we identified as baseline CD counts or HIV viral load positivity, we took three months before immune checkpoint initiation as a cut off so obviously there's a limitation there. We didn't have results of these CD4, CD at a viral load assessments done like the day of or the week before in some patients. So we took three months and we included individuals that had received at least one or more dose of immune checkpoint therapy between January of 2015 to October of 2021, which was our database lock.  And then obviously the regimens included immune checkpoint anti-PD1, PD-L1 monotherapy, or in combination with other anticancer agents including anti-CTLA-4 or chemotherapies targets, which is important to point out here. So the trials that have been mostly done in this space are single-agent checkpoint inhibitors or anti-PD1 with anti-CTLA-4. There's not much data for immune checkpoint inhibition combined with other agents such as targeted therapies, chemotherapies. So we had some of that data in this cohort, which kind of made it interesting. Davide Soldato: Yeah, I think that it's very interesting and it's very wise to choose very broad eligibility criteria for these type of studies because it really answered to the question that we identified and that we spoke about in the beginning.  So going back to the results, you said that the cohort A, so the one that included all the patients, irrespectively of the type of tumor that was diagnosed, it was mainly for evaluating what was the safety of immune checkpoint inhibitors in patients living with HIV and with a concurrent cancer diagnosis. So I was wondering if in this cohort you identified some differences compared to historic data in terms of, for example, incidence of grade three or higher toxicities or incidence of immune-related adverse events in general, and if maybe there was some adverse events that was very characteristic or particular in this cohort. Dr. Abdul Rafeh Naqash: So immune-adverse events is a very interesting question not only from this cohort but in general because it overlaps with this question of autoimmunity and cross T cell cross reactivity. And this is a unique patient population where we have the ability, although not fully but to some extent, to look at the role for CD counts and also look for patterns of adverse events.  To answer your first part of the question, we didn't see any significant differences for the types of adverse events. We did see the incident was a little lower than what you would expect in the real-world setting for non-HIV individuals. Whether that has something to do with how the immune system is constructed in these individuals, nobody knows. We did look at CD4 and CD8 counts. As far as absolute CD4 counts, about 200 or below 200, we didn't see a difference as far as the cumulative incidence for immune checkpoint inhibitor-related adverse events. When we did a ratio of CD4 to CD8 of greater than 0.4 and compared it to less than 0.4, we did see that at around 24 weeks, there was a difference in terms of the cumulative incidence for adverse events. It was around 10% versus 26% when we use that cut-off of 0.4, suggesting that there might be some role of how the peripheral immune system results in the related adverse events in these individuals, but it's a very important question.  I think there are ongoing evaluations that are being done from other prospective studies that had collected blood samples in these individuals. But generally, we saw the same range of adverse events, diarrhea, colitis, pneumonitis, hepatitis. We did have a few patients who had  a history of opportunistic infections, but we didn't see any significant reactivation there which was part of the safety assessment in our analysis.    Davide Soldato: So basically, because I think that in HIV patients, even if those included in the study were almost all were on antiretroviral therapy, but you didn't observe any opportunistic infection that developed during the course of immunotherapy. Dr. Abdul Rafeh Naqash: You're absolutely right, we did not. In fact, we are trying to look at that in a different setting, in a different cohort because there have been some data on mycobacterial reactivation in individuals in general, not just HIV, but in our cohort of 400 odd patients, we did not see any new opportunistic infections. Davide Soldato: I think that one aspect that pops into my mind right now is also that we have kind of some data regarding also possible HPV reactivation in these types of patients treated with immune checkpoint inhibitors. So maybe that could be also something that you would be interested to look at in the future, I imagine.  Dr. Abdul Rafeh Naqash: Yes, we are planning to look at HPV-driven cancers actually for starters, anal and head and neck. We are also looking at hepatitis B-related HCC in a separate ongoing cohort. So there are definitely subsequent steps that we are currently involved in as far as viral-driven cancers and concurrent HIV is concerned. Davide Soldato: Thank you. I think that's very interesting. And I was wondering, you mentioned in the beginning that this patient clearly they have some degree of immune dysregulation or at least some type of dysfunction in terms of immune presentation and immune activation. So I think that one of the concerns or one of the worries of using immune checkpoint inhibitors in this population could also be that the efficacy that we see in patients that do not have HIV could be lower. Could you comment on this if you found any differences both in the cohort including all cancer, but also in the cohort B, that I think you had the strategic idea of pairing these patients living with HIV with patients that were not living with HIV. So I think that this brings very important data to the space. Dr. Abdul Rafeh Naqash: Yes, we tried to look at this one from a tumor-agnostic perspective and a tumor-specific perspective. So the tumor agnostic perspective was looking at a different set of cancers which included skin cancer, melanoma, lung cancer, non-Hodgkin's lymphoma, small cell head and neck, and a couple of other cancers. And one of the things we noticed was that there was a trend, so there was differential efficacy as far as the cancer type is concerned. So for example, skin, Hodgkin's lymphoma, Kaposi sarcoma, melanoma had the highest response rates, somewhere in the range of 60s to 40s. On the other hand, viral-driven cancers such as anal cancer, HCC, head and neck actually had very low response rates, less than 15% or so. So that begs the question of what is going on and we don't necessarily know, which is why we are trying to concentrate on the viral-driven cancers first. Because as you know, melanoma, Kaposi's do have historically shown better responses to checkpoint inhibitors.   Now do we know if when we compare these responses or survival to non-HIV individuals in clinical trials, are the outcomes similar? I would say in some of the tumor types the outcomes were somewhat inferior and in some of the tumor types the outcomes were somewhat similar. So for example, lung, we did compare non-small cell lung cancer. As I mentioned, we had two cohorts, we matched it to a non-HIV cohort and there we looked at progression-free survival and overall survival. And again the caveat is that this is a retrospectively matched cohort, this is not a prospectively matched cohort. So these are individuals that are not matched for each and every variable. They're matched for certain top three or four variables as much as we could accommodate. And based on that we didn't see a difference in the progression-free survival and the overall survival when we did an assessment.  In fact, we looked at it at a 42 month period where we looked at the restricted median survival time and it was not different, was around 17.8% for people with HIV and 18.4% for people without HIV as far as progression-free survival, and around 42% and 41% overall survival at the two-year mark. So basically there is not much significant difference which reiterates the fact that in the right setting, these individuals could be safely treated with immune checkpoint inhibition and could perhaps have similar outcomes. Maybe not in all tumor types, but in some tumor types. But at the end of the day, and we mentioned this in our manuscript also in subsequent work that we are trying to do, we have emphasized on the fact that it has to be a multidisciplinary discussion between the patient, the physician, the medical oncologist, the treating oncologist, and the infectious disease person. Because these individuals have a lot of complicated aspects because of the underlying HIV and taking that into perspective and then assessing risk-benefit is an important discussion.  So the goal of this work was not to establish that immune checkpoint inhibitors are absolutely beneficial or absolutely safe. The goal was more to create awareness that people in the real-world setting actually can benefit, which the next step would be to have more trials and perhaps modify inclusion criteria in clinical trials so that you can have a more inclusive approach, including these individuals.  Davide Soldato: Coming back to the multidisciplinary approach because I think that this is very interesting and should be really implemented when we have this type of patient. From the data that you collected, did you add any indication that maybe this patient treated in the real-world setting were not managed in such a multidisciplinary way? Dr. Abdul Rafeh Naqash: The easiest way to point that out is that most of these people or many of these individuals did not have HIV viral loads or CD4 counts done before treatment initiation. And that's an indirect surrogate for telling you that these are things that should have been thought of, but were not thought of if the individual taking care of these people either did not have expertise as far as HIV is concerned or did not have a colleague on the infectious disease side who was actively managing these people.  So that's an important indirect way where we kind of got a sense that there has to be more awareness about multidisciplinary care. And especially the immune adverse event situation in these individuals can get complicated because of the way their immune system is constructed and having that multidisciplinary care is very important. We didn't specifically collect data on what teams or what subspecialists were involved in each individual's care, but I think that would be an important assessment for maybe a future quality improvement project to look at why or how some of those things were not done so that it can lead to future improvements. Davide Soldato: So, just expanding on that, you said that you didn't have much data in terms of CD4 cells or in terms of viral load. But for what you had inside of your cohort, did you see any modification of these parameters that we know that are very important in patients living with HIV under immune checkpoint inhibitors therapy? Dr. Abdul Rafeh Naqash: Again, a very important immunological question, I think as far as what we saw- so we had close to around 74, 75 individuals that had CD4 T cell counts available. And we didn't see differences between baseline and post-immune checkpoint therapy changes in CD4 counts. Similarly, we didn't see a difference as far as HIV viral load and we had HIV viral loads present in around 107 individuals and we didn't see a difference. Now, again, 30% of our cohort was CD4 count less than 200, and 70% was CD4 count more than 200, , which is again, important to highlight because many trials don't take individuals with the CD4 count less than 200. But in general, we did not see a difference in this pre and post-assessment both for viral load and both for CD4 count. Now trials in this space have ongoing assessments that they are doing. The AIDS Malignancy Consortium does have a trial looking at changes in CD4/CD8 counts or viral loads. In fact, the CITN trial which is a pembrolizumab trial published a couple of years back did have an assessment done as far as CD4 counts and viral loads are concerned. And I think they did see a slight increase in the CD4 counts and there are some aspects about how the immune system may change with an immune checkpoint inhibitor. But I think the strength of the data is not that much, and I think we probably need more patient samples to assess why or how some of that could change or what implications it would have for patients.  Now, there is another concept of HIV viral latency removal that some of the listeners might have heard of, especially in the HIV setting, where you were given an immune checkpoint inhibitor and it can lead to reversal or reduction of the HIV reservoir, which can somehow impact the CD4 counts, and also lead to elimination of the viruses through CD8. But again, that's a more complicated assessment and we didn't have data for it.   Davide Soldato: Thank you very much. That was very interesting also for future perspectives in this topic.  I just wanted to ask you if the idea for the research came more from ensuring equity in terms of care delivery for patients living with HIV or if it was more also to investigate the immunological components that we discussed just as far or a good mix of the two. Dr. Abdul Rafeh Naqash: I think the idea actually stemmed from this individual who's the first author, Dr. Talal El Zarif and co-first author Dr. Amin Nasser from Dana-Farber, reached out a year and a half back and they wanted to look at outcomes from an HIV standpoint and see what the real world setting is. And the goal was they would have their data and we would have our data and we would eventually collect the data together or combine the data together. But then after some conversations, we started looking at the available data, the available literature, saw that there was a decent gap in what we know. And I know there are some brilliant groups in the HIV space, especially at the NCI. In fact, Dr. Kate Lurain and Dr. Ramaswami are good collaborators of ours and they worked in this space and are currently developing trials in this space. But it just did seem like this would be a more interesting approach of answering a real-world question and then also looking at the disparities of it because as an early-phase drug development trialist, I still see a lot of trials, in fact, majority of the trials, say people with HIV or history of HIV are excluded.  Now, the NCI has made important efforts in that space of including those individuals, but I think we still have some ways to go. So basically the idea came from two trainees who were extremely enthusiastic and wanted to pursue this. And I, obviously, seeing their level of enthusiasm and excitement, I was excited too. And then importantly, if you look at the paper, we have a bunch of authors, we have close to 79, 80 authors on that paper. And the primary reason was that each center contributed in certain ways, including patients' data and then expertise. And this ended up being a huge community effort from the oncology community, where everybody's individual effort led to something like this coming to fruition.  So it was a multitude of different aspects, but yes, it all started with a question of how these individuals do and the current data where they're missing gaps, and we wanted to sort of supplement those gaps and provide insights using this important real-world data set. Davide Soldato: Thank you very much for the insight on how the idea came to be.  Is there anything else you would like to add or to summarize for our listeners? Dr. Abdul Rafeh Naqash: Well, first of all, I appreciate the opportunity to discuss our paper here. I would like to thank you and of course the JCO staff for organizing this, and also the JCO Journal for giving us the opportunity to publish this important work. Some of the things that we would like to highlight as outcomes from this paper, as we sort of discussed, but to summarize those: we saw that we didn't have any significant safety concerns, obviously. We saw that some patients in certain tumor types do benefit, similar to what you might expect in a non-HIV setting in the real world as well.  And of course, this was the largest real-world data set of people with HIV and cancer. And we have ongoing efforts in different directions, as I mentioned to you. And we are more than happy to collaborate with anybody who has good ideas because this is a community-level data set. It was created for the community, by the community, and the goal is to utilize this data set. So if there is a listener out there who's interested in collaborating, who has an idea, we're more than happy to share the data set in the right setting. And then hopefully, everybody has the opportunity to lead different efforts in the space. Davide Soldato: Thank you again for being with us today, Dr. Naqash. To hear more from Dr. Naqash, please check out ASCO's JCO Precision Oncology Conversation Podcast.  So this is Davide Soldato. In this episode of JCO Article Insights, we discussed the results of the manuscript titled, “Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium.” Thank you for your attention and stay tuned for the next episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States.  Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod.  Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time.  So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response.  Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much.  Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time.  So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think?  Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating.  So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no.  we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient.  Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery.  The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult.  And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor.  Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek.  Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders.  We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on.  So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials.  Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024.  Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients.  And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential.  And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence.  Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Mohamed Salem @SalemGIOncDoc   Dr. Myriam Chalabi @MyriamChalabi   Dr. Andrea Cercek @AndreaCercek   Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23   Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix          

In hour 1, Randy is back, bent but unbowed after the disappointing midterms. What happened? The Libertarian vote would have given Barb Kirkmier the CD8 seat as well as given the CD8 State Board of Education seat to Peggy Propst. IF they would have voted for Republicans. Libertarian PR Director for CD8, Patty McMahon, called in and begged to differ.  Lauren Boebert's Veteran's Day message was great as she holds on to her CD3 seat for dear life, and callers and Randy discuss what happened and why.See omnystudio.com/listener for privacy information.

The January 6 committee holds its likely final hearing; musician Katy Tessman and Angel Foundation executive Jim Thrubis join Matt for an interview and some music; Rep. Jen Schultz joins Matt to discuss her run for CD8.

The party is split! Hedwig and the Red Man are on the heels of Mavra's kidnappers whilst Ahoy, CD8 and Umbra are tracking down the woman in the robe. Connect with us at https://www.seriallyhooked.com. Sound Effects include: "string 1 loop" by ERH on freesound.org (https://freesound.org/people/ERH/sounds/30192/) "Epic Orchestra" by edtijo on freesound.org (https://freesound.org/people/edtijo/sounds/218744/) "Epic Strings" by AlexProst on freesound.org (https://freesound.org/people/AlexProst/sounds/382250/)

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.30.510367v1?rss=1 Authors: Sutter, P. A., Menoret, A., Jellison, E. R., Nicaise, A. M., Bradbury, A. M., Vella, A. T., Bongarzone, E. R., Crocker, S. J. Abstract: Globoid cell leukodystrophy (GLD) or Krabbes disease is a fatal genetic demyelinating disease of the central nervous system caused by loss-of-function mutations in the galactosylceramidase (galc) gene. While the metabolic basis for disease is known, the understanding of how this results in neuropathology is not well understood. Herein we report that the rapid and protracted elevation of CD8+ cytotoxic T lymphocytes occurs coincident with clinical disease in a mouse model of GLD. Administration of a function blocking antibody against CD8a effectively prevented disease onset, reduced morbidity and mortality and prevented CNS demyelination in mice. These data indicate that subsequent to the genetic cause of disease, neuropathology is driven by pathogenic CD8+ T cells, thus offering novel therapeutic potential for treatment of GLD. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

The party is split as Ahoy and CD8 track their quarry whereas Hedwig and the Red Man watch a performance. Connect with us at https://www.seriallyhooked.com and on Twitter @seriallyhooked (Https://twitter.com/seriallyhooked) Sound Effects include: "Comical Orchestra" by Setuniman on freesound.org (https://freesound.org/people/Setuniman/sounds/160664/) "Sunday Morning in the Great Hall" by FoolBoyMedia on freesound.org (https://freesound.org/people/FoolBoyMedia/sounds/333800/) "Arc of Suspense" by Setuniman on freesound.org (https://freesound.org/people/Setuniman/sounds/170207/) "Epic Strings" by AlexProst on freesound.org (https://freesound.org/people/AlexProst/sounds/382250/) "Tension orchestra chords" by frankum on freesound.org (https://freesound.org/people/frankum/sounds/320498/)

A new research paper was published in Oncotarget on July 28, 2022, entitled, “Chemoradiation-induced alteration of programmed death-ligand 1, CD8+ tumor-infiltrating lymphocytes and mucin expression in rectal cancer.” DNA damage and resulting neoantigen formation is considered a mechanism for synergy between radiotherapy and PD-1/PD-L1 pathway inhibition to induce antitumor immune response. In a new research study, by Marina Baretti, Qingfeng Zhu, Wei Fu, Jeffrey Meyer, Hao Wang, Robert A. Anders, and Nilofer S. Azad from Johns Hopkins University School of Medicine, researchers investigated neoadjuvant chemoradiotherapy (nCRT)-induced changes in CD8+ tumor infiltrating lymphocyte, PD-L1 and mucin expression in rectal cancer patients. “The synergistic effects of CRT and PD-1/PD-L1 immunotherapy has been supported by several retrospective analyses in different cancer types, including esophageal cancer, bladder cancer, and lung cancer also support[ed] [14, 21, 22]. However, the role of nCRT to interact synergistically with immune checkpoint inhibitor treatment to improve tumor control in rectal cancer remains uncertain.” Full press release - https://www.oncotarget.com/news/pr/oncotarget-chemoradiation-induced-alteration-of-programmed-death-ligand-cd-tumor-infiltrating-lymphocytes-and-mucin-expression-in-rectal-cancer/ DOI: https://doi.org/10.18632/oncotarget.28255 Correspondence to: Marina Baretti – Email: mbarett1@jh.edu Keywords: programmed death ligand 1, tumor-infiltrating lymphocytes, immune checkpoints, colorectal cancer, neoadjuvant chemoradiotherapy About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com

This week, please join authors Mikhail Kosiborod and Christian Schulze and Editorialist Stefan Anker as they discuss the original articles "Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial" and "Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From Antihyperglycemic Agents to All-Around Heart Failure Therapy." Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             I'm so excited about the feature discussion this week. It is a paired feature along with their editorial and it's all focused on SGLT2 inhibitors. The first, results from the EMPULSE trial, Effects of Empagliflozin on Symptoms, Physical Limitations and Quality of Life in Patients Hospitalized for Acute Heart Failure; and the second, the EMPAG-heart failure trial, The Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients with Acute Heart Failure. Incredibly important topics, incredibly important discussion. Wait up for it. We're just going to tell you a little bit more about two other original papers in today's issue, and I'm going to go first, Greg. Is that okay? Dr. Greg Hundley:           You bet. Dr. Carolyn Lam:             Now, really interesting topic here. We have strong evidence supporting the effective blood pressure and cardiovascular disease risk lowering properties of healthy diet such as the DASH diet, Mediterranean diet, and so on and so on. But what about the diet consumed by a fifth of the entire world's population? The Chinese cuisine. Interestingly, today's paper addresses just that. This is from authors, Dr. Wu, from Peking University Clinical Research Institute and colleagues who performed a multicenter patient and outcome assessor blind randomized feeding trial among 265 participants with baseline systolic blood pressure of 130 to 159 in four major Chinese cuisines. And these are the Shandong, Huaiyang, Cantonese, and Szechuan cuisines, and here's how they did it. After a seven day run in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine based Chinese heart healthy diet for another 28 days. The primary outcome was systolic blood pressure. The study developed the first heart healthy Chinese diet that fits Chinese food culture and emphasizes its palatability by involving master shifts in developing the recipes. Dr. Greg Hundley:           Oh wow. Carolyn, this is really interesting, especially one fifth of the world's population in studying a heart healthy diet. So did it work? I can't wait to hear the results. Dr. Carolyn Lam:             Well, the change in systolic and diastolic blood pressure from baseline to the end of the study in the control group was five millimeters mercury and 2.8 millimeters mercury reduction, respectively. The net difference of change between the two groups in systolic and diastolic blood pressure were a reduction of 10 and almost four millimeters mercury, respectively. The effect size did not differ among cuisines, and so in summary, with a patient and assessor blind randomized feeding trial, this study really demonstrated that the blood pressure lowering effect of the Chinese heart health diet could indeed be substantial, and importantly, be compatible with medications while palatable and affordable in Chinese adults with high blood pressure, and so these results support the idea that food is medicine and will give many patients with high blood pressure the confidence to adopt heart healthy diets in their lifestyle treatment. Dr. Greg Hundley:           Wow, Carolyn, that is really an interesting article. So many of these articles today could all be features in and of themselves. That was just outstanding. Well, my next paper comes to us from the world of preclinical science, and it's from Dr. Sean Wu from Stanford University School of Medicine. So Carolyn, immune checkpoint inhibitors are monoclonal antibodies that are used to activate the immune system against tumor cells. Now, despite their therapeutic benefits, immune checkpoint inhibitors have the potential to cause immune mediated adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Now histologically, patients with immune checkpoint inhibitor of myocarditis have lymphocytic infiltrates in the heart implicating T-cell mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in immune checkpoint inhibitor myocarditis are unknown. Dr. Carolyn Lam:             Wow. So insights into the etiology of these immune checkpoint associated myocarditis cases must be very important. So what did they find? Dr. Greg Hundley:           Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found to be significantly increased in the blood of patients with immune checkpoint inhibitor myocarditis corresponding with an analogous increase in effector cytotoxic CD8+ cells in the blood and hearts of PD-1 deficient mice with myocarditis. These expanded effector CD8+ cells had unique transcriptional changes, including upregulation of the chemokines CCL5, CCL4, and CCL4L2, and they may serve as attractive diagnostic therapeutic targets for reducing life threatening cardiac immune related adverse events in immune checkpoint inhibitor treated cancer patients, and Carolyn, just like so many of our articles, there's a very nice accompanying editorial by Professor Gianluigi Condorelli that also offers an update on current research pertaining to non-systemic steroid therapy to treat immune mediated myocarditis. Well, Carolyn, how about we jump to some of the other articles in the issue? Dr. Carolyn Lam:             Oh, you bet, Greg. There's an exchange of letters between Drs. Madias and Knops regarding the article “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: The Analysis of All Appropriate Therapy in the PRAETORIAN Trial.” Dr. Greg Hundley:           And also in the mail bag, Professor Mark has a Research Letter entitled “Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction, The SUGAR-DM-HF Study,” and our own Tracy Hampton has several synopses from articles published elsewhere in our piece on cardiovascular news. Well, how about we get onto that feature forum discussion, two papers, two editorialists. I can't wait. Dr. Carolyn Lam:             Me too. Let's go, Greg. Dr. Greg Hundley:           Welcome, listeners to this July 26th feature forum discussion. So remember, listeners, for forum discussions, we have several manuscripts that focus on a singular topic and we bring together the authors, our associate editors, and also an editorialist, and today, I want to introduce, we have with us Dr. Mikhail Kosiborod from Mid America Heart Institute in Kansas City, Missouri, Dr. Christian Shults from University Hospital Jena in Germany, Stefan Anker from Charité in Berlin, Germany, and our Associate Editors, Brendan Everett from Brigham and Women's Hospital in Boston, Massachusetts, and Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome, gentleman, and we'll start with you, Mikhail. Could you describe for us the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Mikhail Kosiborod:   Well, thanks very much, Greg. The background for the study, which was the secondary analysis of the EMPULSE trial was patients that are hospitalized with acute decompensated heart failure represent a very high risk group. We know that they have high risk of death and hospitalizations, and we also know that they have very poor health status that's very high burden of symptoms, physical limitations, and poor quality of life, and so addressing those treatment goals, trying to reduce the risk of clinical events like death and hospitalizations and improve the symptoms and physical limitations in this patient population are very important treatment goals. Now we previously demonstrated in the main results of the EMPULSE trials that using empagliflozin initiating empagliflozin SGLT2 inhibitor in this patient population as compared with placebo provided a significant total clinical benefit, which was a composite of total death, repeat hospitalizations for heart failure, or a change in a Kansas City cardiomyopathy questionnaire, which is a kind of a gold standard measure of patient's health status. What we tried to do in a much more granular fashion in this study is to understand the effects of empagliflozin as compared with placebo on this very important outcome, the Kansas City cardiomyopathy questionnaire, and we actually evaluate all of the key domains and composite symptoms, physical limitations, as well as quality of life. Dr. Greg Hundley:           Very nice, and Mikhail, can you describe for us what study population specifically, and then what was your study design? Dr. Mikhail Kosiborod:   Well, this was a population of patients that were hospitalized with heart failure and that EMPULSE was unique in its design because first of all, previous SGLT2 inhibitor trials mostly focused on patients with chronic heart failures that were in an outpatient setting, including prior trials of empagliflozin, and EMPULSE really focused on acutely hospitalized patient population, but it included patients regardless of ejection fraction. So as they were hospitalized with decompensated heart failure and reduced or preserved ejection fraction. They were enrolled regardless of if they had type 2 diabetes, they were enrolled essentially, regardless of kidney function, only patients with EGFR of less than 20 were excluded, and also importantly, was this study and a unique feature of the study in particular was that we enrolled patients whether they had acute de novo heart failure. That means that was a new diagnosis of heart failure that was bad enough for them to be hospitalized or worsening chronic heart failure requiring hospitalization. So it was really an all-comer trial for patients acutely hospitalized for heart failure. So we had just over 500 patients and they were randomized in the hospital. After a brief period of stabilization, we use empagliflozin, 10 milligrams daily or placebo and treated for 90 days, and the primary outcome at 90 days was a total clinical benefit that I described that was a composite, hierarchical composite of total death hospitalizations, repeat hospitalizations for heart failure and changing KCCQ. In this study, again, we focused predominantly on KCCQ, trying to understand the effects on health status, again, symptoms, physical limitations, and quality of life. Dr. Greg Hundley:           Excellent. And Mikhail, what were your study results? Dr. Mikhail Kosiborod:   Well, what we observed, a couple of things. One is we first examined the effects of empagliflozin on the primary endpoint across the range of KCCQ and baseline, and what we found was that regardless of the degree of symptomatic impairment and baseline, empagliflozin was consistent in providing them total clinical benefits that I described previously, and then kind of shifting to what I think is the most interesting findings, the effects of empagliflozin versus placebo on KCCQ, what we found was that as you would imagine in this population of patients that were acutely hospitalized with heart failures, that had very poor health status, very low KCCQ at baseline, and within the first 90 days, which was observation period, both groups of patients had substantial improvements in KCCQs. As one would expect after acutely decompensated episode of heart failure and treatment in a hospital, everyone got better. But patients treated with empagliflozin had significantly greater improvement in KCCQs than those that were treated with placebo, and that was first of all, a very substantial difference between the two groups. It was more than five points in favor of empagliflozin already at 15 days and was highly statistically significant, and it was maintained throughout the 90 day treatment period. So the fact that we saw both a clinical meaningful and statistically significant improvement in just 15 days, I think is a very important clinical message, and then finally, I guess what I will mention is these benefits of empagliflozin while main outcome we looked at was KCCQ total symptoms, we're focusing on the symptoms, but it was consistent when we looked at physical limitations as well as quality of life. So really, all key domains of KCCQ were impacted in a similar way. Dr. Greg Hundley:           Very nice. So in acute heart failure, marked symptomatic improvement after the administration of the SGLT2 inhibitor empagliflozin at 10 milligrams per day. Well, now listeners, we're going to turn to our associate editor, Dr. Brendan Everett, and Brendan, again, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Brendan Everett:      Well, thanks, Greg, and I think this manuscript caught my eye because of the importance of the clinical question, and Mikhail outlined why I think that was really relevant. So we understand that this class of medications or SGLT2 inhibitors have important effects on outcomes like re-hospitalization in patients with heart failure, and what was particularly striking about this paper is that it took patients rather than those with chronic heart failure, but as Mikhail mentioned, enrolled a patient population that was actually in the hospital, and I think this was an important frontier for this particular question about when to start the SGLT2 inhibitor and what kind of benefits there might be. Furthermore, I think the fact that they did not select the population based on ejection fraction was particularly striking, and of course, I think is remarkable, but now old news, they did not select on the presence or absence of diabetes as well. And so those three components really attracted me to the paper. I also think the outcome is one that really is valuable and worth exploring, and specifically, I'm talking about how patients feel on the medication after a hospitalization for heart failure. Appropriately, we focused on re-hospitalization for heart failure and cardiovascular death in prior trials in this space, and I think we need to embellish those findings or further deepen those findings with a perspective on how patients actually feel when they get the medication, and of course, it goes without saying that what's particularly important here also is that it was a randomized placebo controlled trial, and so the results have some element of internal validity that I think is really important. So those were the things, Greg, that really attracted my attention as I read the paper for the first time. Dr. Greg Hundley:           Thank you so much, Brendan. Well, listeners, we've got a second paper today and we're next going to hear from Dr. Christian Shults, and he also is focusing on really another aspect of the administration of empagliflozin in patients with acute heart failure and that pertains to the renal function of the patients. So Christian, could you describe for us the background pertaining to your study and what was the hypothesis that you were intending to address? Dr. Christian Schulze:     Thanks, Greg. Well, it's great to introduce all study here in this running. So our study impacted those in acute decompensated heart failure. The impact HF trial was a study based on the hypothesis that we wanted to test, whether empagliflozin has effects in acute decompensated heart failure, and we focused on the patient population that was not addressed in EMPULSE, patients that came to the ER and needed to be treated right away, and we wanted to know and this was our main hypothesis, but are the diuretic and [inaudible 00:17:11] effects of the SGLT2 inhibitor on this case, empagliflozin, actually had an impact on diuretic regimens and kidney functions since this is one of the main end points that limits treatment, and also is one of the outcomes of patients with acute decompensated heart failure in the hospital. Dr. Greg Hundley:           Very nice. And so Christian, what study design did you implement and who was included in your study population? Dr. Christian Schulze:     So we also used the randomized two arm study design. We included patients with acute decompensated heart failure independent of left ventricular ejection fraction. Patients needed to have an NT-proBNP of more than 500. The average NT-proBNP in fact was 4,300 in our entire patient population, and we included patients within 12 hours of presentation. So many of these patients have been recruited in the ER, they presented two hour cardiology heart failure service, and then were immediately randomized to the trial in the two arms, and we tested not 10 milligrams of empagliflozin. We actually tested 25 milligrams of empagliflozin based on in-house data that 25 milligrams potentially had a stronger diuretic effect compared to 10 milligrams. Dr. Greg Hundley:           And what did you find? Dr. Christian Schulze:     So we followed patients for five days. It was a relatively short period of time. It was designed to address the in-house phase of patients with acute decompensated heart failure. The mean duration of stay was 6.3 days in the hospital so this was exactly the time that we wanted to test. We had a 30 day endpoint for safety issues, and what we could see is that patients on 25 milligrams on empagliflozin on top of standard diuretic regimens and medical care had 25% higher diuretic outputs compared to patients in the placebo group. We also found no differences in markers of renal injury dysfunction, and could in fact confirm that after 30 days, patients in the empagliflozin group had a better EGFR compared to patients in the placebo group. On top, we saw a more rapid decrease in body weight and also a more profound decrease in NT-proBNT values. Dr. Greg Hundley:           And Christian, just for our listeners to put a little bit of this in perspective, what was the range of serum creatinine for the patients that were enrolled in your study? Dr. Christian Schulze:     So the main EGFR in the entire population was around 60 and the creatinine values were around 107 on average in the entire cohort. So this is a very typical population. We had around 30% of the population with de Novo heart failure, around 20 to 30% of the population was pre-treated for preexisting heart failure. So very typical population of patients with heart failure presenting to the emergency room. Dr. Greg Hundley:           And did you have any kind of lower level EGFR cutoff, I mean, for enrollment into this study? Dr. Christian Schulze:     So when we designed the trial, we actually still had the sub classification of diabetes or impaired glucose or homeostasis as an inclusion criteria. We dropped it before we started the trial because the data came out that this is actually, in fact, not a critical issue for patients with heart failure. So diabetes was not a subgroup in our trial and the lower limit of EGFR was actually a thoroughly defined protocol. Dr. Greg Hundley:           Very nice. Well, listeners, now we're going to turn to our second associate editor, Dr. Justin Grodin from University of Texas Southwestern Medical Center in Dallas, Texas, and Justin, similar to Brendan, and you see many papers come across your desk and so what attracted you to this particular paper by Christian and his colleagues? Dr. Justin Grodin:            Well, Greg, I think first and foremost, and I think very similar to Brendan, but I think what's always striking is if I may just take a step back, decompensated heart failure in the United States is the number one cause for hospitalization among Medicare beneficiaries. So I think really, the brunt and really the truly public health message of the disease is very important in the applicability, and even though that decompensated heart failures is one of the most common things that we ever encounter when we practice, internists, cardiologists, et cetera, we have very, very little clinical trial guidance that tells us how to decongest individuals when they're hospitalized with swelling and heart failure and a lot of these individuals can be quite ill, and we have some clinical trial data, but largely, we have a lot of negative studies or inconclusive studies in this space. So certainly, what drew me to this trial was definitely that context, and obviously, based on the mechanistic data with SGLT2 inhibitors, I think one of the natural questions, which Christian addresses, is that we know that up front, they do augment natriuresis. So I think it's very compelling to marry those two together because this is what many of us that use these medications regularly have been asking is whether or not they would have some efficacy in that regard, and then another thing that caught my eye and me as a cardiorenal investigator was, just as Christian highlighted, was we have a clinical trial that randomly assigned individuals, really that were ill and many of whom were not stabilized within 12 hours of presentation, and we're talking about patients that are coming into the hospital at all times during the day in and I think that's very remarkable that we have something with standard... We have a study with standardized assessments where we're really trying to ask a very practical, pragmatic question, which is do these therapies lower the sodium balance in individuals with decompensated heart failure, and I think what's important is largely, we've got a lot of medications that supplement loop diuretics, which are the class of drugs that the majority of us use, and we have a lot of other therapies that we use that really have very little data or poor data that guide us such as thiazide diuretics, carbonic and hydrase inhibitors, mineralocorticoid receptor antagonists, and so here, we have a clinical trial that asks a question that's on many people's minds. And then we do have very compelling, at least short term pragmatic and mechanistic data that does tell us that these individuals do have a greater natriuretic effect when empagliflozin is used as an adjunct to standardized loop diuretic therapy. So it's a very practical clinical question, and I think what's very important, and we could debate probably all day about the implications of GFR change and kidney function change while we're decongesting somebody with diuretics, but I think what's reassuring to all the clinicians is we really didn't see an effect on kidney function despite a greater natriuretic effect or enhanced diuretic effect, if you will, with the use of empagliflozin. Dr. Greg Hundley:           Very nice. Well, thank you, Justin. Listeners, now we have an editorialist and as you know, editorialists really help us put the scientific presentation of an original manuscript into the perspective of really the global theme of a topic, and we have Stefan Anker from Berlin, and Stefan, can you describe for us how do we put these two manuscripts and results that we've heard about really in the context now of moving forward with the use of SGLT2 inhibitors in the management of patients with acute decompensated heart failure? Dr. Stefan Anker:            Thank you so much. Really, I think these two papers, on the one hand, enhance our certainty about early use, and on the other hand, possibly show us that there might be even more to achieve by, on the one hand, moving even earlier with the application of SGLT2 inhibitors or possibly consider the higher dose. Now let's take one step back. These drugs were developed in type two diabetes and the first successful trial was the [inaudible 00:25:42] outcome trial. Many people have forgotten that this trial tested two doses and not only one, the 10 and the 25 milligram dose, and of course, with the success for improving kidney outcomes and heart failure hospitalization outcomes, we move forward into these two specialist areas, on the one hand, broadening it to the non-diabetic communities, but on the other end, narrowing it by focusing on the 10 milligram dose regardless of whether there is [inaudible 00:26:12]. And we basically now learn A, to use these drugs even earlier than we did in the big trials and we can now be sure to start their use in the hospital, and if you take the average change in quality of life results seen, you actually get a better result for the patient on quality of life when you start earlier than when you start late in the ambulatory studies where basically, in the chronic setting, maybe you have one and a half to two points difference. Here, you now have four and a half points in the study shown by Mikhail, and of course, it's also good to know that you can start this in any type of patient, regardless of their quality of life. The impact study from Christian, they basically moved it now even earlier, moving into the hospital space is possible based on EMPULSE. Moving it into the acute admission space is at least a consideration now based on what Christian here has shown. And he is actually addressing the one question I hear very often in my presentations about SGLT2 inhibitors, what about this 25 milligram dose? Is there a place for this in cardiology as well, and a possible place is shown here, not only that this is a safe thing to do, but also you get urinary output. Of course, we may in the future, want to see this compared, directly compared to the 10 milligram dose, but of course, the world is not created in one day, but needs more than one and so really, I think these two studies, on the one hand, address an important issue, when to start using them. On the other hand, show us a little bit of a glimpse to the future. Dr. Greg Hundley:           Very nice, Stefan, and listeners, we get to take advantage of having these authors, editors, and editorialists together and ask them what they see as the next study to be performed in this sort of sphere of research. So Mikhail, we'll start with you. In 30 seconds or less, what do you see as the next study to be performed in this arena of research? Dr. Mikhail Kosiborod:   I think, Greg, what we've learned recently, including from the EMPULSE trial, we have this population of patients in a hospital with heart failure's a huge issue as Justin mentioned, and until recently, we had very little [inaudible 00:28:31] for them beyond the usual kind of decongestion with loop diuretics and trying to make them feel better, but you look at outcome data. It really was a dearth of effective therapies that have meaningful impact on important outcomes. Now that's changing, SGLT2 inhibitors is one example. There are some other recent examples in this patient population, like a firm HF and iron deficient patients with heart failure. But the bottom line is it's no longer kind of a desert, if you will, of positive trials. We now have something we can do and I think what this proves is that we need to actually invest more, both in terms of resources and time to really do what we we're being able to do in other areas of heart failure and those patients with chronic, half and half where we can start developing pillars of therapy that can actually truly improve outcomes with this patient population and there is a lot going on that makes me optimistic that's going to be the case in the coming years. Dr. Greg Hundley:           Very nice. And Brendan? Dr. Brendan Everett:      Well, I think both trials mentioned today really pushed our understanding of this population forward. I think the biggest clinical question that I face when I'm caring for these patients is that we have four, at least, guideline directed therapies, right? We have beta blockers, we have ARBs, ACE inhibitors and ARNIs. We have mineral receptor antagonists and we have SGLT2 inhibitors. So which do we use in what order and how do we start them, and what kind of parameters do we use to guide us if we're limited either by renal function or by blood pressure or by some other factor. And we often, if not always, have one of those constraints that we're dealing with and so I would say the next step for me is trying to sort out which of these therapies and what order ought to be our highest priority for patients with acute decompensated heart failure as we move quickly from the acute decongestion stage towards discharge and a chronic therapy that will then be followed as an outpatient over the ensuing days and months. Dr. Greg Hundley:           Very nice. And Christian. Dr. Christian Schulze:     Thank you again, and Brandon pointed out very nicely. I mean, we have good evidence now for chronic heart failure treatment. We have the four columns of heart failure medical therapy. Questions that remain open is what do we do with all these patients that are now guideline medicated, come to the hospital with an acute decompensation? Should we carry on with the medication? Should we terminate and in particular, should be carry on with full dose, 50% dose of SGLT2 inhibitors, and the next question is, what dose should we use, in fact, for SGLT2 inhibitors? Is it in group effects or is sotagliflozin comparable to empagliflozin, and then is there a role for a step by scheme that we initially have in high dose therapy that we then downgrade to 10 milligrams on the chronic heart failure treatments, and then of course, quality of life is very important. We should ask this question also in this patient population that is early on treated, do we see benefits that carry on in the outpatient setting and do we see an effect of early treatment on long term benefits? Dr. Greg Hundley:           Justin? Dr. Justin Grodin:            Well, I would have to agree with all of my colleagues here on this call. I think all have raised really good points, but I think one very simple, and I'll echo some of Brendan's statements, but one very simple question is we know that when we decongest people and initiate a negative salt balance in the hospital for decompensated heart failure, we cause neurohormonal activation and there are a lot of downstream untoward effects from chronic decongestive therapies, and I think one of the more compelling things is we still yet have defined what is the best way to decongest individuals with swelling or volume overload in the hospital. Here, we have compelling studies with SGLT2 inhibitors for quality of life and really, the way patients feel. And this is really what's important to them, and then something very pragmatic to clinicians and let's make people pee more, but I think one of the compelling questions, and I don't know if it will be answered, is we have a lot of choices for supplemental therapies and different diuretic strategies when patients come in the hospital for decompensated heart failure, and I do think that these studies do move the needle with SGLT2 inhibitors. I think that's abundantly clear, but we still don't know what is the best way to dry out my patient or make my patient pee so that they feel better, but I do think that these studies do at least set the stage that there's some compelling advantages to SGLT2 inhibitors. Dr. Greg Hundley:           And then lastly, Stefan. Dr. Stefan Anker:            Thank you. Besides the detailed points mentioned by many, and Christian, totally support 25 versus 10 milligram, how long 25 milligram, if at all in the future. Besides this, I'm interested in the big picture question. So what about the post myocardial infarct congestion/heart failure situation, and there will be two trials in the next 18 to 24 months that report on this, and my pet kind of area is actually to treat heart failure where nobody thinks it is heart failure, and what I mean is for instance, advanced cancer patients, cardiac wasting cardiomyopathy. So the heart failure in sick cancer patients, and indeed, we are planning to do exactly that now in a study focusing on hospice care patients to really improve the quality of life, the very thing focus here on the EMPULSE trial. Dr. Greg Hundley:           Well, listeners, we want to thank our authors, Dr. Mikhail Kosiborod from Mid America Heart Institute in University of Missouri, and Christian Shults from the University Hospital in Jena, Germany. Also, our associate editors, Dr. Brendan Everett from Brigham and Women's Hospital in Boston, and Dr. Justin Grodin from University of Texas Southwestern in Dallas, Texas, and also, our editorialist, Dr. Stefan Anker from Charité in Berlin, Germany for bringing us these two manuscripts pertaining to two randomized clinical trials regarding the administration of the SGLT2 inhibitor, empagliflozin in acute heart failure, demonstrating first, marked improvement in heart failure symptoms and health related quality of life. And second, in those with estimated GFRs greater than 30 mls per minute, an augmentation of natriuresis in the setting of the co-administration of diuretics without deterioration in renal function. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late.  So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out.      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  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.     

Calling into our second hour are Laurel Imer, Republican candidate for Congress in CD7, and Peggy Propst, Republican for State Board of Education for CD8, to discuss their campaigns. See omnystudio.com/listener for privacy information.

Al Singer joins immune to discuss mice that have their T cell immune system reversed, revealing the molecular basis for T cell lineage fate determination in the thymus. Hosts: Vincent Racaniello, Cynthia Leifer, Steph Langel, and Brianne Barker Guest: Al Singer Subscribe (free): Apple Podcasts, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode T cell FlipFlop mice reveal lineage determination (Nat Immunol) Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

Guest host Dr. Nathan Pennell, of the Cleveland Clinic Taussig Cancer Institute, and Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, discuss the ATLANTIS trial and other novel therapies in advanced SCLC, NSCLC, and malignant pleural mesothelioma featured at the 2022 ASCO Annual Meeting Poster Sessions.  Transcript   Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast, today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice-chair of Clinical Research for the Taussig Cancer Institute.  My guest today is my friend Dr. Vamsidhar Velcheti, an associate professor and medical director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone Health.  We'll be discussing key posters on lung cancer that will be featured at the 2022 ASCO Annual Meeting. Although the oral sessions tend to get the most press, we want to make sure you don't miss out on some high-impact abstracts that are presented in the poster session.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.orgpodcasts.  Vamsi, it's great to speak with you today.  Dr. Vamsidhar Velcheti: Thank you, Nate. It's a pleasure to discuss these 5 outstanding abstracts.  Dr. Nathan Pennell: Why don't we start with Abstract 9021, “Genomic correlates of acquired resistance to PD-(L)1 blockade in patients with advanced non—small cell lung cancer (NSCLC).” Vamsi, what were your key takeaways from this study?  Dr. Vamsidhar Velcheti: This is an important study in my opinion. This was a very large study of 1,700 patients from Dana Farber and the investigators looked at 45 specimens and matched pre- and post- immunotherapy treated patients. And they looked at the data mechanisms of resistance that were identified in 25 out of the 45 patients, that is 55% of the patients.  5 patients had acquired STK11 mutations. One patient had a KEAP1 alteration. There were several patients who had like KEAP1 SMARCA4 mutations. And interestingly, there were also some patients who developed KRAS-G12C mutation as well on the post-treatment specimens.  So, this is an interesting abstract. We typically don't do biopsies on patients progressing on immunotherapy. At this point, we don't have a standard clinical indication to do so. However, identifying these new novel mechanisms of genomic mechanisms of resistance is actually very important, because a lot of new therapy medications are being developed to target, for example, KEAP1, and could be approached to target microglobulin mutations. So, it's very important to kind of understand the mechanisms of resistance.  Dr. Nathan Pennell: Yeah, I completely agree. I mean, most of the benefits in second line in the refractory setting with targeted treatments came about through studies like this where there was broad sequencing of resistance and trying to understand and I think we're still kind of in the infancy of understanding resistance to immunotherapy, but it's a good start.  Abstract 9019 was another interesting study in non—small cell lung cancer. That was “A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non—small cell lung cancer.” Can you tell us a little bit about that study?  Dr. Vamsidhar Velcheti: Yeah, this is a multicenter phase-2 trial. This is an interesting agent. It's a PD-1/VEGF bispecific antibody developed by Akeso Bio. This is a single-arm study, and they did the study in 3 different cohorts.  One of the cohorts was patients with advanced non—small cell lung cancer who had wild-type EGFR/ALK, and they were treatment-naive. There was another cohort of patients where they enrolled patients with EGFR mutation who developed resistance to EGFR tyrosine kinase inhibitors (TKIs) and essentially progressed on osimertinib. And there was another cohort where patients were enrolled who were PD-1 refractory, they had prior PD-1or PD-1 chemo combination, and they had progressions. So, they enrolled a total of 133 patients, it was a decent-sized study, but a very early efficacy finding study.  In the cohort-1 which is the cohort that is enrolled with untreated patients with advanced non—small cell lung cancer. They had like 20 partial responses out of 26 patients that were evaluable and enrolled in the cohort, and there were 6 patients who had stable disease.  So, overall, the response rate was 76.9% and 100% disease control rate. So, this is a very small cohort and small data set. So, we have to interpret this with caution. But suddenly, a very interesting signal here for this VEGF/PD-1 bispecific antibody.  Dr. Nathan Pennell: The 40% response rate in the immunotherapy (IO) and chemo refractory patients, I thought was fairly interesting, although, as you said, very small numbers in these cohorts will have to be reproduced in larger trials.  Dr. Vamsidhar Velcheti: Right. I think there was a lot of excitement early on the IMpower150, right? With the combination of bevacizumab with chemo-theralizumab.  There seems to be some signal in terms of the addition of a VEGF inhibitor to immunotherapy. And we've seen that consistently in renal cells and other tumor types. So, I think this is a really intriguing signal. I think this definitely warrants further exploration.  So, the other interesting thing was cohort-2 where they enrolled patients who had progressed on EGFR TKIs. So, in that cohort, they had like 19 evaluable patients and 13 patients had a partial response and 5 had stable disease. So, a very respectable response rate of 68.4% and 94.7 disease control rate. So, again, very small numbers, but a nice signal here for the efficacy of the drug.  There was another cohort, which is the cohort-3 where they enrolled patients who progressed on PD-1 therapy, and they enrolled a total of 20 patients with 8 patients having a partial response, following progression on PD-1 therapy.  Dr. Nathan Pennell: Yeah, I look forward to seeing further follow-up on this. It definitely sounds interesting. Moving on to Abstract 8541. This was “Durvalumab (durva) after chemoradiotherapy (CRT) in unresectable, stage III, EGFR mutation-positive (EGFRm) NSCLC: A post hoc subgroup analysis from PACIFIC,' which of course was the study that led to the broad use of durvalumab, the anti-PD-L1 antibody after chemoradiotherapy for unresectable stage III non-small cell, but this was the post hoc subgroup analysis of the EGFR mutation-positive group. And this is a subgroup we've really been curious about whether there was a role for consolidation, immunotherapy, or not. And so, what are your thoughts on the study?  Dr. Vamsidhar Velcheti: I agree with you, Nate, that this is actually some data that I was really, really looking forward to. Before we actually talk about the abstract. What do you do for those patients? If you have an EGFR mutation patient who has stage IIIB, what do you do right now?  Dr. Nathan Pennell: It's a great question. I have a discussion with them about the potential pluses and minuses of doing consolidation durvalumab. But I actually don't always use durvalumab in this setting, because of concerns about if you're using durvalumab and they recur, perhaps there is a problem with toxicity with using osimertinib. Honestly, I go back and forth about what the right thing is to do in this subgroup.  Dr. Vamsidhar Velcheti: No, I think that's the right context. I think that's a good setup to kind of discuss the data from the trial. I'm really excited about this. And I'm glad that we have this data to look at.  So, as you pointed out, the Pacific trial, its U.S. Food and Drug Administration (FDA) approval for durvalumab in the consolidation setting for patients with stage III after chemoradiation. This has now been the standard of care for like a few years now. The problem with the study is that patients with EGFR/ALK were allowed to enroll in the study.  Typically, for most IO trials, we generally tend to see patients with EGFR/ALK being excluded. So, this trial was an exception. In this study, they actually presented a post-hoc exploratory analysis of efficacy and safety of patients who did consolidation with durvalumab, but there was a total of 35 patients of the 713 patients that were randomized in the trial. And out of the 35 patients with EGFR mutation, 24 received durvalumab and 11 received a placebo.  So, of course, you're going to interpret this data with a little bit of caution. This is a full stock analysis, not pre-planned in small numbers. In this dataset, essentially, the median progression-free survival (PFS) was not different among patients treated with durvalumab or placebo, and the median survival was also not statistically significant. Overall, there was not much benefit from adding durvalumab in this setting in patients who have EGFR mutation-positive stage III lung cancer.  Dr. Nathan Pennell: I think that tends to track along with what we who have been treating patients with EGFR mutations for years, and knowing the disappointing response rates, certainly in the advanced stage with immunotherapy, I think we were concerned that in this consolidation phase that it would also potentially be a relatively marginal benefit. I agree with you that 35 patients are too small to make any definitive conclusions, but it certainly isn't supportive of a large benefit.  Dr. Vamsidhar Velcheti: But I think I'm excited about the LAUREL study that's ongoing, hopefully, that'll give us a little bit more definitive answers as to what we should be doing for patients with EGFR mutation-positive disease. Suddenly this is a piece of information that's helpful for treating physicians to make some decisions on clinical management for these patients.  Dr. Nathan Pennell: I agree. Now moving beyond the non—small cell. Let's talk about “Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).” That's Abstract 8561. What were your takeaways here?  Dr. Vamsidhar Velcheti: Yeah, it's always good to see some new therapeutic options for patients with mesothelioma. This is somewhat of an orphan disease and we haven't seen a lot of advances. Granted, we have some new therapeutic options with immunotherapy now, like, there is now a standard of care in the frontline setting.  So, this particular approach with ONCOS-102 is an oncolytic adenovirus expressing GM-CSF. And this is intended to stimulate the local and systemic immune response and remodulate the tumor microenvironment.  This was a small phase 1 study where they had a CFT run-in of 6 patients and a total of 25 patients were randomly assigned to receive ONCOS-102 intratumorally with ultrasound guidance or CT guidance and they injected this oncolytic virus into the tumor directly.  They were also getting treatment with platinum pemetrexed which is the standard of care in the frontline setting. The control here was 6 cycles of platinum pemetrexed. So, they enrolled both the treatment-naive patients in the frontline setting and they also enrolled patients who will progress on a platinum doublet.  I should note that none of these patients were treated with immunotherapy. I think that's something that we'll kind of get back to and we'll discuss. Overall, from a safety standpoint, there were some expected toxicities like pyrexia and nausea which is seen in the experimental group. It's just kind of to be expected with an oncolytic virus. Overall, the 30-month survival rates were 34.3% and 18.2% in the control arm, and the median overall survival (OS) was 19.3 months and 18.3 in the controller.  So, for patients who were treated with the frontline chemotherapy, the survival rate was better with 30 months survival, it was 33.3 [months]. And in the experimental group, it was 0%.  So, overall, they also looked at tumor-infiltrating lymphocytes, they had CD4 around CD8 and granzyme B expressing CDA T-cells, and they had favorable PK from increased immune cell infiltration. So, this is very promising data but of course in a small study, and also in a population that hasn't had immunotherapy patients who are getting platinum doublet. In terms of safety, I think it looks promising. We need to see larger studies, especially with immunotherapy combinations.  Dr. Nathan Pennell: Yeah, I was impressed with the increased tumor infiltration of CD4 and CDA-positive T-cells, and the survival in the first line looked fairly impressive, although again, a very small subgroup of patients. But as you said, a standard of care these days is definitely going to involve immunotherapy. And so, I look forward to seeing combination trials in the future with this drug.  Shifting from mesothelioma over to small cell lung cancer, Abstract 8570 is “Stereotactic radiosurgery (SRS) versus whole brain radiation therapy (WBRT) in patients with small cell lung cancer (SCLC) and intracranial metastatic disease (IMD): A systematic review and meta-analysis.” Do you think that this would influence how we approach patients with brain metastases in the small cell?  Dr. Vamsidhar Velcheti: There are some in the community who kind of advocate for SRS in small cells if they have limited CNS disease. Certainly, I'm not one of them, but I think this is an interesting study in that light like we have never had any proper randomized trial. And we probably won't have randomized trials in that setting. So, at the end of the day, I think we all kind of customize our treatment approaches based on our patients and how much disease burden they have.  But having said that, the authors here have done a pretty large systemic analysis, and they looked at 3,700+ trials, they looked at random effects meta-analysis pooled hazard ratios for overall survival in patients who received SRS in the whole brain with or without SRS boost.  What they found was that overall survival following SRS was not inferior to whole brain RT. What do we really make out of this data? I think, given the heterogeneity, we have to see how the analysis was done and the kind of studies that went into the analysis. But however, I think the bigger question is, is there a population that we need to maybe—perhaps like, if somebody has an isolated brain met, you could potentially consider SRS with a whole brain RT for better local control.  So, the authors actually look at pooled data to look at local control versus intracranial distant control. So, this is a really interesting approach that asks the question, if patients had SRS and whole brain radiation, would it actually offer adequate intracranial distant control meaning like, do they develop new lesions?  So, it does look fairly decent. But again, it all depends on what kind of studies went into the analysis. And I don't think we should read too much into it. But at the same time, it kind of raises the question: is there a population of patients with small cell where it may be potentially appropriate to give SRS?  So, that's what I do in my day-to-day clinical practice. Sometimes there are situations where you kind of do the thing that we don't usually always do like in the small cell, we always think about whole brain radiation as something that we always have to offer, but I want to hear your perspectives too.  Dr. Nathan Pennell: No, I was always taught that you never did anything with whole brain radiation in the small cell even with a solitary metastasis. For a study like this, it's certainly interesting. You wonder how much selection bias there was towards people with fewer brain metastases and perhaps being in better health or better response to systemic disease that were referred for SRS, compared to whole brain radiation.  Part of the issue is the morbidity associated with whole brain radiation is significantly more than with SRS. And now that we are starting to, for the first time, see some patients with small cell [lung cancer] that are living substantially longer with immunotherapy, it might be worth exploring which patients might benefit from having that lower morbidity from whole brain radiation. But I agree with you that I'm not sure that we know who those patients are.  Dr. Vamsidhar Velcheti: Yeah, I think this is a difficult question to answer through a meta-analysis in my opinion. But having said that, your thought in terms of proving systemic therapies, then we kind of revisit the paradigm of offering SRS to some patients may be, especially with new BiTE T-cell engager studies that are ongoing, and hopefully, if you see some positive results, that might change what we do, but it's an important clinical question.  Dr. Nathan Pennell: And finally, in Abstract 8524, we have an interesting analysis of patients with relapsed small cell lung cancer, who received single-agent Lurbinectedin in the phase-3 Atlantis trial. What do you think about this poster, and why should this be on our radar?  Dr. Vamsidhar Velcheti: Yeah, I think this has been an interesting approval, of course, lurbinectedin FDA approved, as you know, like in June of 2020, based on data from a trial that uses 3.2 milligrams per meter square dosing every 21 days in second line setting post-chemotherapy.  What happened after that was there was a trial with the combination with doxorubicin in the second line setting comparative arm in that phase 3 trial topotecan or CAV.  In that trial, it was a negative trial, the primary endpoint was not met. The primary endpoint was overall survival, and it was a negative trial. And there were subgroup analyses done in the trial. The study that is presented now is actually a post-hoc analysis looking at patients who received treatment with this combination with doxorubicin that is like a lurbinectedin with doxorubicin, who had like a total of 10 cycles of the combination, and they switched to lurbinectedin monotherapy.  So, there were a total of 50 patients in that trial. They looked at the responses and the durability of responses in that population. It's a highly select population that made it to 10 cycles and they had stable disease or better and they switched to lurbinectedin monotherapy.  So, the highlight of the abstract is the median overall survival was 20.7 months. Of course, for small cell, that's really impressive. But I think we've got to be really careful in interpreting this data. This is like a small subgroup of highly selected patients who actually benefited from the trial. My question for you, Nate, is do you use lurbinectedin in the second line setting frequently or are you still treating them with topotecan?  Dr. Nathan Pannell: We still often use topotecan. I think lurbinectedin certainly seems to be an active drug, and it has some favorable schedule of administration pretty well tolerated from a tolerability standpoint, but from an efficacy standpoint, I still haven't really seen much that makes it stand out as significantly better than older options like topotecan or irinotecan.  That being said, it is intriguing that there is a subgroup of people who seem to have prolonged disease control with this. The problem, of course, is if you already select the people who make it 10 cycles without progression, then you're already picking the group of people who are doing extremely well. So, it's not surprising that they would continue to do extremely well.  Nonetheless, it's a sizable subgroup of people that seem to benefit and it would really be nice if there was, for example, a biomarker that might tell us which patients would truly benefit from this drug compared to our other options.  Dr. Vamsidhar Velcheti: Yeah, exactly. True. Right, I mean, like all of us have patients who have done exceedingly well on topotecan and I had a patient on paclitaxel for years. So, it's really important to kind of keep that in mind when we look at these sub-proof post hoc analyses.  Dr. Nathan Pennell: Well, thanks Vamsi for sharing these important advances in lung cancer that will be featured at the 2022 ASCO Annual Meeting.  Dr. Vamsidhar Velcheti: Thank you, Nate.  Dr. Nathan Pennell: And thank you to our listeners for joining us today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.    Disclosures:  Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Vamsidhar Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine , AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen  Research Funding (Institution): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  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.   

This month on Episode 36 of Discover CircRes, host Cynthia St. Hilaire highlights original research articles featured in the April 29 and May 13 issues of Circulation Research. This episode also features a conversation with Dr Patricia Nguyen and Jessica D'Addabbo from Stanford University about their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self.   Article highlights:   Zanoli, et al. COVID-19 and Vascular Aging   Wang, et al. JP2NT Gene Therapy in a Mouse Heart Failure Mode   Harraz, et al. Piezo1 Is a Mechanosensor in CNS Capillaries   Zhao, et al. BAT sEVs in Exercise Cardioprotection   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cyndy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. And today, I'll be highlighting the articles from our April 29th and May 13th issues of Circulation Research. I also will speak with Dr Patricia Nguyen and Jessica D'Addabbo from Stanford University about their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self.   Cindy St. Hilaire:        The first article I want to share is titled Vascular Dysfunction of COVID 19 Is Partially Reverted in the Long-Term. The first author is Agostino Gaudio and the corresponding author is Luca Zanoli. And they're from the University of Catania. Cardiovascular complications, such as endothelial dysfunction, arterial stiffness, thrombosis and heart disease are common in COVID 19. But how quickly such issues resolve, once the acute phase of the illness has passed, remains unclear. To find out, this group examined aortic and brachial pulse wave velocity, and other measures of arterial stiffness in 90 people who, several months earlier, had been hospitalized with COVID 19. These measurements were compared with data from 180 controls, matched for age, sex, ethnicity and body mass index, whose arterial stiffness had been assessed prior to the pandemic. 41 of the COVID patients were also examined 27 weeks later to assess any changes in arterial stiffness over time. Together, the data showed arterial stiffness was higher in COVID patients than in controls. And though it improved over time, it tended to remain higher than normal for almost a year after COVID.   Cindy St. Hilaire:        This finding could suggest residual structural damage to the arterial walls or possibly, persistent low-grade inflammation in COVID patients. Either way, since arterial stiffness is a predictor of cardiovascular health, its potential longterm effects in COVID patients deserves further longitudinal studies.   Cindy St. Hilaire:        The second article I want to share is titled Gene Therapy with the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice. The first author is Jinxi Wang and the corresponding author is Long-Sheng Song from the University of Iowa. Junctophilin-2 is a protein with a split personality. Normally, it forms part of the heart's excitation contraction coupling machinery. But when the heart is stressed, JP2 literally splits in two, and sends its N-terminal domain, JP2NT, to the nucleus, where it suppresses transcription of genes involved in fibrosis, hypertrophy, inflammation and other heart failure related processes. However, if this stress is severe or sustained, the protective action of JP2NT is insufficient to halt the progressive failure. This group asked. "What if this N-terminal domain could be ramped up using gene therapy to aid a failing mouse heart?"   Cindy St. Hilaire:        To answer this question, they injected adenoviral vectors encoding JP2NT into mice either before or soon after transaortic constriction, or TAC, tack, which is a method of experimentally inducing heart failure. They found, in both cases, that the injected animals fared better than the controls. Animals injected before TAC showed less severe cardiac remodeling than control mice, while those treated soon after TAC exhibited slower loss of heart function with reduced ventricle dilation and fibrosis. These data suggest that supplementing JP2NT, via gene therapy or other means, could be a promising strategy for treating heart failure. And this data provides a basis for future translational studies.   Cindy St. Hilaire:        The third article I want to share is titled Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries. The first and corresponding author is Osama Harraz from the University of Vermont. Neurovascular coupling is the process whereby transient activation of neurons leads to an upsurge in local blood flow to accommodate the increased metabolic needs of the cell. It's known that agents released from active neurons trigger changes in local capillaries that prompt vasodilation, but how these hemodynamic changes are sensed and controlled is not entirely clear. This group suspected that the mechanosensory protein Piezo1, a calcium channel that regulates dilation and constriction of other blood vessels, may be involved. But whether Piezo1 is even found in the microcirculation of the CNS was unknown. This group shows that Piezo1 is present in cortical capillaries of the brain and the retina of the mouse, and that it responds to changes in blood pressure and flow.   Cindy St. Hilaire:        Ex vivo preparations of mouse retina showed that experimentally induced changes in hemodynamics caused calcium transients and related currents within capillary endothelial cells, and that these were dependent on the presence of Piezo1. While it is not entirely clear how Piezo1 influences cerebral blood flow, its pressure induced activation of CNS capillary endothelial cells suggest a critical role in neurovascular coupling.   Cindy St. Hilaire:        The last article I want to share is titled Small Extracellular Vesicles from Brown Adipose Tissue Mediate Exercise Cardioprotection. The first authors are Hang Zhao and Xiyao Chen. And the corresponding authors are Fuyang Zhang and Ling Tao from the Fourth Military Medical University. Regular aerobic exercise is good for the heart and it increases the body's proportion of brown adipose tissue relative to white adipose tissue. This link has led to the idea that brown fat, possibly via its endocrinal activity, might somehow contribute to exercise related cardioprotection. Zhao and colleagues now show that, indeed, brown fat produces extracellular vesicles that are key to preserving heart health. While mice subjected to four weeks of aerobic exercise were better protected against subsequent heart injury than their sedentary counterparts, blocking the production of EVs prior to exercise significantly impaired this protection. Furthermore, injection of brown fat derived EVs into the hearts of mice lessened the impact of subsequent cardiac injury.   Cindy St. Hilaire:        The team went on to identify micro RNAs within the vesicles responsible for this protection, showing that the micro RNAs suppressed an apoptosis pathway in cardiomyocytes. In identifying mechanisms and molecules involved in exercise related cardio protection, the work will inform the development of exercise mimicking treatments for people at risk of heart disease or who are intolerant to exercise.   Cindy St. Hilaire:        Lastly, I want to bring up that the April 29th issue of Circulation Research also contains a short Review Series on pulmonary hypertension, with articles on: The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure, by Olivier Boucherat; Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension, by Christopher Rhodes and colleagues; New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis, by Christophe Guignabert and colleagues; Group 3 Pulmonary Hypertension From Bench to Bedside, by Corey Ventetuolo and colleagues; and Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart, by Sudarshan Rajagopal and colleagues; and Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease, by Jessica Huston and colleagues.   Cindy St. Hilaire:        Today, Dr Patricia Nguyen and Jessica D'Addabbo, from Sanford University, are with me to discuss their study, Human Coronary Plaque T-cells are Clonal and Cross-React to Virus and Self. And this article is in our May 13th issue of Circulation Research. So, Trisha and Jessica, thank you so much for joining me today.   Jessica D'Addabbo:    Thank you for having us.   Patricia Nguyen:         Yes. Thank you for inviting us to your podcast. We're very excited to be here.   Cindy St. Hilaire:        Yeah. And I know there's lots of authors involved in this study, so unfortunately we can't have everyone join us, but I appreciate you all taking the time.   Patricia Nguyen:         This is like a humongous effort by many people in the group, including Roshni Roy Chowdhury, and Xianxi Huang, as well as Charles Chan and Mark Davis. So, we thank you.   Cindy St. Hilaire:        So atherosclerosis, it stems from lipid deposition in the vascular wall. And that lipid deposition causes a whole bunch of things to happen that lead to a chronic inflammatory state. And there's many cells that can be inflammatory. And this study, your study, is really focusing on the role of T-cells in the atherosclerotic plaque. So, before we get into the nitty gritty details of your study, can you share with us, what is it that a T-cell does normally and what is it doing in a plaque? Or rather, let me rephrase that as, what did we know a T-cell was doing in a plaque before your study?   Patricia Nguyen:         So, T-cells, as you know, are members of the adaptive immune system. They are the master regulators of the entire immune system, secreting cytokines and other proteins to attract immune cells to a diseased portion of the body, for example. T-cells have been characterized in plaque previously, mainly with immunohisto chemistry. And their characterization has also been recently performed using single cell technologies. Those studies have been restricted to mainly mirroring studies, studies in mice in their aortic walls, in addition to human carotid arteries. So, it is well known that T cells are found in plaque and a lot of attention has been given to the macrophage subset as the innate immune D. But let's not forget the T-cell because they're actually composed about... 50% in the plaque are T-cells.   Patricia Nguyen:         And we were particularly interested in the T-cell population because we have a strong collaboration with Dr Mark Davis, who's actually the pioneer of T-cell biology and was the first to describe the T-cell receptor alpha beta receptor in his lab in the 1970s. So, he has developed many techniques to interrogate T-cell biology. And our collaboration with him has allowed us and enabled us to perform many of these single cell technologies. In addition, his colleague, Dr Chen, also was pivotal in helping us with the interrogation and understanding of the T-cells in plaque.   Cindy St. Hilaire:        And I think one of the really neat strengths of your study is that you used human coronary artery plaques. So, could you walk us through? What was that like? I collect a lot of human tissue in my lab. I get a lot of aortic valves from the clinic. And it's a lot of logistics. And a lot of times, we're just fixing them, but you are not just fixing them. So, can you walk us through? What was that experimental process from the patient to the Petri dish? And also, could you tell us a little bit about your patient population that you sampled from?   Jessica D'Addabbo:    So, these were coronary arteries that we got from patients receiving a heart transplant. So, they were getting a heart transplant for various reasons, and we would receive their old heart, and someone would help us dissect out the coronary arteries from these. And then, we would process each of these coronary arteries separately. And this happened at whatever hour the hearts came out of the patient.   Jessica D'Addabbo:    So sometime, I was coming in at 3:00 AM with Dr Nguyen and we would be working on these hearts then, because we wanted the samples to be as fresh as possible. So, we would get the arteries. We would digest out the tissue. And then, we would have certain staining profiles that we wanted to look at so that we could put the cells on fax to be able to sort the cells, and then do all the downstream sequencing from there.   Cindy St. Hilaire:        So, in terms of, I don't know, the time when you get that phone call that a heart's coming in to actually getting those single cells that you can either send a fax or send a sequencing, how long did that take, on a good day? Let's talk only about good days.   Jessica D'Addabbo:    Yeah. A lot of factors went into that, sometimes depending on availability of things. But usually, we were ready with all of the materials in advance. So, I'd say it could be anywhere from six to 12 hours, it would take, to get everything sorted. Then, everything after that would happen. But that was just that critical period of making sure we got the cells fresh.   Patricia Nguyen:         So we have to credit the CT surgeons at Stanford for setting up the program or the structure, infrastructure, that enables us to obtain this precious tissue. That is Jack Boyd and Joseph Woo of CT surgery. So, they have enabled human research on hearts by making these tissues available. Because as you know, a transplant... They can say the transplant's happening at 12:00 AM, but it actually doesn't happen until 4:00 AM. And I think it's very difficult for a lab to make that happen all the time. And I think having their support in this paper was critical. And this has allowed us, enabled us, to interrogate kind of the spectrum of disease, especially focusing on T-cells, which are... They make a portion of the plaque, but the plaque itself has not like a million cells that are immune. A lot of them are not immune. So, enabling us to get the tissue in a timely fashion where they're not out of the body for more than 30 minutes enables us to interrogate these small populations of cells.   Cindy St. Hilaire:        That's actually the perfect segue to my next question, which is, how many cells in a plaque were you able to investigate with the single cell analysis? And what was the percentage again of the T-cells in those plaques or in... I guess you looked at different phases of plaque. So, what was that spectrum for the percentage of T-cells?   Patricia Nguyen:         So, for 10X, for example, you need a minimum of 10,000 captured cells. You could do less, but the utility of the 10X is maximized with 10,000. So, many times before the ability to multiplex these tissues, we were doing like capturing 5,000 for example. And the number of cells follows kind of the disease progression, in the sense that as a disease is more severe, you have more immune cells, in general. And it kind of decreases as it becomes more fibrotic and scarred, like calcified. So, it was a bit challenging to get very early just lipid-only cells. And a lot of those, we captured like 3000 or something like that. And efficiency is like 80% perhaps. So, you kind of capture…   Cindy St. Hilaire:        And also, how many excised hearts are going to have early athero? So, it's...   Patricia Nguyen:         Well, there are... nonischemics will have...   Cindy St. Hilaire:        Oh, okay. Okay.   Patricia Nguyen:         So, the range was nonischemic to ischemic.   Cindy St. Hilaire:        Oh great.   Patricia Nguyen:         So, about a portion... I would say one third of the total heart transplants were ischemic. And a lot of them were non ischemic. But as you know, the nonischemic can mix with ischemia. And so, they could have mild to moderate disease in the other arteries, for example, but not severe like 70%/90% obstruction.   Cindy St. Hilaire:        Wow. That's so great. That's amazing. Amazing sample size you have. So T-cell, it's kind of an umbrella term, right? There's many different types of T-cells. And when you start to get in the nitty gritty, they really do have distinct functions. So, what types of T-cells did you see and did you focus on in this study?   Jessica D'Addabbo:    So, the two main types of T-cells are CD4 positive T-cells and CD8 positive T-cells. And we looked at both of these T-cells from patients. We usually sorted multiple plates from each. And then, with 10X, we captured both. But our major finding was actually that the CD8 positive t-cell population was more clonally expanded than the CD4 population, which led us to believe that these cells were more important in the coronary artery disease progression and in the study that we were doing because for a cell to be clonally expanded, it means it was previously exposed to an antigen. And so, if we're finding these T-cells that are clonally expanded in our plaques, then we're hypothesizing that they were likely exposed to some sort of antigen, and then expanded, and then settled into the plaque.   Cindy St. Hilaire:        And when you're saying expansion, are you talking about them being exposed to the antigen in the plaque and expanding there? Or do you think they're being triggered in the periphery and then honing in as a more clonal population?   Patricia Nguyen:         So, that's a great question. And unfortunately, I don't have the answer to that. So basically-   Jessica D'Addabbo:    Next paper, next paper.   Patricia Nguyen:         Exactly. So, we... Interesting to expand on Jessica's answer. Predominantly what was found, as you said, was memory T-cells, so memory T-cells expressing specific markers, so memory versus naive. And these were effector T-cells. And memory meaning they were previously expanded by antigen engagement, and just happened to be in the plaque for whatever reason. We do not know why T-cells specifically are attracted to the plaque, but they are obviously there. And they're in a memory state, if you will. And some of them did display activation markers, which suggested that they clonally expanded to an antigen. What that antigen is, is the topic of another paper. But certainly, it is important to understand that these patients that we recruit, because they were transplant patients, they're not actively infected, right? That is a exclusionary criteria for transplants, right?   Patricia Nguyen:         So, that means these T-cells were there for unclear reasons. Why they're there is unclear. Whether they are your resident T-cells also is unclear, because the definition of resident T-cell still remains controversial. And you actually have to do lineage tracking studies to find out, "Okay, where... Did they come from the bone marrow? Did they come from the periphery? How did they get there?" Versus, "Okay. They were already there and they just expanded, for whatever reason, inside the plaque."   Cindy St. Hilaire:        So, your title... It was a great title, with this provocative statement, "T-cells are clonal and cross react to virus and self." So, tell us a little bit more about this react to virus and self bit. What did your data show?   Jessica D'Addabbo:    So, because of the way we sequenced the T-cell receptor, we were able to have paired alpha and beta chains. And because we knew the HLA type of the patients, we were able to put the sequences that we got out after we sequenced these through an algorithm called GLIPH, which allows us to look at the CDR3 region of the T cell receptor, which is the epitope binding region. And there are certain peptide. They're about anywhere from three to four amino acids long. These are mapped to certain binding specificities to known peptides. And so, basically, we were able to look at which epitopes were most common in our plaques. And we found that after comparing these to other epitopes, that these were actually more binding to virus. Patricia Nguyen:         So let me add to what Jessica stated, and kind of emphasize the value of the data set, if you will. So, this is, I believe, the first study that provides the complete TCR repertoire of coronary plaque, and actually any plaque that I know of, which is special because we know that there is specificity of TCR binding. It's more complicated than the antibody that binds directly from B cells to the antigen, because the T-cells bind processed antigen. So, the antigens are processed by antigen presenting cells like Dendritic cells and macrophages. And they have a specific HLA MHC class that they need to present to. And they need both arms, the antigen epitope and the MHC, to activate the T-cell. So unfortunately, it's not very direct to find the antigen that is actually activating the T-cell because we're only given a piece of it. Right?            Patricia Nguyen:         But we have provided a comprehensive map of all the TCRs that we find in the plaque. And these TCRs have a sequence, an immuno acid sequence. And luckily, in the literature, there is a database of all TCR specificities. Okay. So, armed with our TCR repertoire, we can then match our TCR repertoire with an existing database of known TCR specificities. Surprisingly, the matching TCRs are specific to virus, like flu, EBV and CMB. And also, because this was done in the era of COVID, we thought it would be important to look at the coronavirus database. We did find that there were matches to the coronavirus database. Even though our finding is not specific to SARS, it does lend to some potential mechanistic link there as well.   So, because this is all computational, it is important to validate. So, the importance of validation requires us to put the TCR alpha beta chain into a Jurkat cell, which is a T-cell line that does not have alpha beta chains on it, and then expose it to what we think is the cognate antigen epitote, with the corresponding HLA MHC APC. Because you don't have all those pieces, it will not work. Yes. So importantly, we did find that what we predicted to have the specificity of a flu peptide had specificity to a flu peptide.   Patricia Nguyen:         So then, the important question was, "Okay, these patients aren't infected, right? Why are these things here? Is there a potential cross reactivity with self peptides?"   Patricia Nguyen:         So luckily, our collaborator, Dr Charles Chan, was able to connect us with another computational algorithm that he was familiar with, whereby we were able to take the peptide sequences from the flu and match them with peptide sequencing from proteins that are self and ubiquitous. And we demonstrated, again, these T-cells were activated in vitro. That is why we concluded that there's a potential cross reactivity between self and virus that can potentially lead to thrombosis associated with viral infections. Of course, this all needs to be proved in vivo.   Cindy St. Hilaire:        Sure, sure.   Patricia Nguyen:         It's that first step for other things.   Cindy St. Hilaire:        The other big immune cell that we know is in atherosclerotic plaques and that's macrophages. And they can help to present antigens and things like that. And they also help to chew up the necrotic bits. And so, do you think that this T-cell component is an earlier, maybe disease driving, process or an adaptive process that goes awry as a secondary event? Patricia Nguyen:         So, I'm a fan of the T-cell. So... I'm with team T cell. I would like to think that it is playing an active role in pathology in this case and not a reactive role, in the sense of just being there. I think that the T-cell is actively communicating with other cells within the plaque, and promoting pro fibrotic and pro inflammatory reactions, depending on the T-cell. So, a subset of this paper was looking at kind of the interactions between the T-cell and other cells within the plaque, like macrophages and smooth muscle cells. And as we know, T-cells are activated and they produce cytokines. Those cytokines then communicate to other cells. And we found that, computationally, when you look at the transcriptome, there is a pro-inflammatory signature of the T-cell that resides in the more complex stage. And then, there's an anti-inflammatory signature that kind of resides in the transition between lipid and fibro atheroma, if you will.   Cindy St. Hilaire:        So, do you know, or is it known, how dynamic these populations are? Obviously, the hearts that you got, the samples you got, didn't have active infections. But do you know perhaps even how long ago they happened, or even how soon after there might be an infection or an antigen presented that you could get this expansion? And could that be a real driver of rupture or thrombosis?   Patricia Nguyen:         So, in theory, you would suppose that T-cells expanding and dividing and producing more and more cytokines would then lead to more macrophages coming, more of their production of proteinases that destroy the plaque. Right? So yes, in theory, yes. I think it's very difficult to kind of map the progression of T cell clonality in the current model that we have, because we're just collecting tissues. However, in the future, as organoids become more in science and kind of a primary tissue, where we can... For example, Mark Davis is making organoids with spleen, and also introducing skin to that.   Patricia Nguyen:         And certainly, we could think of an organoid involving the vasculature with immune cells introduced. And so, I think, in the next phase, project 2.0, we can investigate what... like over time, if you could model atherosclerosis and the immune system contribution, T-cells as well as macrophages and other immune cells, you can then kind of map how it happens in humans. Because obviously, mice are different. We know that mice... Actually, the models of transgenic mice do not rupture. It's very hard to make them rupture. Right?   Cindy St. Hilaire:        Well, if you stop feeding them high fat diet, the plaque goes away.   Patricia Nguyen:         For sure, for sure. So I think.. I mean, Mark Davis is a huge proponent of human based research, like research on human tissue. And as a physician scientist, obviously I'm more inclined to do human based research. And Jessica's going to be a physician someday soon. And I'm sure she's more inclined to do human based research. And certainly, the mouse model and in vitro models are great because you can manipulate them. But ultimately, we are trying to cure human diseases.   Cindy St. Hilaire:        Mice are not little humans. That's what we say in my lab. I similarly do a lot of human based stuff and it's amazing how great mice are for certain things, but still how much is not there when we need to really fully recapitulate a disease model.   So, my last question is kind of regarding this autoimmune angle of your findings. And that is, women tend to have more autoimmune diseases than men, but due to the fact that you are getting heart transplants, you've got a whole lot more men in your study than women. I think it was like 31 men to four women. But, I mean, what can you do? It's the nature of heart transplants. But I'm wondering, did you happen to notice...Maybe the sample size perhaps is too small, but were there any differences in the populations of these cells between women and men? And do you think there could be any differences regarding this more prevalence of autoimmune like reactions in women?   Patricia Nguyen:         So, that's an interesting question, but you hit it on the nose when you said "Your sample is defined mainly by men." And in addition, the samples that were women tend to have less disease. And they tend to be nonischemic in etiology. So, I think that kind of restricts our analysis. And perhaps, I guess, future studies could model using female tissues, for example, instead of only male. But the limitation of all human studies is sample availability. And perhaps, human organoid research can be less limited by that. And certainly, mouse research has become more evenly distributed of male and female mice.   Cindy St. Hilaire:        Yeah. Suffice it to say, human research is hard, but you managed to do an amazing and really important study. It was really elegant and well done. Congratulations on what is an epic amount of time. 12-hour experiments are no joke, and really beautiful data. So, thank you so much for joining me today, Dr Nguyen and Miss almost Dr D'Addabbo. Congrats and I'm really looking forward to seeing your future work.   Jessica D'Addabbo:    Thank you so much.   Patricia Nguyen:         Thanks so much.   Jessica D'Addabbo:    Thank you for having us. This is wonderful.   Cindy St. Hilaire:        That's it for the highlights from the April 29th and May 13th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page and follow us on Twitter and Instagram with the handle @Circres and #Discover CircRes. Thank you to our guests: Dr Patricia Nguyen, and soon to be Doctor, Jessica D'Addabbo, from Stanford University.   This podcast was produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Haler. And this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by the speakers of this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, visit aha journals.org.  

Guests, Mark Pfoff and Lori Saine, Denver's progressive policies causing crime waves, and the politics behind being snubbed Denver's progressive policies are not only destroying the City…. they are causing crime waves in surrounding cities. Former law enforcement investigator Mark Pfoff explains the danger. Plus the Republican Women of Weld County are hosting a debate and inviting everyone but the CD8 primary frontrunner… Lori Saine. She joins the show to talk about the politics behind why she is being snubbed.

Immune reveals a CD8+ regulatory subset of T cell subset that suppress pathogenic T cells and are active in autoimmune diseases and infectious diseases including COVID-19. Hosts: Vincent Racaniello, Cynthia Leifer, Steph Langel, and Brianne Barker Subscribe (free): Apple Podcasts, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode KIR+CD8+ regulatory T cells (Science) Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

Resveratrol supplementation associated with improved glucose regulation in diabetics   National University of Medical Sciences (Pakistan) March 30 2022.    The June 2022 issue of Complementary Therapies in Medicine reported findings from a randomized trial that uncovered positive effects for supplementing with resveratrol in the regulation of glucose and the maintenance of healthy levels of inflammation and oxidative stress in type 2 diabetics. The trial included men and women who were being treated with orally administered drugs for type 2 diabetes.  Forty-five participants received 200 milligrams resveratrol per day and 46 received a daily placebo for 24 weeks. Blood samples collected at the beginning and end of the trial were analyzed for plasma glucose, insulin, hemoglobin A1c (a marker of long-term glucose control), lipids, malondialdehyde (a marker of oxidative stress), circulatory microRNAs associated with diabetes, and markers of inflammation that included tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP).   (NEXT)   Eating peanuts may lead to supple arteries and healthy hearts   Pennsylvania State University, March 29, 2022   Eating peanuts with a meal may help protect against cardiovascular diseases which can lead to heart attacks and stroke, according to an international team of researchers. In the study, overweight and obese but otherwise healthy men who ate about three ounces of peanuts with a high-fat meal had a blunted increase of lipids in their bloodstream. According to the researchers eating peanuts can keep the cells that line the arteries healthy, helping them stay more elastic. The researchers showed that when peanuts are eaten with a meal the typical post-meal increase of triglycerides -- a type of fat found in the bloodstream -- is blunted. According to the researchers, there was a 32 percent reduction in the triglyceride levels after the consumption of the peanut meal compared to the control group. Three ounces of peanuts is about three times the amount of an average serving size, according to the researchers.   (NEXT)   NIH Study confirms: Turkey Tail mushrooms boost immunity in women with breast cancer   University of Minnesota and Bastyr University, March 28, 2022   Turkey Tail mushrooms can boost your immune system so significantly that it may even shrink breast cancer tumors. A $2 million, seven-year clinical study funded by the National Institutes of Health and jointly conducted by the University of Minnesota and Bastyr University showed that Trametes versicolor, or turkey tail mushroom, in freeze-dried form, dramatically boosts immune function for women with Stage I-III breast cancer─ possibly shrinking tumors. One theory is that when patients ingest Turkey Tail mycelium, the immune system's increased populations of NK cells and their associated CD8 glycoproteins are better able to discover and bind to receptor sites on the stroma of tumors, thus allowing NK invasion. If true, then the use of this medicinal mushroom as an adjunct or preventative therapy may help many patients better fight the battle when challenged with tumor-forming cancers.”   (NEXT)   Too Much Screen Time is Really Bad for Teen Well-Being   University of Queensland School of Health, March 31, 2022    Whether it's watching TV or playing games, teens experience serious physical and mental health consequences after just two hours of screen time, according to new research The global study of more than 400,000 adolescents is the first to provide evidence that both passive and mentally active screen time adversely affects teens' mental well-being. Teens are more likely to report psychosomatic symptoms, a combination of physical and psychological complaints, if they exceed two hours of screen time and these effects were similar regardless of physical activity levels. Psychological complaints from teens included feeling low, irritable, nervousness, and sleeping difficulty, and somatic complaints included headaches, abdominal pain, backache, and dizziness.   Guest: Jessica Rose Part 2 

Cool News A new type of killer T-cell can stop attacks on healthy tissue | Interesting Engineering (01:14) A team of scientists has discovered a brand new form of human T cell that suppresses attacks on healthy tissues, which could lead to treatments for illnesses ranging from lupus to cancer.T cells are significant white blood cells in the immune system, playing a crucial role in adaptive immune response by killing diseased or malignant cells Studies in mice have shown that some of these cells may also kill T cells responsible for orchestrating autoimmune responses.Believed that humans share the same cells but not able to prove it The newly discovered class of T cells in the human immune system may be capable of killing other T cells, Aid in the healing of infections and reducing autoimmune disorders. Stanford researchers evaluated the number of these human cells in patients with autoimmune illnesses like multiple sclerosis, lupus, and celiac disease to see if they are immunological inhibitors. Saw that the specific T cells (CD8) were more abundant in patients' blood than in healthy people's blood. Gathered in regions of the body that had been injured by the autoimmune response like the joints in people with rheumatoid arthritis  The researchers looked at genetically altered mice that had 50 percent to 75 percent fewer suppressive CD8 cells than normal mice to see how much protection the cells provide against autoimmunity.Experienced kidney inflammation after being exposed to viruses that can cause autoimmune illness. (Control did not) The paper provides data that these CD8 cells exist in humans, and could indicate that techniques that enhance the number of cells in the body may aid in the treatment of autoimmune diseases.   Tiny 'skyscrapers' help bacteria convert sunlight into electricity | TechXplore (05:24) The researchers, from the University of Cambridge, used 3D printing to create grids of high-rise 'nano-housing' where sun-loving bacteria can grow quickly.3D-printed custom electrodes out of metal oxide nanoparticles that are tailored to work with the cyanobacteria as they perform photosynthesis. Developed a printing technique that allows control over multiple length scales, making the structures highly customisable They extracted the bacteria's waste electrons, left over from photosynthesis, which could be used to power small electronics. These researchers have found that providing the bacteria with the right kind of home increases the amount of energy they can extract by over an order of magnitude. For several years, researchers have been attempting to 're-wire' the photosynthesis mechanisms of cyanobacteria in order to extract energy from them. Lead researcher,  Dr. Jenny Zhang, stated: “There's been a bottleneck in terms of how much energy you can actually extract from photosynthetic systems, but no one understood where the bottleneck was … Most scientists assumed that the bottleneck was on the biological side, in the bacteria, but we've found that a substantial bottleneck is actually on the material side." Dr. Zhang ends it off by talking on cyanobacteria:“Cyanobacteria are versatile chemical factories. Our approach allows us to tap into their energy conversion pathway at an early point, which helps us understand how they carry out energy conversion so we can use their natural pathways for renewable fuel or chemical generation." Concept Touchscreen Uses Temperature to Create Feel of Friction | Gizmodo (10:34) Researchers at Texas A&M have come up with a novel way for touchscreens to feel more than just perfectly smooth by fooling a user's sense of touch through temperature changes. Some theorize a full touchscreen future, but the article argues that being able to feel physical keys with our fingers is an important part of the muscle memory that allows many of us to type at impressive speeds without having to look down and hunt-and-peck on a keyboard. The researchers in a recent study, found that by regulating the temperature of the surface of a touchscreen, they can increase or decrease the amount of friction a finger feels like it's experiencing. The sensation of friction can be increased by as much as 50% by increasing a touchscreen's surface temperature from 23 degrees Celsius to 42 degrees Celsius.The actual temperature changes are imperceptible to the user if doing quick motions The current prototypes don't facilitate temperature adjustments in fine detail, but the eventual goal is to be able to manipulate and quickly change the temperature on any region of a touchscreen.Changes in friction can fool the brain into thinking it's feeling physical buttons like keyboards, playback controls, even joysticks and action buttons for gaming. There's a long way to go before this approach becomes a viable way to make virtual touchscreen keyboards easier to interact with.Being able to rapidly heat and cool a precise area would be very difficult, but it is a cool first step and idea.   Israeli scientists reverse aging process in human eggs | The Jerusalem Post (14:11) A team of researchers at the Hebrew University of Jerusalem, managed to successfully identify one of the aging mechanisms that prevent egg cells from successfully maturing.Stating they found the aging mechanism, it is reversible and they can “treat it.” This is significant with women putting off having kids until later on in life. After the age of 35, women's eggs begin to rapidly deteriorate and in-vitro fertilization (IVF) treatments become less effective. By the time a woman reaches her late 30s, her eggs have accrued enough cellular damage to prevent them from properly maturing or being fertilized. Wasserzug-Pash, who conducted the research, discussed this: “This research allows us to understand how human eggs age, which is important also for understanding how aging occurs in other areas … We can affect this aging mechanism with drugs and with [medical] intervention. We've gone one step forward in being able to help women suffering from age-related infertility. They will suffer less, have to go through fewer difficult procedures, and run into fewer disappointments when it comes to trying to conceive and start a family.” The team found that there is a way to prevent this damage from happening, thereby reversing the aging processes at work in egg cells. Led on the research, Dr. Michael Klutstein, touches on how they can treat the virus-like sequences that occurs in our genome that affects our DNA & ultimately eggs: “If we use drugs that prevent these viruses from operating, and these are just antiviral drugs, then we stop this mechanism from happening and slow down the aging process,”  Researchers in the lab examined both mice and human egg cells that were taken from several different age groups. Along with a control group and a group taking an antiviral drug They found, in all cases, the older oocytes, or eggs, that had received the antiviral drug appeared to be younger than the ones that had not been treated.The older, 35 to 40 year old eggs, “behaved more like eggs in their 20s.” The next step will be to establish the correct protocol for treating human eggs in an IVF setting, as well as ensure that the treatment does not negatively affect the embryo. Anti-aging molecules safely reset mouse cells to youthful states | New Atlas (19:33)  The Yamanaka factors at the center of this study are a set of four reprogramming molecules that can reset the molecular clock found in the cells of the body. Returning unique patterns of chemicals known as epigenetic markers, which evolve through aging, to their original states. New research at the Salk Institute has sought to build on previous research on these factors by demonstrating how these molecules can reverse signs of aging in middle-aged and elderly mice, with no evidence of health problems following the extended treatment.Previously used the approach to reverse signs of aging in mice with a premature aging disease, and improve the function of tissues found in the heart and brain.  The purpose of the new study was to investigate the effects on healthy animals as they approached the latter stages of life The mice groups treated with the Yamanaka factors:Middle-aged mice from 15 through to 22 months old, equivalent to 50 to 70 years old in humans Another group was treated from 12 to 22 months, equal to 35 to 70 years of age. Another group received the molecules for just one month, at the age of 25 months, or 80 years old in human terms. Not only did the mice exhibit no neurological or blood cell changes, nor signs of cancers, they in many ways resembled more youthful animals.  ​​Epigenetic patterns typical of younger mice were observed in the kidneys and skin, while the skin cells were able to proliferate and minimize scarring following injury, a capability that typically declines with age.  Co-corresponding author on the study Juan Carlos Izpisua Belmonte provides the thoughts on the study's results:“We are elated that we can use this approach across the life span to slow down aging in normal animals … The technique is both safe and effective in mice. In addition to tackling age-related diseases, this approach may provide the biomedical community with a new tool to restore tissue and organismal health by improving cell function and resilience in different disease situations, such as neurodegenerative diseases.” From here, the scientists plan to investigate the influence the Yamanaka factors might have on specific molecules and genes, and develop new ways to deliver them.     

Guests, Peggy Propst and Michael Thau, fake COVID testing and abusive progressive education policies Investigative columnist Michael Thau reveals how fake COVID testing pushed the panic porn needed to create what he calls the fake pandemic. Plus…. parents are fighting back against abusive progressive education policies, Peggy Propst is a candidate for the new CD8 seat on the Colorado Board of Education and joins the show.

南非和瑞典的研究團隊各自發表了很初步的針對Omicron變種病毒的初步中和抗體研究。寫在前面，這人數都不多，且都是初步的資料，解讀要很小心。 1.南非研究僅有12個人，都是打完第二劑BNT疫苗者一個月內的血清，其中有6個人之前有自然感染過。在實驗室測試是否血清可以中和活病毒。 2.相比於原始株，中和抗體平均有41倍的下降。 3.之前打過兩劑疫苗+自然感染者中和抗體則明顯較高，6個有5個還是可中和Omicron。 4.瑞典的研究則是用假病毒，取17個捐血者(BD)還有17個之前感染過的醫護人員(HW)，他們血清中都對原本武漢株有高的中和抗體，來看Omicron的中和抗體下降程度。 5.結果發現個別差異很大，中和抗體從1~23倍的下降都有。但幾乎所有血清都還是可以中和Omicron。 6.平均是下降7倍，好像比想像中好。 04b解讀： 1.南非當地用真病毒來做，瑞典還沒拿到所以是用假病毒做。但一路以來用真假病毒做其實結果都還算吻合。 2.為何兩個研究差異這麼大，可能有許多原因，瑞典研究沒有清楚交代抽血的時間點，之前打過什麼疫苗，還有之前有沒有過自然感染。另外這些試驗人數都不多，個別差異可能很大，還是要累積更多數據才能下確切結論。 3.南非研究顯示暴露過三次抗原者（一次自然感染，兩次BNT）對Omicron中和抗體較高。因此可能可以推論，加強針打下去應該也是對Omicron有幫助。我相信輝瑞很快也會有打完加強針的血清來測試的結果，因為他們才剛做完萬人的加強針臨床試驗。 4.雖然這兩個研究一個降41倍一個降7倍，但多半血清都還是可以中和Omicron，並沒有達到完全失效。我想初步來說這還算是個好消息。 5.之前各種變種病毒：Delta中和抗體大概是降7倍左右，Beta大概是10倍左右。這個倍數給大家參考。41倍看上去真的是滿嚇人的，如果這是真的，應該會嚴重影響到疫苗或自然感染對於有症狀感染的保護力。但是否可以防重症，我想有很大的機會還是會有用的。 接下來的一兩週，類似這樣的中和抗體研究應該會如雨後春筍一樣出來，讓我們繼續看下去吧。 更新：錄音時輝瑞剛剛發新聞稿，這裡我來說清楚些： 1.輝瑞以打完兩劑BNT後21天的血清，還有打完三劑加強針後一個月的血清來看是否可中和Omicron的假病毒。各自還有用武漢原始株，Beta還有Delta來對照。每組大概20人。 2.打完兩劑者，對武漢株中和抗體為155，對Beta是36約下降了4~5倍，對Omicron則是6！下降了25倍之多。 3.打完三劑者，對武漢株中和抗體為398，但對其他變種病毒也有顯著的拉升！相對下降的倍數就沒這麼多了。對Delta是339，對Beta是191，對Omicron可以到154，僅下降了2.5倍。 4.針對Omicron的中和抗體，會在打第三針後從6到154，增加到25倍。其所到達的濃度，跟之前第二針打完針對原始株的中和抗體的濃度155是相當的。所以預期應該能有不錯的保護力。 5.此外還針對了防重症的T細胞免疫做出研究。針對細胞毒殺T細胞會辨認的31個位點(CD8+ epitopes)，之前的變種病毒大概僅有1~2個受影響，Omicorn則是6個。但有25個（78%）還是不受影響的。因此對重症應該還是可以有一定的保護力。 6.結論指出：因為打完疫苗皆有B細胞和T細胞的免疫力，兩劑疫苗可能對防Omicron重症仍有效。 7.要強調這還是初步研究，輝瑞會持續做更多實驗室研究還有蒐集疫苗在真實世界的有效性，來評估接下來該怎麼做。 8.輝瑞會研發針對Omicorn的次世代疫苗，看是否可以有更好的保護力，還有延長保護的時間。 04b解讀： 1.輝瑞也是用假病毒做，而不像昨天第一篇南非當地用真病毒來做。但一路以來用真假病毒做其實結果都還算吻合。 2.兩劑BNT後中和抗體降25倍，而昨天南非，德國的研究分別是差41倍和24~37倍不等。解讀這些研究要小心看他抽血的時間點，之前打過什麼疫苗，還有之前有沒有過自然感染等等。另外這些試驗人數都不多，個別差異可能很大，還是要累積更多數據才能下確切結論。 3.我比較疑惑的是德國研究有抓打三劑BNT後半個月，三個月來看。結果半個月相比於Delta中和抗體下降37倍只有58%的人可以中和，三個月則下降32.8倍只有25%的人可以中和。和輝瑞自己做的結果差距有點大。且我的確擔心持久性的問題，就算輝瑞你現在做到打完加強針一個月後中和抗體好棒棒，但這次可以維持多久？如果如同德國做出來，三個月後只剩25%可以中和這病毒，難道以後三個月打一針嗎？ 4.大家也別太擔心，我想接下來研究會越來越多，更多研究出來我們應該會比較接近真相。不要因為單一研究就直接下定論，多看一下。我當然會持續幫大家追蹤。 南非：https://www.ahri.org/wp-content/uploads/2021/12/MEDRXIV-2021-267417v1-Sigal.pdf 瑞典：https://twitter.com/benjmurrell/status/1468341478363746310?s=21 德國：https://www.medrxiv.org/content/10.1101/2021.12.07.21267432v2 輝瑞新聞稿：https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-provide-update-omicron-variant Pfizer-BioNTech Covid-19 shot loses power against Omicron variant, but booster restores protection https://www.statnews.com/2021/12/08/pfizer-biontech-covid-19-shot-loses-power-against-omicron-variant-but-booster-restores-protection/ Omicron變種病毒懶人包 傳染力 重症 疫苗有效性 要打加強針嗎？ https://linshibi.com/?p=39815 小額贊助支持本節目： https://pay.firstory.me/user/linshibi Powered by Firstory Hosting

FDA 批准布格替尼作为ALK阳性的非小细胞肺癌的一线用药Lancet Respir Med 急性呼吸衰竭患者机械通气强度与死亡率的关系NEJM 对危重机械通气患者采取非镇静或浅镇静的比较JAMA 质子泵抑制剂或H2受体抑制剂对机械通气患者住院死亡率的影响Nature Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫布格替尼（brigatinib）布格替尼（Brigatinib）是一种间变性淋巴瘤激酶（ALK）抑制剂。2017年布格替尼被批准用于治疗ALK阳性的晚期非小细胞肺癌；2020年5月，布格替尼被FDA批准用于治疗ALK阳性的转移性非小细胞肺癌的一线治疗。《ALTA研究2年随访：布格替尼在克唑替尼难治性、ALK阳性的非小细胞肺癌的2期临床研究》Journal of Thoracic Oncology，2020年3月 (1)这项多中心、随机对照、2期临床研究，纳入克唑替尼难治性、ALK阳性的非小细胞肺癌患者共222人，随机分为口服布格替尼 90mg qd组（A组）、 布格替尼 180mg qd 7天后90mg qd 维持治疗组（B组），中位随访时间:19.6个月和24.3个月经治疗后客观缓解率分别为46%对56%，无进展生存期为9.2个月和16.7个月，总生存期为29.5个月和34.1个月。基线时，A组和B组分别有71%和67%的脑转移。脑转移患者经治疗后，颅内客观缓解率为50%和67%，颅内缓解持续时间为9.4和16.6个月，颅内无进展生存期为12.8个月和18.4个月。随访中没有观察到新发的安全事件。结论：克唑替尼难治性、ALK阳性的非小细胞肺癌中，布格替尼180 mg qd 7天后、予90mg qd维持治疗，显示了良好而持久的抗肿瘤效果，显著延长生存期和颅内病灶缓解时间。《ALTA-1L研究的第二个中期分析：布格替尼与克唑替尼在治疗晚期ALK阳性的非小细胞肺癌疗效的比较》Journal of Clinical Oncology，2020年11月 (2)在开放标签3期ALTA-1L试验中，纳入晚期ALK阳性、非小细胞肺癌患者共275人，随机分为布格替尼组（180 mg qd，7天后90mg qd），或克唑替尼250 mg bid。中位随访时间为24.9个月，布格替尼显著延长无进展生存期（P < .0001，24.0 vs 11.0个月）。布格替尼延缓了生活质量评分恶化的进展（P = 0.049）。研究同时发现，布格替尼的血浆浓度-时间曲线下的面积不是无进展生存期的预测因子。结论：布格替尼作为一种一日一次的ALK抑制剂在疗效上优于克唑替尼，有望成为ALK阳性的非小细胞肺癌的一线疗法。机械通气机械通气又称为正压通气，可完全替代或部分替代自主呼吸，目的是改善氧合不足、肺泡通气不足或两者同时。在急性和慢性呼吸衰衰竭期间，机械通气的主要受益是改善气体交换和减少呼吸做功。正压通气的肺部不良影响包括：肺气压伤、呼吸机相关肺损伤、内源性呼气末正压通气、通气/血流比例失调、膈肌萎缩、呼吸机无力和黏液腺毛运动减弱。此外，正压通气可能降低心输出量并影响血液动力学检测，与胃肠道应激性溃疡、内脏灌注减少、胃肠动力不足、液体潴留、急性肾衰竭、颅内压升高、肌无力、炎症和睡眠障碍相关。《前瞻性队列研究：急性呼吸衰竭患者机械通气强度与死亡率的关系》Lancet Respiratory Medicine，2020年9月 (3)尽管使用了肺保护性通气，但急性呼吸衰竭的死亡率仍然很高。最近的研究表明，基线通气参数与急性呼吸窘迫综合征患者预后之间存在相关性。该前瞻性队列研究的目的是评估急性呼吸衰竭患者长期暴露于不同强度的、机械通气与ICU死亡率之间的关系，共纳入13408例、接受≥4小时机械通气的患者。研究中，18%的患者死于ICU，对年龄和疾病严重程度进行调整后，发现机械通气驱动力 （driving pressure）与死亡风险显著升高有关（风险比1·064）；机械通气的机械功率（mechanical power）与死亡风险显著升高有关（风险比1·060）。这些关联在机械通气期间持续存在。结论：即使持续时间很短，高强度机械通气的累计暴露量是有害的。在进一步的研究中，应当对限制高强度机械通气以降低急性呼吸衰竭患者死亡率的治疗策略进行评估。《对照研究：健康受试者和危重病人膈肌的组织多普勒成像》American Journal of Respiratory and Critical Care Medicine，2020年10月 (4)组织多普勒成像是一种测量组织运动速度的超声心动图方法。该研究将此技术应用于膈肌，以评估膈肌在收缩和放松时的运动速度。研究对20名健康志愿者进行膈肌组织多普勒检查，以评估膈肌运动速度模式，测量其正常值，并确定测量值在观察者间的变异性。然后，在116例连续的ICU患者中，对脱机期间膈肌的偏移、增厚和组织多普勒参数（峰值收缩速度、峰值松弛速度、速度-时间积分和组织多普勒导出的最大松弛率）进行了评估。在一个18例患者亚组中，同时使用组织多普勒记录跨膈压（Pdi）、峰值Pdi、压力-时间乘积和膈肌最大舒张率。在可重复性方面，所有组织多普勒参数的相关系数为>0.89（P < 0.001）。除速度-时间积分外，健康志愿者和脱机成功患者的组织多普勒参数均低于脱机失败患者，分别为：峰值收缩速度1.35±0.34 cm/s、1.50±0.59 cm/s、2.66±2.14 cm/s（P < 0.001）；峰值松弛速度1.19±0.39 cm/s、1.53±0.73 cm/s、3.36±2.40 cm/s（P < 0.001）；组织多普勒最大舒张率分别为3.64±2.02 cm/s2、10.25±5.88 cm/s2、29.47±23.95 cm/s2（P < 0.001）。收缩速度峰值、与跨膈压峰值和压力-时间乘积有显著相关性，而最大舒张速率与最大舒张速率有显著相关性。结论：膈组织多普勒可实时评估膈肌组织的运动速度。膈肌组织多普勒衍生参数区分了脱机试验失败的患者和成功的患者，并与Pdi衍生参数有良好的相关性。《荟萃分析：危重病人的肌力与临床预后之间的关系》European Respiratory Journal，2020年9月 (5)研究的目的是评估肌无力与机械通气死亡率、或脱机成功率之间的联系，以及每种评估工具预测结果的能力。荟萃分析共分析了60项研究，包括4382名患者。ICU相关肌无力与总死亡率增加相关，风险比从1.2到4.48不等。其中刺激双侧膈神经产生的颤搐性跨膈压（transdiaphragmatic twitch pressure，TwPdi）对总死亡率的预测能力最高，敏感度为87%、特异性36%、曲线下面积 0.74。肌无力与机械通气脱机失败率增加相关，风险比为2.64至19.07不等。隔肌 增厚分数（diaphragm thickening fraction，DTF）对脱机失败率的预测能力最高，敏感性76%、特异性86%、曲线下面积为0.86。结论：ICU相关肌无力与高死亡率和更长时间机械通气相关。《综述：肺和膈保护通气》American Journal of Respiratory and Critical Care Medicine，2020年6月 (6)机械通气可引起急性膈肌萎缩和损伤，这与不良临床结果有关。肺部保护性通气的重要性和影响已得到广泛认识和确认，而膈肌保护性通气的概念最近已成为一种潜在的补充治疗策略。这一观点是在欧洲重症医学学会胸膜压工作组召开的一次国际专家会议的讨论中提出的，基于越来越多的损伤机制的证据，提出了一种综合肺和膈膜保护机械通气的概念框架。文章提出隔肌保护的目标基于呼吸努力和病人-呼吸机同步。讨论了在一定条件下隔肌保护与肺保护之间可能发生的冲突；我们强调，当冲突发生时，肺保护必须优先于隔肌保护。为了实施肺和膈保护通气，需要新的监测、设置呼吸机和滴定镇静的方法。未来，体外生命支持技术、膈神经刺激和临床决策支持系统等辅助干预措施也可能在特定的患者中发挥重要作用。由于干预的复杂性，评估这种新模式的临床影响将具有挑战性。结论：肺和膈保护通气的概念为显著改善危重病人的临床结果提供了一个引人注目的新理念。小羽点评：机械通气本身会导致膈肌功能障碍（ventilator induced diaphragmatic dysfunction，VIDD），控制型机械通气时甚至在第一天就可以发生，显著延长了通气和住院时间、导致撤机困难、并发症风险升高，这可能与膈肌损伤、萎缩、蛋白水解有关，通过氧化应激介导，但临床上有效避免该现象的最佳方法尚无定论。目前主要的策略是：保持适当水平的自主呼吸、避免病人-呼吸机不同步、根据膈肌活动监测指标调整呼吸机参数等。 《随机对照研究：对危重机械通气患者采取非镇静或浅镇静的比较》New England Journal of Medicine，2020年3月 (7)在危重的机械通气患者中，每日唤醒已被证明能够缩短通气时间和ICU住院时间。该研究的目的是讨论非镇静与浅镇静计划相比是否会影响死亡率。这项多中心、随机、对照试验中，随机分为非镇静组、和每日唤醒的浅镇静组，共纳入700名患者。非镇静组的平均Richmond躁动和镇静评分（RASS评分）从第1日的－1.3分提高至第7日的－0.8分；浅镇静组则从第1日的－2.3分提高至第7日的－1.8分。非镇静组和镇静组的90日死亡率分别为42.4%和37.0%（P=0.65）。两组患者离开ICU的天数、和不使用呼吸机的天数无显著差异。非镇静组患者中，无昏迷且无谵妄的中位天数为27日；浅镇静组患者中，无昏迷且无谵妄的中位天数为26日。非镇静组1例患者和浅镇静组10例患者发生了血栓栓塞事件。结论：在接受机械通气的ICU患者中，非镇静和浅镇静治疗策略90天死亡率无显著差异。《PEPTIC研究：质子泵抑制剂与抗组胺-2受体抑制剂剂对ICU有创机械通气患者住院死亡率的影响》JAMA，2020年1月 (8)研究的目的比较应用质子泵抑制剂（PPI）与组胺-2受体抑制剂（H2RB），在ICU有创机械通气患者中，预防应激性溃疡的疗效和对住院死亡率的影响。共26 982名患者被随机分配至PPI组或H2RB组，平均年龄58岁。PPI组和H2RB组中，90天住院死亡率分别为18.3%和17.5%（P=0.054），严重上消化道出血发生率分别为1.3%和1.8%的H2RB组（P = .009)。治疗组艰难梭菌感染率、ICU和住院时间无显著差异。在PPI组1例患者出现过敏反应。结论：在需要机械通气的ICU患者中，使用质子泵抑制剂与组胺-2受体阻滞剂相比，在预防应激性溃疡的医院死亡率方面没有统计学差异。呼吸机相关性肺炎呼吸机相关性肺炎（VAP）是指患者气管插管48小时后发生的肺炎，与以下因素相关：进入下呼吸道的微生物数量和宿主的机械、体液、细胞防御受损。约75%的重症患者在入院48小时内发生院内微生物定植。此外，肺部感染的主要途径是微量吸入已定植于口咽部、胃肠道的微生物，因此广泛使用的抑酸药提高胃液的pH值会改变上消化系统几乎无菌的状态，增加呼吸机相关性肺炎的发生几率。多重耐药菌危险因素包括：住院时间较长（>5天）和/或过去90天使用过抗生素。《双盲随机对照研究：心脏停搏后早发性呼吸机相关性肺炎的预防》New England Journal of Medicine，2019年11月 (9)院外心脏停搏、电击复律后后，接受体温管理的患者发生呼吸机相关性肺炎的风险增加。目前尚未证明抗生素短期预防性用药的益处。这项多中心、双盲、随机、安慰剂对照试验，纳入心脏停搏后、在ICU接受机械通气治疗、并且接受32～34℃目标体温管理的成人患者共 198例。于入院6小时内开始阿莫西林克拉维酸或安慰剂2日。7天内，抗生素预防组的早发呼吸机相关性肺炎发生率低于安慰剂组（19% vs 34%；风险比 0.53；P=0.03）。晚发性呼吸机相关性肺炎发生率、不使用呼吸机的天数、ICU停留时间和第28天时死亡率，两组均无差异。第7天未发现耐药菌增多。结论：院外发生心脏停搏后，接受32～34℃目标体温管理策略的患者，2日的阿莫西林克拉维酸降低了早发性呼吸机相关性肺炎的发生率。《2项前瞻性研究：英国ICU疑似呼吸机相关肺炎患者的肺曲霉菌病》American Journal of Emergency Medicine，2020年11月 (10)疑似呼吸机相关肺炎患者中，曲霉菌感染仍然缺乏十分敏感的诊断。这篇文章的目的是评估疑似呼吸机相关肺炎的曲霉菌感染的患病率和预后。文章纳入的这2项前瞻性研究招募了360名影像学、临床、实验室检查疑似的、呼吸机相关性肺炎的危重症患者，并获得了194名患者的血清样本和肺泡灌洗液，并进行了真菌学测试。最后根据临床、影像学和真菌学标准的定义诊断曲霉菌感染。在评估的194名患者中，曲霉菌感染患病率为12.4%，24例曲霉菌感染中有4人血清中半乳甘露聚糖阳性，16例肺泡灌洗液中半乳甘露聚糖阳性，两者均阳性共4例，3例肺泡灌洗液中培养出曲霉菌。疑似曲霉菌感染的患者ICU住院时间更长（25.5天 vs 15.5天，P = 0.02），死亡率略高（33.3% vs. 22.8%，P = 0.23）。结论：在调查疑似呼吸机相关肺炎患者时，即使不是曲霉菌感染高危，仍应考虑曲霉菌感染的可能。《DEDECAP研究：气管切开拔管前应用高流量氧疗联合堵管或联合吸引的比较》New England Journal，2020年9月 (11)应用气管切开套管的患者拔管前，通常做法是将气管切开套管堵管24小时，确定患者可否能自主呼吸。该研究的目的是比较这种做法是否比根据呼吸道吸引频率更好决定是否能够拔管更好。来自西班牙的研究人员在5个ICU进行了这项研究，纳入330例、气管切开后、有意识的、危重成人患者，患者的平均年龄58岁，68.2%为男性。一组接受24小时堵管试验+间歇性高流量氧疗（对照组），另一组接受连续高流量氧疗+将吸引频率作为拔管准备指标（干预组）。干预组至拔管的时间比对照组短（中位数，6天 vs. 13天）。干预组的肺炎和气管支气管炎发生率低于对照组，住院时长也比对照组短。 结论：与24小时堵管试验+间歇性高流量吸氧相比，依据吸引频率制定的拔管决策+连续高流量氧疗缩短了拔管时间，失败率不存在差异。《基础研究：Fc区优化的抗体可以诱导CD8对病毒性呼吸道感染的免疫》Nature，2020年10月(12)针对病毒病原体的抗体是控制病毒感染的一种很有前途的治疗方式，之前的一些研究已经证实，抗体的抗病毒效果需要Fab区和Fc区的协同作用。抗体Fc区在免疫系统中的各类细胞上的受体结合，激活免疫系统清除病毒、杀死被感染的细胞。这项研究的目的是，通过对抗流感IgG单抗的Fc区选择性的修饰，使之能够特异性的与已激活的Fcγ受体、Fcγ IIa受体结合，则能够进一步增强树突状细胞成熟、诱导保护性CD8+T细胞应答，从而提高预防或治疗致命性呼吸道病毒感染的疗效。结论：当IgG抗体选择性激活树突状细胞-T细胞通路时，能够诱导对病毒感染的保护性、适应性免疫，这对发展抗体疗法，提高对抗病毒的疗效具有重要意义。参考文献1.Huber RM, Hansen KH, Paz-Ares Rodríguez L, West HL, Reckamp KL, Leighl NB, et al. Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. J Thorac Oncol. 2020;15(3):404-15.2.Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592-603.3.Urner M, Juni P, Hansen B, Wettstein MS, Ferguson ND, Fan E. Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study. Lancet Respir Med. 2020;8(9):905-13.4.Soilemezi E, Savvidou S, Sotiriou P, Smyrniotis D, Tsagourias M, Matamis D. Tissue Doppler Imaging of the Diaphragm in Healthy Subjects and Critically Ill Patients. Am J Respir Crit Care Med. 2020;202(7):1005-12.5.Medrinal C, Combret Y, Hilfiker R, Prieur G, Aroichane N, Gravier FE, et al. ICU outcomes can be predicted by noninvasive muscle evaluation: a meta-analysis. Eur Respir J. 2020;56(4).6.Goligher EC, Dres M, Patel BK, Sahetya SK, Beitler JR, Telias I, et al. Lung and Diaphragm-Protective Ventilation. Am J Respir Crit Care Med. 2020.7.Olsen HT, Nedergaard HK, Strøm T, Oxlund J, Wian K-A, Ytrebø LM, et al. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. New England Journal of Medicine. 2020;382(12):1103-11.8.Australian PIft, New Zealand Intensive Care Society Clinical Trials Group AHSCCSCN, the Irish Critical Care Trials G, Young PJ, Bagshaw SM, Forbes AB, et al. Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial. JAMA. 2020;323(7):616-26.9.François B, Cariou A, Clere-Jehl R, Dequin P-F, Renon-Carron F, Daix T, et al. Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest. New England Journal of Medicine. 2019;381(19):1831-42.10.Loughlin L, Hellyer TP, White PL, McAuley DF, Conway Morris A, Posso RB, et al. Pulmonary Aspergillosis in Patients with Suspected Ventilator-associated Pneumonia in UK ICUs. Am J Respir Crit Care Med. 2020;202(8):1125-32.11.Hernández Martínez G, Rodriguez ML, Vaquero MC, Ortiz R, Masclans JR, Roca O, et al. High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation. N Engl J Med. 2020;383(11):1009-17.12.Bournazos S, Corti D, Virgin HW, Ravetch JV. Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection. Nature. 2020.

This week on the Dr. Joe Galati podcast, we are talking about the month of November being Stomach Cancer Awareness month. There is a lot of information to gather here, considering many of the common G.I. complaints that people have could be early warning signals that something more serious is wrong. Don't ignore the symptoms that are perceived as being OK to have, such as bloating, nausea, heartburn, and difficulty swallowing. Like all serious conditions, early intervention is the key to long-term survival. Making a return visit is Dr. Sudha Kodali, answering some additional questions about liver cancer from her October appearance on the program. Check out that podcast here. Here again, it's the awareness of our own personal risk factors, and symptoms that we need to be familiar with. Lastly, some exciting new research out of Sweden is indicating that exercise increases the function of the CD8+ white blood cells in fighting different types of cancer. Yet another reason to get up, dust off your sneakers, and get moving.Websites to remember:Medical Practice: Liver Specialists of TexasDr. Galati's Book Site: Eating Yourself SickFacebook: Dr. Joe GalatiDr. Galati's YouTube: YouTube ChannelPlease send feedback and suggestion. You can message me here.You can reach Dr. Galati and his practice, LIVER SPECIALISTS OF TEXAS, by calling 713-794-0700. Ask for Teresa the practice administrator for details.Make sure you subscribe to all of the podcast episodes, rate them, send us feedback, and share them with your community.Available on:SPOTIFYTUNEINAPPLE PODCASTPOCKET CASTSOVERCASTACASTIHEART RADIO PODCASTGOOGLE PODCASTSTITCHERYOUTUBE See acast.com/privacy for privacy and opt-out information.

During the American Society of Clinical Oncology (ASCO) 2020 Meeting, the Multiple Myeloma Hub was pleased to speak to Enrique M. Ocio, Marqués de Valdecilla University Hospital, Santander, ES. In this podcast, Enrique M. Ocio discusses the results of the phase I/II trial that evaluated quadruplet combinations in patients with transplant-ineligible multiple myeloma.Enrique M. Ocio begins by describing how first-line treatments for this population of patients have changed recently, and then provides results from a study investigating the use of isatuximab (an anti-CD8 monoclonal antibody) in combination with quadruplet regimens; bortezomib + cyclophosphamide + dexamethasone (VCd) or bortezomib + lenalidomide + dexamethasone (VRd). He provides efficacy, safety and tolerably data as well as measurable residual disease analysis, and concludes with his perspective on which treatments should be used for elderly patients. Hosted on Acast. See acast.com/privacy for more information.

The importance of a big Debbie Lesko win in tomorrow's special election in CD8. Shania Twain said she would have voted for President Trump, then apologized for saying it. See omnystudio.com/listener for privacy information.