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Dr. Deb Muth 00:02What if I told you that before a single drop of chemotherapy goes into a cancer patient’s body, we can take a blood sample, grow their actual living cancer cells in a lab, and test 70 different drugs against those cells, all outside the patient’s body, to find out which ones actually work. And what if I told you that the conventional oncology doesn’t routinely use this test? Well, today we’re going to talk about why that matters and we’re going to go through and I’m going to share a story that is very personal to me. It’s about a 38 year old man with a rare complex cancer diagnosis and the precision testing that is helping to keep that cancer from progressing. Stay with me. This is one that is going to change how you think about cancer treatment. Dr. Deb Muth 01:05You guys can put a little ad right in here before we start the next segment here. Hey everybody, welcome back to Let’s Talk Wellness Now. I’m Dr. Deb and today we’re going deep. I mean really deep. It’s some of the most cutting edge cancer testing I have ever seen in clinical practice. Now, normally I don’t talk about cancer. And I would not be sharing this story if it was anyone other than my own family. I do have permission to share and talk about this publicly. So I want to do this. I want to make sure that I share this message. And he is giving his blessing to share this story because we both believe that it can save lives. So his name is Cameron. He’s 38 years old. And he is my son-in-law. And two years ago, he came to me with a small lymph node underneath his arm and a bullseye rash. So of course, being the lime literate person that I am, my first inclination was to say, yeah, this makes sense. You have an enlarged lymph node because you have this bullseye rash. You got bit by the tick. Let’s keep an eye on it. If it doesn’t go away, let me know. So Fast forward a year and a half later, he comes to me and says, mom, what do you think about this? This thing is getting a little bit larger. And I said, yeah, it’s a little larger. Not sure. Let’s keep an eye on it. He wasn’t feeling anything. All his labs looked okay. And then one day he was out chopping wood and he started getting numbness in that arm and he felt it again. And it had exploded in size. And so after some evaluation with my daughter and him, we decided to do a ultrasound. And we thought what was going to come back was a fatty tumor. It felt like one looks like one responded to one. He’s 38 years old. He’s healthy. There’s nothing in our mind that’s ever thinking the result that we’re going to get back. Dr. Deb Muth 03:28Is a possible lymphoma. Needless to say, we were shocked by that ultrasound result. And we go fast forward, we have the biopsy. I requested a total excisional biopsy. I was told by the oncologist that that was old school. They don’t do that that way anymore. And I need to stay out of this. I need to let the experts take care of this because that’s what they do best. And this came from a breast surgeon here in Wisconsin. And so I stepped back for a moment. I let him do his biopsy and what came back was adenocarcinoma of an unknown origin. Had we excised the entire lymph node, we would have had more tissue to work with. I think we could have gotten a better diagnosis. So over the course of the next two and a half, three months, we have some more imaging done. We have some more testing done. They send a pathology out to Mayo Clinic. And what continues to come back is this incongruent test results. If anybody’s ever had this, it’s extremely frustrating. One test shows lymphoma. Now it shows breast cancer. Then the next week it shows estrogen receptor HER2 positive breast cancer. Two weeks later, another test comes back and it says, no, it’s not HER2, it’s triple negative breast cancer. And now it looks like it’s out of the lymph nodes. Now it looks like it’s in the lymph nodes. And we do a PET scan and they can’t find cancer anywhere except in this axilla area. But now we find a lymph node on the right side. So it must have spread.Let’s go ahead and do a biopsy on that. And so they biopsy the right side and the right side comes back with nothing other than tattoo ink. Now, all of this is kind of crazy. I am not a cancer specialist. I want to start by saying that I am not a cancer specialist. What I am sharing today is from a mother-in-law’s perspective, from a medical detective’s perspective, I do know how to do research. I do know how to find answers. And so what I’m going to share with you Dr. Deb Muth 05:54Is totally my opinion and totally my experience. And I’m not telling anybody to do anything different than what their doctors are telling them to do. But I am telling you to ask questions. So I go deep down the rabbit hole and find out that Tattoo Ink can appear like metastatic cancer on a PET scan. And we all know everybody gets tattoos today. They’re all over everyone. And yet we’re not thinking about how this tattoo ink can cause problems for us down the road, not to mention that there are heavy metals in them and it’s a toxin and it’s creating an inflammatory process in your body that your body’s constantly trying to get rid of. So the surgeon says to us, well, yes, that’s normal that that lymph nodes inflamed. It’s normal that there’s tattoo ink in it. The body’s doing what it’s supposed to do. It’s trying to get rid of a toxin. Okay. I will agree with that, but My son-in-law is covered with tattoos everywhere. And why didn’t we mention the tattoo ink that was found in the left axilla? We are only mentioning it in the right axilla. So there’s a lot of controversy, a lot of confusion. Many of you would never know any of this because A, you either don’t look at your lab results. And if you do, you don’t understand what you’re looking at. And that creates a problem for us, right? You don’t know what questions to ask. So we go into the doctor and the doctor tells us you have cancer and we’re going to swoop you in. And in the next two weeks, you’re going to be doing chemotherapy and radiation. And six months from now, we’re going to be doing surgery and there’s no time for questions and you’re scared shitless and you’re just doing what you can to survive. And I get that. And I totally understand that. And I appreciate that. But I’m telling you that If that is your choice, that is your choice. But as you’re doing that, take the time to ask the right questions. When this happened to us, there was a lot of challenging things with the oncology team. Nobody bothered to allow them to be a partner in their care. They dictated their care, but didn’t allow them to be a partner. So, Dr. Deb Muth 08:17Here’s what most oncologists do when patients get a cancer diagnosis. They look at the tumor type, they look at the stage, they look up the NCC guidelines, the National Comprehensive Cancer Network, and they follow the algorithm. Now, I have an enormous respect for conventional oncology. I really do. Working with cancer is probably one of the hardest things in medicine that anyone can do. The advances in this field over the last 10 years have been remarkable. But here’s my issue. Standard treatment assumes your cancer is the same as the cancer in the clinical trial that created the guidelines. It’s assuming that you and your cancer are the exact same as everyone else. You are the unique fingerprint, not the cancer. And this is the problem because your cancer is unique, just as unique as if you had your fingerprint taken, the mutations driving your tumor, the drugs your cancer cells are sensitive to, the metabolic vulnerabilities of your cancer. These are all different from the person sitting next to you in the chemo suite that has the same triple negative breast cancer or HER2 positive breast cancer or prostate cancer or colon cancer that you have. So what do do about that? Well, in my world, in the integrative medicine world, we test precisely, intelligently with the tools that most oncologists have never heard of. Or if they have, they haven’t incorporated it into their treatment modality for a variety of reasons. Either it’s not acceptable by the organization that they work for, they don’t understand it, They’re not going to be able to change their protocol anyway because they have to follow the NCCN protocol. So they don’t do it or they use a portion of it and they don’t do anything outside the protocol. So today I want to cover three things with you, three tools that we used that I think every cancer patient should be asking for when they start treatment or wherever you are in treatment at this point. Dr. Deb Muth 10:44you need to have these tests done. I don’t have any affiliation with any of these companies. I don’t get paid to tell you any of this. So let me just start by saying that I understand the chemistry behind these and how important it is to give you precision cancer treatment. And that’s why I’m talking about them today. The first one we’re going to talk about is the North Star response. This is your cancer surveillance score in the blood. How much cancer is circulating in the blood. The North Star Select, your cancer’s genomic blueprint from a blood draw. And the Datar Cancer Genetic Chemoscale, the live cell drug sensitivity test that tells us which drugs actually kill your cancer. So let’s go. Let’s dive into this. Let me just take a drink here. I’m going to cough a little bit. I apologize. I have this horrible tickle. It just never seems to go away, but that is not for today to discuss. So what is all of this? OK, the North Star response is a test that was developed by a company called Billion to One. And yes, that name is intentional because of the precision involved. It’s a next generation sequencing test, meaning it reads DNA at an incredibly detailed level. And it looks at something called methylated circulating tumor DNA or methylated CT DNA. Now let me break this down in plain English for you, because this can get a little overwhelming. When the cancer cells die or shed, they release tiny fragments of DNA into your bloodstream. We call this cell-free DNA or CFDNA, and it’s hidden within that cell-free DNA. And there are fragments that come from tumor cells. We call those CT DNA or circulating tumor DNA. Here’s what makes North Star’s response different. Rather than just looking for mutations in that tumor DNA, which is what most liquid biopsies do, and a liquid biopsy is just a blood test, Dr. Deb Muth 13:03This test looks at something called methylation patterns. Think of methylation like a dimmer switch on a gene. In healthy cells, certain genes are switched on and off in a very predictable way. In cancer cells, those dimmer switches go haywire. And cancer DNA has a characteristic hypermethylation, meaning switches are turning on and should be off or off and they should be on. And these patterns are essentially a cancer fingerprint in the blood. Now the North Star response scans more than 2000 locations in the genome for these cancer specific methylation patterns. And then it adds them all up into a single number called the tumor methylation score or TMS. So for Cameron, Cameron’s blood which was drawn on April 20th, 2026, his baseline tumor methylation score came back at 13. Now here’s the critical thing, to understand this was his baseline test, his starting point. And the real power of this test is in serial monitoring, meaning we run it again and again and again over time. And if that number goes up, the cancer activity is likely increasing. If it goes down, we’re likely suppressing the tumor activity. And if it stays flat or falls, that’s telling us that the disease is responding. So this is now in the blood. We have an actual fingerprint and every test from here forward will be compared to this number. Now let’s talk a little bit about this because I was not familiar with this test at all. I wasn’t sure what to expect. I wasn’t sure what to do with it. I did not order this test. He’s working with Inveda Medical and they are fabulous over there. I will tell you that from the beginning. This is coming from a practitioner and from a mother-in-law. They were absolutely wonderful to us. So when I saw this North Star, I didn’t know, should it be zero? Should it be a hundred? And when I talked to the doctor, he said, Dr. Deb Muth 15:29This number is actually really good. An average person walking around who’s never been diagnosed with cancer, who doesn’t have cancer, their number will be between 75 and 100. Cameron’s was 13. I think that’s fantastic. But what was the first question that went through my head? It’s probably the same question that you guys are doing. How can he have cancer with a number of 13 when it’s less than the normal average? And if we’re supposed to use this to track what’s happening with his cancer, how are we going to do that once we remove the cancer? Is this number going to go to zero? And it could possibly do that. And we may not be able to use this to track whether or not the disease is actually gone. But what we can do is use this to track over the course of his lifetime to see if the cancer cells are coming back long before we detect them on imaging. And that’s the huge part of this.So this is not a test that just anybody should go out and get because you’re worried about cancer. It is a test that should be done in somebody that is already diagnosed with cancer. So let’s start by making sure we explain that, okay? So imagine if every time your cancer cells are active and they’re shedding and they’re multiplying and they’re fighting back, they’re leaving a signature in your blood not just any signature, but a specific chemical tag that says, cancer’s here. That’s what the North Star Response Test reads. Those tags across thousands of locations and gives us a single score. So we track that score over time like a thermometer for your tumor. If it goes up, we get concerned. If it stays stable or goes down, we celebrate. And we can catch a change in the blood often months before it will show up on a scan. Pretty important when we’re talking about surveilling somebody for cancer returning, when we’re worried about it, and everybody knows the cancer patient is always worried after they get that clean bill health that something’s gonna come back, and most of the time they’re told that there is no way for them to determine that or know that from a blood test. And here is the blood test that can tell us, yes, it can. Dr. Deb Muth 17:51So I would really encourage you guys to talk to your oncologist about this. If you can’t find an oncologist that will do this, talk to an integrative cancer doctor. They will most likely be familiar with it. If not, ask them to find it for you and order it for you. So next, let’s talk about that genetic blueprint because North Star Select is a different test also by billion to one run on the same blood draw, but this one is doing something completely different. This is a comprehensive genomic liquid biopsy. Liquid biopsy just means blood tusks, meaning it’s looking for specific mutations in 84 cancer related genes, all from a blood sample, no biopsy needle, no surgery, just a blood draw. It looks for CNVS, single nucleotide variants, tiny one-letter typos in the DNA code. It looks for indels, small insertions or deletions in the DNA. It looks for copy number changes, the sections of the genomes that are duplicated or deleted. It looks at fusions. So when two genes incorrectly link together to create a dangerous hybrid, MSI status, micro satellite instability, which tells us whether immunotherapy is likely to work. And it has extraordinary sensitivity. It can detect a mutation that represents as little as 0.15 % of cell free DNA in the bloodstream. That is an almost impossibly small signal in the ocean of genetic noise. So what did this show for Cameron? This is where Cameron’s case gets clinically fascinating and where it tells the story of how his cancer is being held in check. Two major mutations were identified as actionable. One was called CRAS G12C. Dr. Deb Muth 20:11And it’s a variant-ELI fraction at 0.1%. Now, CRAS, if you’ve spent any time in integrative oncology, you’ve heard this name. CRAS is one of the most well-known oncogenes in cancer biology. Think of it like an accelerator pedal in the car. In a healthy cell, CRAS pushes the cell to grow when it receives the signal to do so. And then it stops. In cancer, crass gets stuck in the go position, like on the accelerator, foot on the accelerator, to the floor, going as fast as you can around that track, right? But it’s stuck there permanently. It doesn’t turn off and it’s supposed to be turning off. The G12C variant specifically is a mutation at a very precise location. Position 12 of the CRAS protein, where a glycine is replaced by cysteine. And this matters because CRAS G12C is now a drugable target. There are FDA approved drugs specifically designed to lock this mutation into its inactive state, essentially putting a foot on the brake. Now those are drugs like, and I’m gonna slaughter these names, Sordisib, a brand name is Lumacras, and Atacras, the brand name is Crastol. Neither is yet FDA approved for breast cancer, but they are approved for lung and colorectal cancer with CrasG2C. And Cameron’s tests identified 10 active clinical trials within a region that he could potentially qualify for with this mutation. The fact that his CRAS G12C is circulating at only 0.1%. That is a very low fraction. We call that a VAF, V-A-F, very low fraction. And it tells us something important. It means that this mutation is present in a small subclone of the tumor. It’s not the overall tumor burden. So either way, when we identify, we know it’s there. Dr. Deb Muth 22:37We can catch it and we can watch it. Now, here’s another interesting thing that we saw. His TP53 was at 0.23%. This is a tumor suppressor gene, the guardian of genome. And this gene is responsible for telling damaged cells to either repair themselves or self-destruct. And when it mutates as it is here in the position R196Q, that guardian goes off duty. The cell no longer has a reliable mechanism to prevent uncontrolled growth. So TP53 mutations are present in roughly 50 % of all human cancers. And there’s currently no FDA approved drug directly targeting the TP53 but there are clinical implications. TP53 mutant tumors may respond differently to chemotherapy and several investigational approaches, including TP53 vaccines and aurora kinase inhibitors are under active investigation. So we are seeing things happen in this part of cancer right now. Now there’s something called the VUS list and we are watching This is what we’re watching. beyond those two actionable mutations, NORSTAR Select identified what we call variants of an unknown significance, VUS, adenocarcinoma of an unknown significance, ACUP. These are mutations where we don’t yet have enough clinical evidence to determine whether they’re driving cancer or not, but we watch them. So on our mutation list was CDH1, a gene linked to hereditary gastric and lobular breast cancer, CDKN2A, a tumor suppressor cell cycle regulator, CDK12, involved in DNA repair, EGFR, ERBB, this is HER2 receptor, tyrosine kinases. Dr. Deb Muth 24:55I thought this one was pretty interesting since he had an IHC that showed a three plus HER2, but then when we confirmed it with FISH, FISH showed that was negative, but now we’re actually seeing genes expressing this HER2. So is there a HER2? Is there not a HER2? This is really important because if we don’t get these diagnoses right in cancer the first time, people will spend months and years treating the wrong type of cancer with the wrong type of medication. And this may be in part why some people do better than others. If we get it right out of the gate, they do good. If we don’t get it right out of the gate, they don’t do so good. Very important to have the actual genetic makeup of the tumor that’s growing in somebody. Now last, we have something called Notch C1, NRAS and RAF1. These are key pathway components. Now all of these were at very low baffs under 0.5%. These are just whispers, not shouts, but whispers that this cancer is excreting, but your body is listening. We have to be listening. We have to be able to watch these things and monitor these. Now here’s another note of clinical interest. It was an androgen receptor positive cancer. So also detected as a VUS.We know from tissue pathology that Cameron’s tumor was androgen receptor positive. So seeing this in circulation confirms that this AR expression of the cells are present in the bloodstream and that an anti-androgen approach remains worth considering. What that means is suppressing the testosterone. What all of you know I’m about ready to say is that I hate ever suppressing hormones, especially in a 38 year old male. That is not necessarily a good thing. So before we go suppressing hormones willy-nilly, we have to know that it’s the right thing to do. And we have to be able to combat all of the complications that are going to result of that. A 38-year-old male with no testosterone could lead to heart disease down the road, could lead to bone loss, could lead to dementia, Alzheimer’s. Not to mention the sexual side effects that are going to be present. And in a man that is very, very Dr. Deb Muth 27:20Difficult for someone to manage. So you have to be very specific and you want to be very, very diligent about what you’re doing in these cases like this. Now the MSI status was not detected. This tells us that cancer is not a microsatellite instability high, meaning that standard monotherapy may have a lower baseline response of probability and the strategic integration that we’re working with with in Vita could create an immunogenesis genicity becomes even more critical. So immunotherapy is going to be very critical in a cancer case like this and working with somebody that understands that and can carefully navigate that, especially if you have an autoimmune disease like Hashimoto’s or lupus, this is all very, very pristine and has to be looked at very carefully and done very diligently in order for somebody to do this without overstimulating that immune system and causing more problems. So when we looked at the blood and found this DNA fingerprint of the cancer cells circulating in the body, from that, what we see exactly is the genetic switches that are stuck on. They’re stuck on in the wrong position. This tells us which drugs were designed to fix exactly that problem. And it opens the door to clinical trials built for these specific mutations. It also gives us a list of things to watch for over time. And if one of those tiny little signals starts to grow, we know that cancer is gaining a ground in that area. And if it shrinks or disappears, we know we’re winning. This is like, I cannot tell you how exciting this is in the cancer world and the medical world because this is really pristine cancer therapy that we’re dealing with here. And to be able to have this is just so important to life saving events in treating cancer. So. Dr. Deb Muth 29:41Let’s talk about something called the Dittar Chemoscale. This is the battle before the battle. Okay, so I’ve saved the most remarkable test for last, and this is one from a company called Dittar Cancer Genetics. They’re based out of the UK. They are CAP and CLIA certified, which means it meets the rigorous standards required for clinical laboratory testing in the US. And this test is called the ChemoScale. And it is a live cell chemosensitivity assay. So let me explain exactly what that means because it sounds complex, but the concept is actually quite elegant. When we drew the blood from Cameron, the Dittar’s laboratory isolated what are called circulating tumor associated cells or CTACs. And these are actually living cancer cells and they’re associated cells that are traveling through his bloodstream. Excuse me. So let’s think about that for a moment. Real live cancer cells isolated from a blood draw. Those living cancer cells were placed into a lab environment and exposed to over 70 different drugs, both conventional chemotherapy agents and what we call repurposed drugs. I’ll talk more about those in a minute. The lab then measured how many of those cancer cells were killed by each drug expressed as a percentage of cell death. So the scale runs from zero to a hundred and below 25%, that drug doesn’t work well against any type of cancer in that person. Might work great in somebody else, but in that particular person’s cancer that they have, it’s not gonna work so great. Anything that’s 25 to 50 % is intermediate and above 50 % is a high response. And that’s really where Dr. Deb Muth 31:43we want to be. We want to see anything higher than 50 % because that’s a great medication that can be used to kill the cancer. This is not a theoretical test. This is not based on tumor’s genetic sequence and the computer algorithm that predicts the drug response. This is a HIS actual tumor cell being killed or not being killed in real time. That is the difference. So in traditional chemotherapy, we have our protocols. If you have triple negative breast cancer, if you have HER2 positive breast cancer, if you have prostate cancer, if you have colon cancer, here’s the protocol that you’re going to use because that’s the type of cancer you have. That’s what’s been studied. Now, the problem is most of these cancers have mutated over time, especially depending on how long they’ve been in your body, because that’s what they do to try to survive. They have to change so they can survive because your immune system’s constantly trying to kill them. And so this is a really important thing. And if we don’t take an individual into response or into our thought process when we’re creating these protocols, we may give a drug that doesn’t work at all towards that cancer and you just wasted seven cycles of chemotherapy with a drug that never would have worked in the first place or had such low resistance to it that it’s now just created side effects for you but did nothing to the cancer. And then we pull out another drug and we try that. And then we pull out another drug and we try that. Instead of us knowing precisely what we can use and what we can do. And this goes for both the conventional world and the alternative world. In the alternative world of cancer, we use things like IV vitamin C and tumeric and lately ivermectin and fenbendazole and mendendazole and all kinds of other things. And if we are not truly aware that this is going to do anything, we could be wasting somebody’s time and money. So I love that this test is available. I want to walk you through a little bit about what Dr. Deb Muth 34:01we are what we saw in our case, because I think this can make a big impact on people to ask the right questions. So this particular blood test looked at several different drugs. Cameron had sensitivity from 44 % up to 61 % on different medications. Now he was really lucky. The three main drugs that they would use to treat his cancer he had greater than a 50 % response to. So that was great. However, the drugs that were recommended for him to use out of the gate had less than 50 % activity. So he would have had one drug that was really good, one drug that was not so good. And we don’t know what the outcome would have been, right? So I think this is such an incredible, incredible test to have done. This is critical friends. I’m telling you if his oncologist had chosen the two drugs based on the general guidelines for his tumor, his cells would have largely not survived. But because we ran this test, we know. So we know to avoid the drugs that won’t work and we focus on the firepower where it really counts. So I want to also talk about this repurposed drug result because this is where it gets integrated for us. Now, this section is what I want everyone in our community, our Let’s Talk Wellness community, our members to understand. This is where conventional medicine and integrative medicine intersect in a peer-reviewed clinical validated way. So the Dittar test looks at live cancer cells against what they call repurposed drugs, meaning pharmaceuticals and natural compounds that were developed for the purposes, for other purposes, like it could be an antibiotic, it could be an herbal medicine, it could be all kinds of things, vitamins, whatever. But they have demonstrated anti-cancer activity in research. And when we’re talking about integrative medicine, this is a lot of where we get Dr. Deb Muth 36:26The integrative protocols from because these particular drug compounds are known for having anti-cancer benefits. And so that’s how integrative protocols get developed. But again, it could be just like medication, like cancer drugs. If your body doesn’t have a susceptibility to it, then you’re using a product that’s not necessarily going to work. And we all know we cannot take everything that somebody recommends just simply because it has an anti-benefit to whatever it is we’re treating. There’s only so many supplements you can take. There’s only so many things you can do before you get burnt out on taking it. We call it supplement fatigue. And so we want to be very precise with what we’re doing and target this very specific area. So one of the things that showed up really, really well for our case was artemisium, sweet wormwood. It’s an anti-malarial drug that has very potent anti-cancer effects. Now I found this extremely interesting in Cameron’s case because he does have a positive tick-borne illness called Babesia. And this is one of the things that we use to treat Babesia. The other thing I think is very interesting in this case is we are studying how parasites affect cancer these days. And that’s how Ivermectin, Fenbendazole, and Menbendazole have all gotten thrown into the treatment of cancer. And so for this drug or this herb to be sensitive to this type of cancer is really intriguing to me in the world of parasites and how parasites are truly decreasing the body’s immune system and causing cancer to grow. Another thing that worked, showed up really well for him was Valprolac acid. It’s an anti-seizure drug with HDAC inhibitor properties, and this disrupts cancer cell gene expression. There was a soy formula that showed up really well. Naltrexone, you guys have heard me talk about low dose naltrexone, LDN. This actually stimulates an endogenous opioid immune response feeling, and this drug actually showed up really well. Dr. Deb Muth 38:49Something as simple as quercetin. It’s an anti-inflammatory. This is a crass inhibitor in some studies. So this is really important. I’m sure most of you have heard about the benefits of green tea and green tea also actually has anti-angiogenic or anti-cancer benefits to it. Hydroxychloroquine, very popular drug. It’s another anti-malarial drug. So again, now we have two anti-malarial drugs that are susceptible to this type of cancer. And on top of it, he has a positive babesia test. So just saying, you got to connect the dots sometimes. You got to think outside the box sometimes. Metformin is very well known as a anti-proliferative in cancer. We use it to suppress the sugar because sugar feeds cancer. Nobody should be eating sugar if they have cancer. So this one showed up as well. And then CBD, we all know of the benefits of THC, the Rick Simpson oil, and CBD can be tested to see if that is beneficial to a particular cancer cell. This is different than THC. THC works very differently in cancer. CBD is your healthy component of it. It’s the part of the marijuana plant that does not make you high. So very important here. So now let me be very clear, because I always try to be very clear. This is not FDA approved. I’m going to repeat that. This is not FDA approved. This test is a laboratory developed test, not FDA cleared. These results represent in vitro testing, meaning in a lab, not inside the human body. And the results can differ in what we call in vivo, inside the body. And this is why I always say work with a qualified clinician who can interpret these results in full clinical context. But here’s why this matters. We now have evidence, live evidence of a cancer cell that shows sensitivities to compounds that are accessible, relatively safe, and some of which he may already be using, which some of them we were. Dr. Deb Muth 41:13We were already using some of them, which made us sit back and say, this cancer has been in there for two years. If it’s a triple negative breast cancer, it’s supposed to be an aggressive breast cancer that should have spread to a different organ already after two years. It is not, it has stayed in one spot. Also interesting in this case is that there is no breast tumor that they could find anywhere. This was all confined to the axilla into the lymph node. So to have this growing for this period of time with such a small tumor marker number, that 13 that we talked about in the North Star test originally, and to see some mutations, there’s a lot of questions to this particular case. And there are lots of questions to everybody’s cancer case. They are not all straightforward cancer cases. So this is what’s important to understand this fingerprint of these cancer cells so that you can identify exactly, exactly what’s going on and treat it exactly the correct way. Super important. So this kind of information gives us the direction in an integrative protocol. It’s not guessing. This is not eat more tumor, I can hope for the best. This is personalized tumor specific precision guided integrative oncology. It is very precise. There are several countries, several clinics like this around the country that offer this type of therapy. If it’s something that you’re interested in doing, I would encourage you to look at in Vita Medical. Hope for Cancer is another great facility. There are several great facilities around the country. Like I said, that could put together an integrative approach for you if this is something that you are thinking about doing. If you’re looking for answers, if you’re in stage four or stage three and you are not getting the results that you want to get, you want to look at a different approach. You want to do a combo approach of integrative medicine and traditional medicine and alternative medicine. Dr. Deb Muth 43:37I think this is so important to look at and have experts on your team. You know, in our case, Cameron’s cancer is very complex. It’s genomically aggressive in its presentation, yet it’s not progressing to distant areas, which is so wonderful. And I want to be careful here. I can’t tell you with certainty that this is any one thing. Biology is complex. Cancer is adaptive. It’s trying to survive. That’s what it is supposed to do. It is changing its shape. It’s changing its genetic structure. It’s changing everything to try to survive and try to hide against your immune system. Now we are not even close to the finish line in our journey, but what I can tell you is that what the integrative precision approach has done that standard care alone might not do. I can tell you that today and I will share our journey along the way for any of you that are going through this that want to look at a different approach as well because I think it’s important to have this information. So first of all, we know the tumor’s fingerprint. North Star response gives us that TMS score. so we can track it over time. And if the cancer tries to gain ground, we’ll see it in the blood before a scan, we’ll show it. We know the cancer’s genetic vulnerability. We know how to handle the DNA now. We know the watch list of things to look for. And when those signals start to grow, we have a roadmap of how to address it next, how to change it. We know which drugs will automatically work against the tumor cells. We’re not guessing based on a tumor type. We tested the cells. We know how many drugs in the commercial world and in the repurposed world will and will not work. And this is going to guide the treatment protocol that we walk forward with. So we’re not giving him drugs that won’t work or have a low response. Dr. Deb Muth 45:55We’re avoiding them completely and that matters because every ineffective drug is a dose of toxicity with no benefit. There is no lie to this. Chemotherapeutic drugs are toxic. That’s how they kill the cells, but they kill the good cells and the bad cells. And if we can avoid using a drug that’s not going to work, that is so important. And then we’re layering in those repurposed and natural compounds with proven activity against specific cells. This is not complementary fluff. This is biologically active tumor tested precision medicine. Very, very important. So here is what I need you all to know and what I want you to walk away with today. If you or someone you love is facing a cancer diagnosis before treatment starts, before the first infusion goes in, I want you to ask these questions so quick. Go grab something to write with. Pause this if you need to, because this is really, really important for you to do that. And we’re going to take a break for just a second while you guys go and do that. We’re going to give you a word from our sponsor, and then we’re going to come back. And I’m going to give you the four questions that I want you to ask specifically of your medical team so that you have the answers and the ammunition that you need to work with. So we’ll be right back. Dr. Deb Muth 47:29All right, everybody, welcome back. I hope you got your pencil, your paper, your pen, your phone, whatever you’re going to take notes with because this is important. So I’m to give you four questions that I want you to ask your medical team before you get started. Question one, can we do a chemo sensitivity test before we choose a chemotherapy regime? Ask specifically about DATAR, D-A-T-A-R. cancer genetics, Oncostat Plus, or a similar functional chemosensitivity platform. Very, very important to ask those specific things. All right, question two. Can we do a comprehensive liquid biopsy to identify actionable mutations and monitor tumor burden? Ask about North Star Select, Billion to One, Guardian 360, or Foundation One Liquid CDX? I’m gonna say those for you one more time, because I said them kind of fast. North Star Select by Billion to One, Guardian 360 or Foundation One Liquid CDX? Okay, question three. Can we establish a baseline tumor methylation score, TMS, so we have a surveillance marker to track over time? and ask specifically about the North Star Response Test. All right, question four. Is there an integrative oncology center that can layer precision guided natural compounds alongside conventional treatment? Research institutes like Inveda Medical Center, CTA CA Integrative Medicine, or Hope for Cancer, these people are doing integrative medical miracles. Let me tell you, I have researched every one of them. I have spoken to each of them individually before we made our decision of who we were going to work with. They are all fantastic. You want to work with an integrative nurse practitioner who understands oncology. And if you’re working with an integrative practitioner, you want to ask them these same questions about this test so that you can get the best outcome. Dr. Deb Muth 49:56For what you’re dealing with. You are allowed to ask these questions. You are allowed to want more information from that protocol that was designed for the average patient. You’re not average and your cancer is not average either. And your care doesn’t have to be. You do not have to settle for the same thing that the person sitting next to you in the IV suite is dealing with when you both have different cancers excreting different genetic material. This is so incredibly important. want to make sure you understand precision medicine is what changes the lives for people every single day, every single day. So I started this episode by telling you about a 38 year old man with a cancer that baffled conventional medicine and integrative medicine, an occult primary that was not found complex genetic genomic profile, a presentation that in many hands might have resulted in a one size fits all treatment protocol and a prayer. And instead we ran the tests, we mapped the fingerprint, we watched the cells, we guided the protocol, and we are still fighting with precision, with data, with intelligence. This is what Let’s Talk Wellness is all about not giving up. This is what not accepting we don’t know as a final answer and demanding the level of scrutiny and personalization that every cancer patient deserves. So if this episode resonates with you, please share it because somewhere out there, there is a person who is about to get the wrong chemotherapy because no one ran the right test. And maybe, just maybe, that This episode will be the reason someone asks the right question at the right moment. If you’re going through something like this, you need a group, you need somebody to connect with, please join our free Facebook group called Seen At Last. It is where we support one another, we share this information, we share knowledge, and we help people for free support and ask the right questions. Dr. Deb Muth 52:23And if you’re inclined in your heart to pray, pray for Cameron, we could use every ounce of prayer. If you are in a position where you can help support this journey financially, we do have a fund going in free funder. I can post the link below. Every little bit helps. If you have $5, $500, it doesn’t matter. We’re raising money for this treatment. And along the way, I am documenting every step of what we’re going through so I can provide more episodes like this for you guys to share the outcome and share what our journey is like so that it can help the next person along. I really always believe that whatever happens to us happens to us because we’re meant to share it. That’s why I’ve shared my personal journey. I’m sharing his personal journey and we want to help other people. So until next time, I’m Dr. Deb. Keep asking questions, keep advocating, and never ever accept being unseen.The post Episode 274 – Stop Guessing on Chemotherapy: The Live Cell Test Most Doctors Miss first appeared on Let's Talk Wellness Now.

"It's critical to identify those mutations found that are driving the cancer's growth and guide the personalized treatment based on those results. And important to remember, too, early testing is crucial for patients with non-small cell lung cancer (NSCLC). In studies, it has been found to be associated with improved survival outcomes and reduced mortality," ONS member Vicki Doctor, MS, BSN, BSW, RN, OCN®, precision medicine director at the City of Hope Atlanta, GA, Chicago, IL, and Phoenix, AZ, locations, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about the oncology nurse's role in NSCLC biomarker testing. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  This podcast is sponsored by Lilly Oncology and is not eligible for NCPD contact hours. ONS is solely responsible for the criteria, objectives, content, quality, and scientific integrity of its programs and publications. Episode Notes  This episode is not eligible for NCPD. ONS Podcast™ episodes: Episode 363: Lung Cancer Treatment Considerations for Nurses Episode 359: Lung Cancer Screening, Early Detection, and Disparities Episode 238: Cancer Genomics for Every Oncology Nurse Episode 157: Biomarker Testing Improves Outcomes for Patients With Non-Small Cell Lung Cancer ONS Voice articles: Non-Small Cell Lung Cancer Prevention, Screening, Diagnosis, Treatment, Side Effects, and Survivorship Only a Third of Patients With Advanced Cancer Get Biomarker Testing, Limiting Use of Potentially Effective Precision Therapies Precision Medicine in Lung Cancer: How Comprehensive Testing Optimizes Patient Outcomes Targeted Therapies Are Transforming the Treatment of Non-Small Cell Lung Cancer ONS book: Guide to Cancer Immunotherapy (second edition) ONS course: Genomic Foundations for Precision Oncology Clinical Journal of Oncology Nursing article: Using Nurse Navigators to Improve Timeliness of Biomarker Testing for Non-Small Cell Lung Cancer Oncology Nursing Forum article: Precision Medicine Testing and Disparities in Health Care for Individuals With Non-Small Cell Lung Cancer: A Narrative Review Other ONS resources: Best Practices for Biomarker Testing in Non-Small Cell Lung Cancer: A Case Study Genomics and Precision Oncology Learning Library Genomics Case Study: Precision Medicine in the Setting of Metastatic Non-Small Cell Lung Cancer Biomarker Database (refine by non-small cell lung cancer) Genomic Biomarkers Huddle Card Targeted Therapy Huddle Card National Comprehensive Cancer Network homepage To discuss the information in this episode with other oncology nurses, visit the ONS Communities.  To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org Highlights From This Episode "These biomarkers are used to provide information about cancer's characteristics or behavior. In oncology precision medicine specifically, molecular tests can help with diagnosing a cancer that is maybe an unknown primary. It can help with monitoring response to therapy, detect recurrence of disease before other tests can find that, predict prognosis or how aggressive the cancer may be, and guide treatment decisions for targeted therapies." TS 3:14 "Some of the key biomarkers recommended by the National Comprehensive Cancer Network (NCCN) to be tested in patients who have NSCLC are EGFR, ALK, KRAS, BRAF, MET exon 14 skipping mutation, HER2 which is a protein expression from an ErbB protein, PD-L1 which is a protein expression that's used to guide immunotherapy choices, and then finally there are three fusions: ROS1, RET, and NTRK. [These] are pretty rare but really important to be tested for in patients who have NSCLC." TS 3:46 "Another important challenge for nurses related to this topic is that these results may not reveal a targeted mutation for the patient and that could be very disappointing. So, being able to provide that emotional support to a patient if they have that result … you can actually reinforce with them that if [they] go onto another treatment that the physician decides to put [them] on, the tumor can change. New pathogenic variants can develop based on the treatment that they're getting, and another test can be done. And maybe at that time—a new biomarker that could be targeted—we'd be seeing on the new test." TS 7:32  "Another circumstance we didn't talk about yet is that maybe the result came back saying that the quality was not sufficient. And sometimes that happens, but that doesn't mean that we're at the end of the road, necessarily. So, you could explain to the patient that that may mean that possibly, a new biopsy would be ordered by the physician. Or if a new biopsy or another tissue sample is not available, then maybe the physician would pivot to sending a blood specimen for the molecular testing. So that would definitely be a way [nurses] could support their patients." TS 11:52 "In the case of patients with NSCLC, early testing is so important. So, advocating for that prompt biomarker testing to be done, making sure that it's comprehensive, that it's actually looking for all of those—I think it was 12 biomarkers—that I mentioned earlier. That this testing is done as soon as possible after diagnosis or progression. Something that I talk about all the time—personalized care, precision medicine—really matters. So, tailoring treatments for patients based on the biology of the tumor that's driving the cancer's growth is really crucial if you're going to be working as an oncology nurse. Another crucial thing, because it's changing so quickly, is to stay informed." TS 16:23

BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.” In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. “GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. “Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.” DOI - https://doi.org/10.18632/oncotarget.28586 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28586 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib 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. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.08.548192v1?rss=1 Authors: Aguilan, J., Pedrosa, E., Dolstra, H., Nur Baykara, R., Barnes, J., Zhang, J., Sidoli, S., Lachman, H. Abstract: Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.03.522525v1?rss=1 Authors: Hu, X., Zhu, Q., Lou, T., Hu, Q., Niu, X., He, L., Huang, H., Xu, Y., Qiu, M., Shen, Y., Jia, J.-M., Tao, Y. Abstract: White matter abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling that is essential for peripheral myelination has been genetically associated with schizophrenia and white matter lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used a pan-ErbB inhibition strategy and demonstrated the synergistic functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulation of ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the differentiation of newly-formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, mature oligodendrocytes with ErbB inhibition reduce the expression of lactate dehydrogenase A, failing to provide lactate to electrically active axons. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings reveal the indispensable roles of ErbB signaling in white matter integrity and function, and provide insights into the multifaceted contributions of white matter abnormalities to cognitive impairment. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

CME credits: 1.00 Valid until: 17-08-2023 Claim your CME credit at https://reachmd.com/programs/cme/what-are-nrg1-gene-fusions-and-the-rationale-for-targeting-erbb/14338/ tbd

Two American Cancer Society grantees—one with a recent publication on the early mechanisms of lung cancer initiation, the other with a new study out on the development of melanoma resistance during the earliest phases of treatment—joined the podcast for a conversation about catching the problem early. This conversation is geared for a scientific audience, until the last few minutes. Sabrina Spencer, PhD, is Associate Professor of Biochemistry at University of Colorado, Boulder. She recently published a study in Nature Communications on “Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signaling:” https://www.nature.com/articles/s41467-021-21549-x?elqTrackId=2842c2f36cc243139afc4151f4f48ee6. Xaralabos (Bob) Varelas, PhD, is Associate Professor of Biochemistry at Boston University School of Medicine. He recently published work in Proceedings of the National Academy of Sciences of the United States of America titled, “Aberrant epithelial polarity cues drive the development of precancerous airway lesions:” https://www.pnas.org/content/118/18/e2019282118. 1:08 – Dr. Varelas on his recent study, which offered insights into mechanisms that drive the onset of lung squamous cell carcinomas 4:20 – Dr. Spencer asks clarifying questions about how they disrupted the polarity… 5:08 – …and whether the Crumbs3 mutation occurs in patients or was a way to initiate the system 7:56 – A provocative question from Dr. Spencer: “would that mean that a precancerous lesion would be a candidate for treatment with some of these clinically approved drugs?” 9:25 – “Can you connect increased ERBB signaling to actual increased cell cycling?” 10:48 – Dr. Spencer talks about her interest in the origin of drug resistance in cancer and her recent paper, which focused on melanoma 20:15 – Dr. Varelas asks how broadly applicable these findings are to other cancers 22:10 – “Why do you think some of the cells escape? Is there an underlying difference in the cells to begin with? Or are some cells randomly taking on some kind of adaptive mechanism?” 28:11 – The impact of American Cancer Society funding on their research

Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)

Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)

Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)

Investor Ideas Potcasts #593, Cannabis News and Stocks on the Move: (TSX: WEED) (NASDAQ: CGC), (TSX: VLNS) (OTCQX: VLNCF), (OTC: LRSV) and (OTC: ERBB)

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.377226v1?rss=1 Authors: Hu, X., Xiao, G., He, L., Niu, X., Li, H., Xu, Q., Wei, Z., Qiu, M., Tanaka, K. F., Shen, Y., Tao, Y. Abstract: Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By analyzing the differentiation states of cells that were pulse-labeled with a viral reporter, we found that, during juvenile to adolescent development, Plp-tTA targeted mainly mature oligodendrocytes (MOs), while Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA supported the reporter pulse-labeling results, and consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage after early development. These features enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused pathological demyelination, whereas in OPCs induced apoptosis that caused developmental hypomyelination. These results established an upstream pathogenic role of ErbB overactivation in oligodendrocytes, providing molecular and cellular insights into the primary oligodendropathy in demyelinating diseases. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.289223v1?rss=1 Authors: Hu, X., Xiao, G., He, L., Zhu, Q., Niu, X., Li, H., Xu, Q., Wei, Z., Huang, H., Luan, Y., Qiu, M., Tanaka, K. F., Shen, Y., Tao, Y. Abstract: White matter abnormalities are an emerging pathological feature of schizophrenia. However, their attributions to the disease remain largely elusive. ErbB receptors and their ligands, some of which are essential for peripheral myelination, confer susceptibility to schizophrenia. By synergistically manipulating ErbB receptor activities in a oligodendrocyte-stage-specific manner in mice after early development, we demonstrate the distinct effects of ErbB signaling on oligodendrocytes at various differentiation states. ErbB overactivation, in mature oligodendrocytes, induces necroptosis causing demyelination, whereas in oligodendrocyte precursor cells, induces apoptosis causing hypomyelination. In contrast, ErbB inhibition increases oligodendrocyte precursor cell proliferation but induces hypomyelination by suppressing the myelinating capabilities of newly-formed oligodendrocytes. Remarkably, ErbB inhibition in mature oligodendrocytes diminishes axonal conduction under energy stress and impairs working memory capacity independently of myelin pathology. This study reveals the etiological implications of oligodendrocyte vulnerability induced by ErbB dysregulation, and elucidates the pathogenetic mechanisms for variable structural and functional white matter abnormalities. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.23.167833v1?rss=1 Authors: Meng, X., Borges, B. C., Long, P., Kanold, P. O., Corfas, G. Abstract: Myelination of central nervous system axons increases the conduction speed of neural impulses and contributes to the function and maintenance of neural circuits. Accordingly, loss of myelin leads to axonal loss and to severe brain dysfunction. In contrast, much less is known about the functional consequences of mild hypomyelination on central network connectivity. To address this gap in knowledge, we studied mice that have mild hypomyelination due to loss of oligodendrocyte ErbB receptor signaling. We focused on the primary auditory cortex (A1) due to the crucial role that temporal precision plays in the processing of auditory information. We find that loss of oligodendrocyte ErbB receptor signaling causes reduction in myelin in A1. We mapped and quantified the intracortical inputs to L2/3 neurons using laser-scanning photostimulation combined with patch clamp recordings. We found that hypomyelination reduces inhibitory connections to L2/3 neurons without affecting excitatory inputs, thus altering excitatory/inhibitory balance. Remarkably, these effects are not associated with changes in the expression of GABAergic and glutamatergic synaptic components, but with a reduction of parvalbumin (PV) neuron density and PV mRNA levels. These results demonstrate that mild hypomyelination can impact cortical neuronal networks and cause a network shift towards excitation. Copy rights belong to original authors. Visit the link for more info

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)

Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)

Featuring perspectives from Dr Shirish M Gadgeel on the later-line management of metastatic squamous cell carcinoma of the lung. Recent advances in the management of advanced non-small cell lung cancer (NSCLC) (0:00) Case: A woman in her early 70s with metastatic squamous cell carcinoma (SCC) of the lung receives carboplatin/paclitaxel and pembrolizumab as first-line therapy on the KEYNOTE-021 trial (02:25) Response to pembrolizumab and chemotherapy in advanced SCC of the lung (04:34) Efficacy of pembrolizumab alone or in combination with chemotherapy for advanced NSCLC (07:41) Choice of immune checkpoint inhibitor/chemotherapy regimen as first-line therapy for metastatic SCC of the lung (12:22) Results of the Phase III CheckMate 227 trial evaluating nivolumab alone, with ipilimumab or with chemotherapy as first-line therapy for metastatic NSCLC (15:43) Interim overall survival analysis of the Phase III IMpower110 study investigating atezolizumab versus platinum-based chemotherapy for metastatic NSCLC in the first-line setting (18:32) Cancer site and adverse events induced by immune checkpoint inhibitors (20:05) Genetic alterations in patients with SCC of the lung; rationale for targeting the ERBB signaling pathway (22:18) Results of the Phase III LUX-Lung 8 trial of afatinib versus erlotinib as second-line treatment for advanced SCC of the lung (25:53) Secondary analysis of LUX-Lung 8: Association of ERBB mutations with clinical outcomes among patients with afatinib- or erlotinib-treated SCC of the lung (28:04) Role of HER2 mutations and HER2 amplification in patients with NSCLC; incidence of HER2 alterations in patients with SCC of the lung (30:14) Targeting HER2 alterations with the tyrosine kinase inhibitors afatinib and dacomitinib in patients with NSCLC (34:15) Efficacy of the antibody-drug conjugate trastuzumab deruxtecan (DS-8201) in patients with NSCLC and HER2 alterations (36:11) Activity of T-DM1 in patients with NSCLC and HER2 mutations (38:04) Management of gastrointestinal side effects associated with afatinib (40:22) Activity of afatinib in heavily pretreated ERBB2 mutation-positive advanced NSCLC (43:01) Afatinib in patients with metastatic or recurrent lung cancer with HER2 mutations  (45:15) Case: A man in his early 80s develops metastases to the liver during treatment with durvalumab after chemoradiation therapy for Stage III SCC of the lung and is found to have FGFR1 amplification (47:15) FGFR signaling as a target for NSCLC therapy; outcomes with the FGFR inhibitor AZD4547 in patients with metastatic SCC of the lung and FGFR alterations (51:04) SWOG-S1400 Lung Cancer Master Protocol (Lung-MAP) — Biomarker-targeted therapy for patients with previously treated Stage IV SCC of the lung (56:02) Case: A woman in her early 50s with ALK-rearranged metastatic lung adenocarcinoma experiences a dramatic response to crizotinib on the PROFILE 1014 study (1:02:39) Response to ALK inhibitors for ALK-rearranged metastatic NSCLC (1:06:54) CME information and select publications

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's 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 Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today? Dr Greg Hundley:             My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.                                                 As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation. Dr Carolyn Lam:                Interesting, so what did they find, how did they do this? Dr Greg Hundley:             Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription. Dr Carolyn Lam:                And so? What did they find? Dr Greg Hundley:             Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.                                                 So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.                                                 So, Carolyn, how about your next study? Dr Carolyn Lam:                Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial. Dr Greg Hundley:             Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us? Dr Carolyn Lam:                Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.                                                 Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.                                                 So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.                                                 Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension. Dr Greg Hundley:             Wow, so we're getting back toward renal denervation? How about that?                                                 Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.                                                 Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure. Dr Carolyn Lam:                Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes? Dr Greg Hundley:             The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.                                                 The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.                                                 So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy. Dr Carolyn Lam:                Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.                                                 So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz? Dr Greg Hundley:             You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us? Dr Carolyn Lam:                Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.                                                 Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.                                                 So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.                                                 So, Greg, interesting stuff, huh? Dr Greg Hundley:             You bet! Let's go on and here a little bit more about diabetes. Dr Carolyn Lam:                And dapagliflozin coming right up.                                                 Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.                                                 All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please? Dr Stephen Wiviott:        So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.                                                 Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.                                                 And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation. Dr Carolyn Lam:                Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis? Dr Eri Kato:                         So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.                                                 So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.                                                 There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.                                                 Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.                                                 So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.                                                 And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.                                                 So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction. Dr Carolyn Lam:                Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined? Dr Eri Kato:                         We collected data at the baseline and the heart failure was collected based on the medical record. Dr Carolyn Lam:                So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds? Dr Darren McGuire:        First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.                                                 And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.                                                 So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results? Dr Carolyn Lam:                Subodh, I'm going to let you go first. Dr Subodh Verma:           First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.                                                 I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.                                                 So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.                                                 So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.                                                 But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically. Dr Carolyn Lam:                Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.                                                 But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find? Dr Stephen Wiviott:        I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.                                                 In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.                                                 So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.                                                 And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.                                                 And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.                                                 Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction. Dr Carolyn Lam:                Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next? Dr Darren McGuire:        I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.                                                 And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes. Dr Carolyn Lam:                Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?                                                 You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

Dr Jean-Pascal Machiels of Cliniques Universitaires Saint-Luc, Brussels, Belgium talks to ecancertv at ESMO 2014 in Madrid Spain. He presents results from a phase III trial on the tyrosine kinase inhibitor, afatinib and the significant improvements it has shown in progression-free survival for patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy. Afatinib is a compound that irreversibly blocks the ErbB family of cell surface receptors, which includes epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4.

You have to be aware of these speculative bubbled frenzies and paid-promotion scams even if you're just an average Joe investor. I personally have received dozens of thank you's from readers who listened to my advice to stay away from these lousy investments and themselves saved millions of dollars in unnecessary losses. Remember my simple rule: don't ever buy a penny stock. Here's an audacious real-life, real-time example of how this penny stock promotion game works. Indeed, this is the most brazen stock promotion game I've ever seen, and I've seen them all. This company gets paid $17,500 dollars by BreedIT, a lousy penny stock trading at 19 cents per share, to write an article touting the BreedIT stock which they then pay to get sent out over the newswire services and which then even gets picked up on Marketwatch's Newswire feeds. 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And the kicker is that up until the recently popped marijuana penny stock bubble got started, this BreedIT company which currently says it's in the business of "develops, licenses, and markets agro-breeding solutions for plant breeders and researchers" was actually called ProGaming and touted itself as "an online gaming platform for multiplayer skill game competitions on the internet." So let me be clear since this company and it's hypester shills have tried to associate my name with it -- I predict that BRDT will be right back down to its 52-week low of 3 cents per share and that it's headed much lower than that over the next few years. I don't think it has any product for "agro-breeding solutions for plant breeders" that will ever sell enough to make this company worth $1 million, much less the current $17 million market cap it has. After I mention how much money I have saved warning retail investors about pot penny stocks, the attacks commence immediately. Insiders and hypesters are sensitive about people calling out their scams. My favorite attack from the hypsters recently is the guy on Twitter who calls me an idiot for having nailed an 80% crash in ERBB. Now the hypesters are deleting their tweets to me cuz I made them look stupid by calling out their scams. Sigh. Forget penny stocks. The key is to have a strategy for finding the best revolutionary stocks on the planet and navigating the broader market swings with them. I covered much of this recently on a panel I sat on with Bill Harris of Personal Capital, Jim Hurd of Green Science Exchange, talking about how "disruption from drones, robots, wearables, nanotech, and cleantech is coming our way." Sticking with the best revolutionary stocks that I've outlined for years such as Apple, Google, Facebook while avoiding penny stocks and other scams will put you far ahead of most retail investors. It still won't be easy and it will be stressful, but a good game plan for the long-term is what it's all about. I don't know when the ongoing bubble-blowing bull market will pop or what will actually cause it to pop. I am doing my best to look out over the next year or two and get a feel for where the economy, earnings and stocks and other financial assets are headed, but when it comes to investing, I want to just slowly scale into the most revolutionary stocks on the planet and use tranche-trading to maximize my gains and minimize my risks over the next decade or two. If and when the markets do crash, which could be another 3 or 5 years out for all I know, I expect I will have navigated it by having lots of cash on the sides to continue building my favorite revolutionary stocks. Longer-term I think we'll have 10x our money on another Google or another Apple kind of 100x gain in some of our stocks, and that's the reason I risk my hard-earned capital to begin with. In the meantime, there are also great pitches being thrown at all traders as the markets bubble and swing. I've recently been focusing some on finding great bubbled up tech shorting opportunities, and there are a plethora of them in this bubble-blowing bull market.

This week on #PotStockRadio Eric @EbizDizzle Ry @ryanmodfrey and Trace @supergravy will talk to Tranzbyte COO Stephen Shearin         @American_Green about all of the @Tranzbyte companies including American Green and One Bode. We'll ask him about Avon, Colorado on April 12th and the direction the what we all know in the pot stock world as ERBB! We'll also be talking about the week that was with the #wolfpack and @WolfofWeedST as well as what's happening at WolfOfWeedStreet.com. Don't forget that when the pack's advice pays off to spread the good #karma and #payitforward but donating to your favorite charity. Than take a picture of your donation and put it up on Twitter and tag it with #wolfpack. We apprecite the support and any questions or feedback about the show can be directed to eric@potstockradio.com

Douglas Lauffenburger discusses how amplification of the receptor tyrosine kinase AXL promotes migration of triple negative breast cancer cells.

Mathematical modeling of signaling pathways can be used to identify candidate targets for cancer therapies.

In dieser Arbeit wurde die biologische Funktion der PTP-Meg2 in der zellulären Signaltransduktion untersucht. Analysen mittels c-DNA-Filter, „Real Time PCR” und Immunblot zeigen eine ubiquitäre Expression der PTP-Meg2 auf ähnlichem, jedoch geringem Niveau in fast allen untersuchten Krebszelllinien unterschiedlicher Gewebeherkunft, wobei die Expressions-stärke nicht in direktem Zusammenhang mit krebsrelevanten Eigenschaften wie Invasivität und Metastasierung steht. Die induzierte Differenzierung von MCF 7-Zellen durch Natriumbutyrat steigert die Meg2-Expression um das 5-fache, wogegen die Differenzierung von SW948- und SK-N- SH-Zellen mit TPA bzw. Retinolsäure die Meg2-Expression reprimiert. Zellfraktionierung und Immunfluoreszenz zeigen eine primär zytosolische, aber partiell auch vesikuläre bzw. strukturierte Lokalisation der PTP-Meg2, für welche die CRALBP-Domäne der PTP-Meg2 mitverantwortlich ist. Untersuchungen der endogenen Meg2-Aktivität nach Immunpräzipitation und in vitro Phosphatasetests zeigen eine erhöhte Phosphataseaktivität nach Stimulation von Zellen mit FCS, EGF und LPA, wogegen TPA stark inhibierenden wirkt. Aktivitätsstudien mit GST-Meg2-Fusionsproteinen zeigen, dass die CRALBP-Domäne die Meg2-Phosphataseaktivität negativ reguliert. Im Protein-Lipid-Overlay interagiert PTP-Meg2 mit PI(3)P, PI(4)P, PI(5)P und Phosphatidylserin. Eine Interaktion mit PI(4)P führt zu einer erhöhten Meg2 Aktivität. Pervanadat-Stimulation von Zellen führt zu einer Tyrosinphosphorylierung sowie einer Mobilitätsänderung der PTP-Meg2, was auch mit einer katalytisch inaktiven Meg2-Mutante beobachtet wurde. PTP-Meg2 interagiert in vitro und in Koexpressionsstudien mit dem EGF-Rezeptor in Abhängigkeit von dessen Aktivierung. Eine physiologische Relevanz konnte nicht gezeigt werden. Die Depletion der PTP-Meg2 durch spezifische siRNA führt zu einer erhöhten Tyrosinphosphorylierung einiger, noch zu identifizierender Proteine. PTP-Meg2 vermindert, die inaktive PTP-Meg2CS-Mutante erhöht die durch v-ErbB und EGF-Rezeptor, nicht aber die durch HER2 und v-Ki-Ras induzierte Transformation von NIH3T3-Zellen im Focusbildungstest. Zudem bewirkt PTP-Meg2CS, mit Ausnahme der v-Ki-Ras infizierten Zellen, eine leicht erhöhte ERK1/2-Aktivität. Ferner stimuliert PTP-Meg2 die Migration von NIH3T3-Zellen im Wundheilungsexperiment. Ein Einfluss auf die basale und durch Stimuli induzierte Proliferation von Zellen in Wachstumstests wurde nicht beobachtet. Ein durch siRNA-vermittelter Meg2- „knockdown“ führte zur Induktion bzw. Repression der Expression von Genen, wie z.B. einiger Liganden, Caveolin-2, Nck und Rock, was auf eine Beteiligung der PTP-Meg2 an der Regulation von Signalwegen kleiner GTPasen bzw. von endo- sowie exocytotischen Prozessen schließen lässt.

Concentrations of soluble c-erbB-2 were determined in the sera of 64 patients with distant metastasis from advanced breast cancer receiving second-line hormone or chemotherapy in comparison to 35 breast cancer patients without detectable recurrent disease and 17 healthy blood donors. The sera of non-metastatic breast cancer patients contained s-erbB-2 concentrations similar to those of healthy blood donors. Patients with distant metastasis from advanced breast cancer had significantly higher values of s-erbB-2 in comparison to patients with non-disseminated disease (mean: 59.6 vs. 11.6 U/ml; p = 0.022). A significant correlation was observed between s-erbB-2 serum levels and serum LDH concentrations (p < 0.001), levels of alkaline phosphatase (p < 0.001), and the presence of hepatic metastasis (p = 0.001). Time to tumor progression was significantly shorter in patients with s-erbB-2 levels above 40 U/ml (mean: 23.4 vs. 56.7 months; p = 0.002). Furthermore, breast cancer patients with hepatic metastasis and those with elevated s-erbB-2 serum levels above 40 U/ml had limited response to hormone or chemotherapy. Non-responders had significantly higher s-erbB-2 levels (mean: 270.3, range: 42-500 U/ml;) compared with the responder group (mean: 23.1, range: 0-149 U/ml; p < 0.001). Logistic regression analysis indicated that elevated s-erbB-2 serum levels above 40 U/ml independently predicted an unfavorable response to second-line hormone or chemotherapy in patients with advanced metastatic breast cancer. Copyright (C) 2002 S. KargerAG, Basel.

A human yeast artificial chromosome (YAC) library was screened by polymerase chain reaction with oligonucleotide primers defined for DNA sequences of the BCR gene and the protooncogenes c-raf-1, c-fms, and c-erB-2. Alu-PCR-generated human DNA sequences were obtained from the respective YAC clones and used for fluorescence in situ hybridization experiments under suppression conditions. After chromosomal in situ suppression hybridization to GTG-banded human prometaphase chromosomes, seven of nine initially isolated YAC clones yielded strong signals exclusively in the chromosome bands containing the respective genes. Two clones yielded additional signals on other chromosomes and were excluded from further tests. The band-specific YACs were successfully applied to visualize specific structural chromosome aberrations in peripheral blood cells from patients with myelodysplasia exhibiting del(5)(q13q34), chronic myeloid leukemia and acute lymphocytic leukemia with t(9;22)(q34;q11), acute promyelocytic leukemia (M3) with t(15;17)(q22;q21), and in a cell line established from a proband with the constitutional translocation t(3;8)(p14.2;q24). In addition to the analysis of metaphase spreads, we demonstrate the particular usefulness of these YAC clones in combination with whole chromosome painting to analyze specific chromosome aberrations directly in the interphase nucleus.