Podcasts about jak2

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That's especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn't get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to key publications and audioEric Topol (00:06):Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.Pradeep Natarajan (00:31):Thanks Eric, really delighted and honored to be with you and have this discussion.Eric Topol (00:36):Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.Two New Lipid Targets With RNA DrugsPradeep Natarajan (01:16):Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.(02:11):Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.Eric Topol (03:02):Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there's inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I'm still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.Pradeep Natarajan (03:53):Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.(04:57):Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?Eric Topol (06:27):Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.What About Lp(a)?Pradeep Natarajan (07:13):Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many different reasons why a biomarker might be elevated, and so if you detect a signal that correlates a biomarker, a concentration to a clinical outcome, it could be related to that biomarker, but it could be to the other reasons that the biomarker is elevated and sometimes it relates to the outcome itself.(08:10):Now human genetics is very attractive because if you find alleles that strongly relate to that exposure, you can test those alleles themselves with the clinical outcome. Now the allele assignment is established at birth. No other factor is going to change that assignment after conception, and so that provides a robust, strong causal test for that potential exposure in clinical outcome. Now, lipoprotein(a) is unique in that it is highly heritable and so there are lots of different alleles that relate to lipoprotein(a) and so in a well powered analysis can actually test the lipoprotein(a) SNPs with the clinical outcomes and similar to how there is a biomarker association with incident myocardial infarction and incident stroke, the SNPs related to lipoprotein(a) show the same. That is among the evidence that strongly supports that this might be causal. Now, fast forward to many years later, we have at least three phase three randomized clinical trials testing agents that have been shown to be very potent at lowering lipoprotein(a) that in the coming years we will know if that hypothesis is true. Importantly, we will have to understand what are the potential side effects of these medicines. There are antisense oligonucleotides and siRNAs that are primarily in investigation. Again, this is an example where there's a strong genetic observation, and so these genetic based longer interval dosing therapies may be attractive, but side effects will be a key thing as well too. Those things hard to anticipate really can anticipate based on the human genetics for off target effects, for example.(09:52):It's clearly a risk signal and hopefully in the near future we're going to have specific therapies.Eric Topol (09:57):Yeah, you did a great job of explaining Mendelian randomization and the fact the power of genetics, which we're going to get into deeper shortly, but the other point is that do you expect now that there's these multiple drugs that lower Lp(a) efficiently, would that be enough to get approval or will it have to be trials to demonstrate improved cardiovascular outcomes?Pradeep Natarajan (10:24):There is a great regulatory path at FDA for approval just for LDL cholesterol lowering and inclisiran is on the market and the phase three outcomes data has not yet been reported because there is a wide appreciation that LDL cholesterol lowering is a pretty good surrogate for cardiovascular disease risk lowering. The label will be restricted to LDL cholesterol lowering and then if demonstrated to have clinical outcomes, the label could be expanded. For other biomarkers including lipoprotein(a), even though we have strong conviction that it is likely a causal factor there hasn't met the bar yet to get approval just based on lipoprotein(a) lowering, and so we would need to see the outcomes effects and then we would also need to understand side effects. There is a body of literature of side effects for other therapies that have targeted using antisense oligonucleotides. We talked about potential side effects from some siRNA platforms and sometimes those effects could overtake potential benefits, so that really needs to be assessed and there is a literature and other examples.(11:31):The other thing I do want to note related to lipoprotein(a) is that the human genetics are modeled based on lifelong perturbations, really hard to understand what the effects are, how great of an effect there might be in different contexts, particularly when introduced in middle age. There's a lot of discussion about how high lipoprotein(a) should be to deliver these therapies because the conventional teaching is that one in five individuals has high lipoprotein(a), and that's basically greater than 75 nanomoles per liter. However, some studies some human genetic studies to say if you want to get an effect that is similar to the LDL cholesterol lowering medicines on the market, you need to start with actually higher lipoprotein(a) because you need larger amounts of lipoprotein(a) lowering. Those are studies and approaches that haven't been well validated. We don't know if that's a valid approach because that's modeling based on this sort of lifelong effect. So I'm very curious to see what the overall effect will be because to get approval, I think you need to demonstrate safety and efficacy, but most importantly, these manufacturers and we as clinicians are trying to find viable therapies in the market that it won't be hard for us to get approval because hopefully the clinical trial will have said this is the context where it works. It works really well and it works really well on top of the existing therapies, so there are multiple hurdles to actually getting it directly to our patients.How Low Do You Go with LDL Cholesterol?Eric Topol (13:02):Yeah, no question about that. I'm glad you've emphasized that. Just as you've emphasized the incredible lessons from the genetics of people that have helped guide this renaissance to better drugs to prevent cardiovascular disease. LDL, which is perhaps the most impressive surrogate in medicine, a lab test that you already touched on, one of the biggest questions is how low do you go? That is Eugene Braunwald, who we all know and love. They're in Boston. The last time I got together with him, he was getting his LDL down to close to zero with various tactics that might be extreme. But before we leave these markers, you're running preventive cardiology at man's greatest hospital. Could you tell us what is your recipe for how aggressive do you go with LDL?Pradeep Natarajan (14:04):Yeah, so when I talk to patients where we're newly getting lipid lowering therapies on, especially because many people don't have a readout of abnormal LDL cholesterol when we're prescribing these medicines, it's just giving them a sense of what we think an optimal LDL cholesterol might be. And a lot of this is based on just empirical observations. So one, the average LDL cholesterol in the modern human is about 100 to 110 mg/dL. However, if you look at contemporary hunter gatherers and non-human primates, their average LDL is about 40 to 50 and newborn babies have an LDL cholesterol of about 30. And the reason why people keep making LDL cholesterol lowering medicines because as you stack on therapies, cardiovascular disease events continue to reduce including down to these very low LDL cholesterol values. So the population mean for LDL cholesterol is high and everybody likely has hypercholesterolemia, and that's because over the last 10,000 years how we live our lives is so dramatically different and there has not been substantial evolution over that time to change many of these features related to metabolism.(15:16):And so, to achieve those really low LDL cholesterol values in today's society is almost impossible without pharmacotherapies. You could say, okay, maybe everybody should be on pharmacotherapies, and I think if you did that, you probably would reduce a lot of events. You'll also be treating a lot of individuals who likely would not get events. Cardiovascular disease is the leading killer, but there are many things that people suffer from and most of the times it still is not cardiovascular disease. So our practice is still rooted in better identifying the individuals who are at risk for cardiovascular disease. And so, far we target our therapies primarily in those who have already developed cardiovascular disease. Maybe we'll talk about better identifying those at risk, but for those individuals it makes lots of sense to get it as low as possible. And the field has continued to move to lower targets.(16:07):One, because we've all recognized, at least based on these empirical observations that lower is better. But now increasingly we have a lot of therapies to actually get there, and my hope is that with more and more options and the market forces that influence that the cost perspective will make sense as we continue to develop more. As an aside, related aside is if you look at the last cholesterol guidelines, this is 2018 in the US this is the first time PCSK9 inhibitors were introduced in the guidelines and all throughout that there was discussions of cost. There are a lot of concerns from the field that PCSK9 inhibitors would bankrupt the system because so many people were on statins. And you look at the prior one that was in 2013 and cost was mentioned once it's just the cost effectiveness of statins. So I think the field has that overall concern.(17:01):However, over time we've gotten comfortable with lower targets, there are more medicines and I think some of this competition hopefully will drive down some of the costs, but also the overall appreciation of the science related to LDL. So long-winded way of saying this is kind of the things that we discussed just to give reassurance that we can go to low LDL cholesterol values and that it's safe and then we think also very effective. Nobody knows what the lower limit is, whether zero is appropriate or not. We know that glucose can get too low. We know that blood pressure can be too low. We don't know yet that limit for LDL cholesterol. I mean increasingly with these trials we'll see it going down really low and then we'll better appreciate and understand, so we'll see 40 is probably the right range.Eric Topol (17:49):40, you said? Yeah, okay, I'll buy that. Of course, the other thing that we do know is that if you push to the highest dose statins to get there, you might in some people start to see the hyperglycemia issue, which is still not fully understood and whether that is, I mean it's not desirable, but whether or not it is an issue, I guess it's still out there dangling. Now the other thing that since we're on LDL, we covered Lp(a), PCSK9, the siRNA, is ApoB. Do you measure ApoB in all your patients? Should that be the norm?Measuring ApoBPradeep Natarajan (18:32):Yeah, so ApoB is another blood test. In the standard lipid panel, you get four things. What's measured is cholesterol and triglycerides, they're the lipids insoluble in blood to get to the different tissues that get packaged in lipoprotein molecules which will have the cholesterol, triglycerides and some other lipids and proteins. And so, they all have different names as you know, right? Low density lipoprotein, high density lipoprotein and some others. But also in the lipid panel you get the HDL cholesterol, the amount of cholesterol in an HDL particle, and then most labs will calculate LDL cholesterol and LDL cholesterol has a nice relationship with cardiovascular disease. You lower it with statins and others. Lower risk for cardiovascular disease, turns out a unifying feature of all of these atherogenic lipoproteins, all these lipoproteins that are measured and unmeasured that relate to cardiovascular disease, including lipoprotein(a), they all have an additional protein called ApoB. And ApoB, at least as it relates to LDL is a pretty good surrogate of the number of LDL particles.(19:37):Turns out that that is a bit better at the population level at predicting cardiovascular disease beyond LDL cholesterol itself. And where it can be particularly helpful is that there are some patients out there that have an unexpected ratio between ApoB and LDL. In general, the ratio between LDL cholesterol and ApoB is about 1.1 and most people will have that rough ratio. I verify that that is the expected, and then if that is the expected, then really there is no role to follow ApoB. However, primarily the patients that have features related to insulin resistance have obesity. They may often have adequate looking LDL cholesterols, but their ApoB is higher. They have more circulating LDL particles relative to the total amount of LDL cholesterol, so smaller particles themselves. However, the total number of particles may actually be too high for them.(20:34):And so, even if the LDL cholesterol is at target, if the ApoB is higher, then you need to reduce. So usually the times that I just kind of verify that I'm at appropriate target is I check the LDL cholesterol, if that looks good, verify with the ApoB because of this ratio, the ApoB target should be about 10% lower. So if we're aiming for about 40, that's like 36, so relatively similar, and if it's there, I'm good. If it's not and it's higher, then obviously increase the LDL cholesterol lowering medicines because lower the ApoB and then follow the ApoB with the lipids going forward. The European Society of Cardiology has more emphasis on measuring ApoB, that is not as strong in the US guidelines, but there are many folks in the field, preventive cardiologists and others that are advocating for the increasing use of ApoB because I think there are many folks that are not getting to the appropriate targets because we are not measuring ApoB.Why Aren't We Measuring and Treating Inflammation?Eric Topol (21:37):Yeah, I think you reviewed it so well. The problem here is it could be part of the standard lipid panel, it would make this easy, but what you've done is a prudent way of selecting out people who it becomes more important to measure and moderate subsequently. Now this gets us to the fact that we're lipid centric and we don't pay homage to inflammation. So I wrote a recent Substack on the big miss on inflammation, and here you get into things like the monoclonal antibody to interleukin-6, the trial that CANTOS that showed significant reduction in cardiovascular events and fatal cancers by the way. And then you get into these colchicine trials two pretty good size randomized trials, and here the entry was coronary disease with a high C-reactive protein. Now somehow or other we abandon measuring CRP or other inflammatory markers, and both of us have had patients who have low LDLs but have heart attacks or significant coronary disease. So why don't we embrace inflammation? Why don't we measure it? Why don't we have better markers? Why is this just sitting there where we could do so much better? Even agents that are basically cost pennies like colchicine at low doses, not having to use a proprietary version could be helpful. What are your thoughts about us upgrading our prevention with inflammation markers?Pradeep Natarajan (23:22):Yeah, I mean, Eric, there is an urgent need to address these other pathways. I say urgent need because heart disease has the dubious distinction of being the leading killer in the US and then over the last 20 years, the leading killer in the world as it takes over non-communicable diseases. And really since the early 1900s, there has been a focus on developing pharmacotherapies and approaches to address the traditional modifiable cardiovascular disease risk factors. That has done tremendous good, but still the curves are largely flattening out. But in the US and in many parts of the world, the deaths attributable to cardiovascular disease are starting to tick up, and that means there are many additional pathways, many of them that we have well recognized including inflammation. More recently, Lp(a) that are likely important for cardiovascular disease, for inflammation, as you have highlighted, has been validated in randomized controlled trials.(24:18):Really the key trial that has been more most specific is one on Canakinumab in the CANTOS trial IL-1β monoclonal antibody secondary prevention, so cardiovascular disease plus high C-reactive protein, about a 15% reduction in cardiovascular disease and also improvement in cancer related outcomes. Major issues, a couple of issues. One was increased risk for severe infections, and the other one is almost pragmatic or practical is that that medicine was on the market at a very high price point for rare autoinflammatory conditions. It still is. And so, to have for a broader indication like cardiovascular disease prevention would not make sense at that price point. And the manufacturer tried to go to the FDA and focus on the group that only had C-reactive protein lowering, but that's obviously like a backwards endpoint. How would you know that before you release the medicine? So that never made it to a broader indication.(25:14):However, that stuck a flag in the broader validation of that specific pathway in cardiovascular disease. That pathway has direct relevance to C-reactive protein. C-reactive protein is kind of a readout of that pathway that starts from the NLRP3 inflammasome, which then activates IL-1β and IL-6. C-reactive protein we think is just a non causal readout, but is a reliable test of many of these features and that's debatable. There may be other things like measuring IL-6, for example. So given that there is actually substantial ongoing drug development in that pathway, there are a handful of companies with NLRP3 inflammasome inhibitors, but small molecules that you can take as pills. There is a monoclonal antibody against IL-6 that's in development ziltivekimab that's directed at patients with chronic kidney disease who have lots of cardiovascular disease events despite addressing modifiable risk factors where inflammatory markers are through the roof.(26:16):But then you would also highlighted one anti-inflammatory that's out there that's pennies on the dollar, that's colchicine. Colchicine is believed to influence cardiovascular disease by inhibiting NLRP3, I say believed to. It does a lot of things. It is an old medicine, but empirically has been shown in at least two randomized controlled trials patients with coronary artery disease, actually they didn't measure C-reactive protein in the inclusion for these, but in those populations we did reduce major adverse cardiovascular disease events. The one thing that does give me pause with colchicine is that there is this odd signal for increased non-cardiovascular death. Nobody understands if that's real, if that's a fluke. The FDA just approved last year low dose colchicine, colchicine at 0.5 milligrams for secondary prevention given the overwhelming efficacy. Hasn't yet made it into prevention guidelines, but I think that's one part that does give me a little bit pause. I do really think about it particularly for patients who have had recurrent events. The people who market the medicine and do research do remind us that C-reactive protein was not required in the inclusion, but nobody has done that secondary assessment to see if measuring C-reactive protein would be helpful in identifying the beneficial patients. But I think there still could be more work done on better identifying who would benefit from colchicine because it's an available and cheap medicine. But I'm excited that there is a lot of development in this inflammation area.Eric Topol (27:48):Yeah, well, the development sounds great. It's probably some years away. Do you use colchicine in your practice?Pradeep Natarajan (27:56):I do. Again, for those folks who have had recurrent events, even though C-reactive protein isn't there, it does make me feel like I'm treating inflammation. If C-reactive protein is elevated and then I use it for those patients, if it's not elevated, it's a much harder sell from my standpoint, from the patient standpoint. At the lower dose for colchicine, people generally are okay as far as side effects. The manufacturer has it at 0.5 milligrams, which is technically not pennies on the dollar. That's not generic. The 0.6 milligrams is generic and they claim that there is less side effects at the 0.5 milligrams. So technically 0.6 milligrams is off label. So it is what it is.CHIP and Defining High Risk People for CV DiseaseEric Topol (28:40):It's a lot more practical, that's for sure. Now, before I leave that, I just want to mention when I reviewed the IL-1β trial, you mentioned the CANTOS trial and also the colchicine data. The numbers of absolute increases for infection with the antibody or the cancers with the colchicine are really small. So I mean the benefit was overriding, but I certainly agree with your concern that there's some things we don't understand there that need to be probed more. Now, one of the other themes, well before one other marker that before we get to polygenic risk scores, which is center stage here, defining high risk people. We've talked a lot about the conventional things and some of the newer ways, but you've been one of the leaders of study of clonal hematopoiesis of indeterminate potential known as CHIP. CHIP, not the chips set in your computer, but CHIP. And basically this is stem cell mutations that increase in people as we age and become exceptionally common with different mutations that account in these clones. So maybe you can tell us about CHIP and what I don't understand is that it has tremendous correlation association with cardiovascular outcomes adverse as well as other system outcomes, and we don't measure it and we could measure it. So please take us through what the hell is wrong there.Pradeep Natarajan (30:14):Yeah, I mean this is really exciting. I mean I'm a little bit biased, but this is observations that have been made only really over the last decade, but accelerating research. And this has been enabled by advances in genomic technologies. So about 10 years or plus ago, really getting into the early days of population-based next generation sequencing, primarily whole exome sequencing. And most of the DNA that we collect to do these population-based analyses come from the blood, red blood cells are anucleate, so they're coming from white blood cells. And so, at that time, primarily interrogating what is the germline genetic basis for coronary artery disease and early onset myocardial infarction. At the same time, colleagues at the Broad Institute were noticing that there are many additional features that you can get from the blood-based DNA that was being processed by the whole exome data. And there were actually three different groups that converged on that all in Boston that converged on the same observation that many well-established cancer causing mutations.(31:19):So mutations that are observed in cancers that have been described to drive the cancers themselves were being observed in these large population-based data sets that we were all generating to understand the relationship between loss of function mutations in cardiovascular disease. That's basically the intention of those data sets for being generated for other things. Strong correlation with age, but it was very common among individuals greater than 70; 10% of them would have these mutations and is very common because blood cancer is extremely, it's still pretty rare in the population. So to say 10% of people had cancer causing driver mutations but didn't have cancer, was much higher than anyone would've otherwise expected. In 2014, there were basically three main papers that described that, and they also observed that there is a greater risk of death. You'd say, okay, this is a precancerous lesion, so they're probably dying of cancer.(32:17):But as I said, the absolute incidence rate for blood cancer is really low and there's a relative increase for about tenfold, but pretty small as it relates to what could be related to death. And in one of the studies we did some exploratory analysis that suggested maybe it's actually the most common cause of death and that was cardiovascular disease. And so, a few years later we published a study that really in depth really looked at a bunch of different data sets that were ascertained to really understand the relationship between these mutations, these cancer causing mutations in cardiovascular disease, so observed it in enrichment and older individuals that had these mutations, CHIP mutations, younger individuals who had early onset MI as well too, and then also look prospectively and showed that it related to incident coronary artery disease. Now the major challenge for this kind of analysis as it relates to the germline genetic analysis is prevalence changes over time.(33:15):There are many things that could influence the presence of clonal hematopoiesis. Age is a key enriching factor and age is the best predictor for cardiovascular disease. So really important. So then we modeled it in mice. It was actually a parallel effort at Boston University (BU) that was doing the same thing really based on the 2014 studies. And so, at the same time we also observed when you modeled this in mice, you basically perturb introduce loss of function mutations in the bone marrow for these mice to recapitulate these driver mutations and those mice also have a greater burden of atherosclerosis. And Eric, you highlighted inflammation because basically the phenotype of these cells are hyper inflamed cells. Interestingly, C-reactive protein is only modestly elevated. So C-reactive protein is not fully capturing this, but many of the cytokines IL-1β, IL-6, they're all upregulated in mice and in humans when measured as well.(34:11):Now there've been a few key studies that have been really exciting about using anti-inflammatories in this pathway to address CHIP associated cardiovascular disease. So one that effort that I said in BU because they saw these cytokines increased, we already know that these cytokines have relationship with atherosclerosis. So they gave an NLRP3 inflammasome inhibitor to the mice and they showed that the mice with or without CHIP had a reduction in atherosclerosis, but there was a substantial delta among the mice that are modeled as having CHIP. Now, the investigators in CANTOS, the manufacturers, they actually went back and they survey where they had DNA in the CANTOS trial. They measured CHIP and particularly TET2 CHIP, which is the one that has the strongest signal for atherosclerosis. As I said, overall about 15% reduction in the primary outcome in CANTOS. Among the individuals who had TET2 CHIP, it was a 64% reduction in event.(35:08):I mean you don't see those in atherosclerosis related trials. Now this has the caveat of it being secondary post hoc exploratory, the two levels of evidence. And so, then we took a Mendelian randomization approach. Serendipitously, just so happens there is a coding mutation in the IL-6 receptor, a missense mutation that in 2012 was described that if you had this mutation, about 40% of people have it, you have a 5%, but statistically significant reduction in coronary artery disease. So we very simply said, if the pathway of this NLRP3 inflammasome, which includes IL-6, if you have decreased signaling in that pathway, might you have an even greater benefit from having that mutation if you had CHIP versus those who didn't have CHIP. So we looked in the UK Biobank, those who didn't have CHIP 5% reduction, who had that IL-6 receptor mutation, and then those who did have CHIP, if they had that mutation, it was about a 60% reduction in cardiovascular disease.(36:12):Again, three different lines of evidence that really show that this pathway has relevance in the general population, but the people who actually might benefit the most are those with CHIP. And I think as we get more and more data sets, we find that not all of the CHIP mutations are the same as it relates to cardiovascular disease risk. It does hone in on these key subsets like TET2 and JAK2, but this is pretty cool as a preventive cardiologist, new potential modifiable risk factor, but now it's almost like an oncologic paradigm that is being applied to coronary artery disease where we have specific driver mutations and then we're tailoring our therapies to those specific biological drivers for coronary artery disease. Hopefully, I did that justice. There's a lot there.Why Don't We Measure CHIP?Eric Topol (36:57):Well, actually, it's phenomenal how you've explained that, but I do want to review for our listeners or readers that prior to this point in our conversation, we were talking about germline mutations, the ones you're born with. With CHIP, we're talking about acquired somatic mutations, and these are our blood stem cells. And what is befuddling to me is that with all the data that you and others, you especially have been publishing and how easy it would be to measure this. I mean, we've seen that you can get it from sequencing no less other means. Why we don't measure this? I mean, why are we turning a blind eye to CHIP? I just don't get it. And we keep calling it of indeterminate potential, not indeterminate. It's definite potential.Pradeep Natarajan (37:51):Yeah, no, I think these are just overly cautious terms from the scientists. Lots of people have CHIP, a lot of people don't have clinical outcomes. And so, I think from the lens of a practicing hematologists that provide some reassurance on the spectrum for acquired mutation all the way over to leukemia, that is where it comes from. I don't love the acronym as well because every subfield in biomedicine has its own CHIP, so there's obviously lots of confusion there. CH or clinical hematopoiesis is often what I go, but I think continuing to be specific on these mutations. Now the question is why measure? Why aren't we measuring it? So there are some clinical assays out there. Now when patients get evaluated for cytopenias [low cell counts], there are next generation sequencing tests that look for these mutations in the process for evaluation. Now, technically by definition, CHIP means the presence of these driver mutations that have expanded because it's detectable by these assays, not a one-off cell because it can only be detected if it's in a number of cells.(38:55):So there has been some expansion, but there are no CBC abnormalities. Now, if there's a CBC abnormality and you see a CHIP mutation that's technically considered CCUS or clonal cytopenia of unknown significance, sometimes what is detected is myelodysplastic syndrome. In those scenarios still there is a cardiovascular disease signal, and so many of our patients who are seen in the cancer center who are being evaluated for these CBC abnormalities will be detected to have these mutations. They will have undergone some risk stratification to see what the malignancy potential is. Still pretty low for many of those individuals. And so, the major driver of health outcomes for this finding may be cardiovascular. So those patients then get referred to our program. Dana-Farber also has a similar program, and then my colleague Peter Libby at the Brigham often sees those patients as well. Now for prospective screening, so far, an insurance basically is who's going to pay for it.(39:51):So an insurance provider is not deemed that appropriate yet. You do need the prospective clinical trials because the medicines that we're talking about may have side effects as well too. And what is the yield? What is the diagnostic yield? Will there actually be a large effect estimate? But there has been more and more innovation, at least on the assay and the cost part of the assay because these initial studies, we've been using whole exome sequencing, which is continuing to come down, but is not a widely routine clinical test yet. And also because as you highlighted, these are acquired mutations. A single test is not necessarily one and done. This may be something that does require surveillance for particular high risk individuals. And we've described some risk factors for the prevalence of CHIP. So surveillance may be required, but because there are about 10 genes that are primarily implicated in CHIP, that can substantially decrease the cost of it. The cost for DNA extraction is going down, and so there are research tests that are kind of in the $10 to $20 range right now for CHIP. And if flipped over to the clinical side will also be reasonably low cost. And so, for the paradigm for clinical implementation, that cost part is necessary.Eric Topol (41:10):I don't know the $10 or $20 ones. Are there any I could order on patients that I'm worried about?Pradeep Natarajan (41:17):Not yet clinical. However, there is a company that makes the reagents for at least the cores that are developing this. They are commercializing that test so that many other cores, research cores can develop it. I think it's in short order that clinical labs will adopt it as well too.Eric Topol (41:36):That's great.Pradeep Natarajan (41:37):I will keep you apprised.What About Polygenic Risk Scores?Eric Topol (41:39):I think that's really good news because like I said, we're so darn lipid centric and we have to start to respect the body of data, the knowledge that you and others have built about CHIP. Now speaking of another one that drives me nuts is polygenic risk score (PRS) for about a decade, I've been saying we have coronary disease for most people is a polygenic trait. It's not just a familial hypercholesterolemia. And we progressively have gotten better and better of the hundreds of single variants that collectively without a parental history will be and independently predict who is at double, triple or whatever risk of getting heart disease, whereby you could then guide your statins at higher aggressive or pick a statin, use one or even go beyond that as we've been talking about. But we don't use that in practice, which is just incredible because it's can be done cheap.(42:45):You can get it through whether it's 23andMe or now many other entities. We have an app, MyGeneRank where we can process that Scripss does for free. And only recently, Mass General was the first to implement that in your patient population, and I'm sure you were a driver of that. What is the reluctance about using this as an orthogonal, if you will, separate way to assess a person's risk for heart disease? And we know validated very solidly about being aggressive about lipid lowering when you know this person's in the highest 5% polygenic risk score. Are we just deadheads in this field or what?Pradeep Natarajan (43:30):Yeah, I mean Eric, as you know, lots of inertia in medicine, but this one I think has a potential to make a large impact. Like CHIP mutations, I said news is about 10% in individuals greater than 70. The prospect here is to identify the risk much earlier in life because I think there is a very good argument that we're undertreating high risk individuals early on because we don't know how to identify them. As you highlighted, Dr. Braunwald about LDL cholesterol. The other part of that paradigm is LDL cholesterol lowering and the duration. And as we said, everybody would benefit from really low LDL cholesterol, but again, you might overtreat that if you just give that to everybody. But if you can better identify the folks very early in life, there is a low cost, low risk therapy, at least related to statins that you could have a profound benefit from the ones who have a greater conviction will have future risk for cardiovascular disease.(44:21):You highlighted the family history, and the family history has given the field of clues that genetics play a role. But as the genome-wide association studies have gotten larger, the polygenic risk scores have gotten better. We know that family history is imperfect. There are many reasons why a family member who is at risk may or may not have developed cardiovascular disease. A polygenic risk score will give a single number that will estimate the contribution of genetics to cardiovascular disease. And the thing that is really fascinating to me, which is I think some of a clinical implementation challenge is that the alleles for an individual are fixed. The genotyping is very cheap. That continues to be extremely cheap to do this test. But the weights and the interpretation of what the effects should be for each of the SNPs are continually being refined over time.(45:18):And so, given the exact same SNPs in the population, the ability to better predict cardiovascular diseases getting better. And so, you have things that get reported in the literature, but literally three years later that gets outdated and those hypotheses need to be reassessed. Today, I'll say we have a great relative to other things, but we have a great polygenic risk score was just reported last year that if you compare it to familial hypercholesterolemia, which has a diagnostic yield of about 1 in 300 individuals, but readily detectable by severe hypercholesterolemia that has about threefold risk for cardiovascular disease. By polygenic risk score, you can find 1 in 5 individuals with that same risk. Obviously you go higher than that, it'll be even higher risk related to that. And that is noble information very early in life. And most people develop risk factors later in life. It is happening earlier, but generally not in the 30s, 40s where there's an opportunity to make a substantial impact on the curve related to cardiovascular disease.(46:25):But there is a lot of momentum there. Lots of interest from NIH and others. The major challenge is though the US healthcare system is really not well set up to prevention, as you know, we practice healthcare after patient's developed disease and prevent the complications related to progression. The stakeholder incentives beyond the patient themselves are less well aligned. We've talked a lot here today about payers, but we don't have a single payer healthcare system. And patients at different times of their lives will have different insurers. They'll start early in life with their parents, their first employer, they'll move on to the next job and then ultimately Medicare. There's no entity beyond yourself that really cares about your longevity basically from the beginning and your overall wellness. That tension has been a major challenge in just driving the incentives and the push towards polygenic risk scores. But there are some innovative approaches like MassMutual Life Insurance actually did a pilot on polygenic risk scoring.(47:33):They're in the business of better understanding longevity. They get that this is important data. Major challenges, there are federal protections against non-discrimination in the workplace, health insurance, not necessarily life insurance. So I think that there are lots of things that have to be worked out. Everybody recognizes that this is important, but we really have to have all the incentives aligned for this to happen at a system-wide level in the US. So there's actually lots of investment in countries that have more nationalized healthcare systems, lots of development in clinical trials in the UK, for example. So it's possible that we in the US will not be the lead in that kind of evidence generation, but maybe we'll get there.The GLP-1 DrugsEric Topol (48:16):Yeah, it's frustrating though, Pradeep, because this has been incubating for some time and now we have multi ancestry, polygenic risk scores, particularly for heart disease and we're not using it, and it's not in my view, in the patient's best interest just because of these obstacles that you're mentioning, particularly here in the US. Well, the other thing I want to just get at with you today is the drugs that we were using for diabetes now blossoming for lots of other indications, particularly the glucagon-like peptide 1 (GLP-1) drugs. This has come onto the scene in recent years, not just obviously for obesity, but it's anti-inflammatory effects as we're learning, mediated not just through the brain but also T cells and having extraordinary impact in heart disease for people with obesity and also with those who have heart failure, about half of heart failure for preserved ejection fraction. So recently you and your colleagues recently published a paper with this signal of optic neuropathy. It was almost seven eightfold increase in a population. First, I wanted to get your sense about GLP-1. We're also going to get into the SGLT2 for a moment as well, but how do you use GLP-1? What's your prognosis for this drug class going forward?Pradeep Natarajan (49:55):As it relates to the paper, I can't claim credit as one of my former students who is now Mass Eye and Ear resident who participated, but we can talk about that. There's obviously some challenges for mining real world data, but this was related to anecdotes that they were observing at Mass Eye and Ear and then studied and observed an enrichment. In general though, I feel like every week I'm reading a new clinical trial about a new clinical outcome benefit as it relates to GLP-1 receptor agonists. This is kind of one thing that stands out that could be interrogated in these other clinical trials. So I would have that caveat before being cautious about ocular complications. But the data has been overwhelmingly beneficial, I think, because at minimum, obesity and inflammation are relayed to myriad of consequences, and I'm really excited that we have therapies that can address obesity that are safe.(50:52):There's a legacy of unsafe medicines for obesity, especially related to cardiovascular disease. So the fact that we have medicines that are safe and effective for lowering weight that also have real strong effects on clinical outcomes is tremendous. We in cardiology are increasingly using a range of diabetes medicines, including GLP-1 receptor agonists and SGLT2 inhibitors. I think that is also the secular changes of what influences cardiovascular disease over time. I talked about over the last 10 years or so with this increase in deaths attributable to cardiovascular disease. If you look at the influences of traditional clinical risk factors today, many of them have decreased in importance because when abnormal, we recognize them, in general we modify them when recognized. And so, many of the things that are unaddressed, especially the features related to insulin resistance, obesity, they start rising in importance. And so, there is a dramatic potential for these kinds of therapies in reducing the residual risks that we see related to cardiovascular disease. So I'm enthusiastic and excited. I think a lot more biology that needs to be understood of how much of this is being influenced specifically through this pathway versus a very effective weight loss medicine. But also interesting to see the insights on how the effect centrally on appetite suppression has profound influences on weight loss as well too. And hopefully that will lead to more innovations in weight management.The SGLT-2 DrugsEric Topol (52:25):And likewise, perhaps not getting near as much play, but when it came on the cardiovascular scene that an anti-diabetic drug SGLT2 was improving survival, that was big, and we still don't know why. I mean, there's some ideas that it might be a senolytic drug unknowingly, but this has become a big part of practice of cardiology in patients with diabetes or with preserved ejection fraction heart failure. Is that a fair summary for that drug?Pradeep Natarajan (53:00):Yeah, I totally agree. I mean, as there has been increased recognition for heart failure preserved ejection fraction, it has been almost disheartening over the last several years that we have not had very specific effective therapies to treat that condition. Now, it is a tremendous boon that we do have medicines interestingly focused on metabolism that are very helpful in that condition for heart failure with preserved ejection fraction. But there is still much more to be understood as far as that condition. I mean, the major challenge with heart failure, as you know, especially with heart failure preserved ejection fraction, it likely is a mix of a wide variety of different etiologies. So in parallel with developing effective therapies that get at some aspect is really understanding what are the individual drivers and then targeting those specific individual drivers. That requires a lot of unbiased discovery work and further profiling to be done. So lot more innovation, but relative to heart failure itself, it is not had widespread recognition as heart failure reduced ejection fraction. So much more to innovate on, for sure.Eric Topol (54:07):Right, right. Yeah, I am stunned by the recent progress in cardiovascular medicine. You have been center stage with a lot of it, and we've had a chance to review so much. And speaking of genetics, I wanted to just get a little insight because I recently came across the fact that your mother here at the City of Hope in Southern California is another famous researcher. And is that, I don't know what chromosome that is on regarding parental transmission of leading research. Maybe you can tell me about that.Pradeep Natarajan (54:41):Yeah, I mean, I guess it is a heritable trait when a parent has one profession that there is a higher likelihood that the offspring will have something similar. So both of my parents are PhDs, nonphysicians. There is a diabetes department at the City of Hope, so she's the chair of that department. So very active. We do overlap in some circles because she does investigate both vascular complications and renal complications. And then sometimes will ask my advice on some visualization. But she herself has just had a science translational medicine paper, for example, just a couple of months ago. So it's fun to talk about these things. To be honest, because my parents are researchers, I was not totally sure that I would be a researcher and kind of wanted to do something different in medicine. But many of my early observations and just how common cardiovascular disease is around me and in my community and wanting to do something useful is what got me specifically into cardiology.(55:45):But obviously there are numerous outstanding, important questions. And as I went through my career, really focused on more basic investigations of atherosclerosis and lipids. What got me excited sort of after my clinical training was the ability to ask many of these questions now in human populations with many new biological data sets, at least first centered on genetics. And the capabilities continue to expand, so now I teach first year Harvard medical students in their genetics curriculum. And when I talk to them just about my career arc, I do remind them they're all doing millions of things and they're exploring lots of things, but when they get to my shoes, the capabilities will be tremendously different. And so, I really advise them to take the different experiences, mainly in an exercise for asking questions, thoughtfully addressing questions, connecting it back to important clinical problems. And then once they start to understand that with a few different approaches, then they'll totally take off with what the opportunities are down the road.Eric Topol (56:51):No, it's great. I mean, how lucky somebody could be in the first year of med school with you as their teacher and model. Wow. Pradeep, we've really gone deep on this and it's been fun. I mean, if there's one person I'm going to talk to you about cardiovascular risk factors and the things that we've been into today, you would be the one. So thank you for taking the time and running through a lot of material here today, and all your work with great interest.Pradeep Natarajan (57:24):Thanks, Eric. I really appreciate it. It's tremendous honor. I'm a big fan, so I would be glad to talk about any of these things and more anytime.***************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Ben Zimmer, CEO of Priovant Therapeutics, focuses on developing therapies for rare autoimmune diseases specifically dermatomyositis, which affects the skin, muscles, and organs, and non-infectious uveitis, a severe ocular inflammatory condition. While these conditions are symptomatically different, mechanistically, they have features in common related to the underlying pathology of the diseases. The drug in development is an oral once-daily therapy that addresses the inflammatory conditions and cytokines driving the pathology. Ben explains, "During COVID, there was a lot of talk about the cytokine storm and these are molecules involved in immune cell signaling. So, they're basically ways that different types of immune cells signal to each other to do different things. There's a large variety of different cytokines and some autoimmune diseases. There are only maybe one or two cytokines or a small number that are driving the pathology of the disease."   "Both dermatomyositis and non-infectious uveitis are highly inflammatory conditions with a lot of different pathogenic cytokines, a lot of different inflammatory axes involved. And so, one of the neat things about our drug, brepocitinib, is that it works on a set category of enzymes called JAKs, and then there are four different types of JAKs, JAK1, JAK2, JAK3, and you might guess JAK4, but it's actually called TYK2. And our drug inhibits TYK2 and JAK1. And by doing that, it suppresses the signaling of a large number of different cytokines." "Uveitis and dermatomyositis have a number of overlapping pathogenic cytokines involved, as well as some different cytokines, but they are both suppressed through the inhibition of TYK2 and JAK1, which our drug does. So, our thesis is to find these highly inflammatory indications, highly inflammatory diseases with high morbidity, which can be expressed in many different organ systems." #PriovantTherapeutics #RareDisease #OrphanIndication #Uveitis #NIU #Dermatomyositis #JAK1 #TYK2 priovanttx.com  Download the transcript here

Ben Zimmer, CEO of Priovant Therapeutics, focuses on developing therapies for rare autoimmune diseases specifically dermatomyositis, which affects the skin, muscles, and organs, and non-infectious uveitis, a severe ocular inflammatory condition. While these conditions are symptomatically different, mechanistically, they have features in common related to the underlying pathology of the diseases. The drug in development is an oral once-daily therapy that addresses the inflammatory conditions and cytokines driving the pathology. Ben explains, "During COVID, there was a lot of talk about the cytokine storm and these are molecules involved in immune cell signaling. So, they're basically ways that different types of immune cells signal to each other to do different things. There's a large variety of different cytokines and some autoimmune diseases. There are only maybe one or two cytokines or a small number that are driving the pathology of the disease."   "Both dermatomyositis and non-infectious uveitis are highly inflammatory conditions with a lot of different pathogenic cytokines, a lot of different inflammatory axes involved. And so, one of the neat things about our drug, brepocitinib, is that it works on a set category of enzymes called JAKs, and then there are four different types of JAKs, JAK1, JAK2, JAK3, and you might guess JAK4, but it's actually called TYK2. And our drug inhibits TYK2 and JAK1. And by doing that, it suppresses the signaling of a large number of different cytokines." "Uveitis and dermatomyositis have a number of overlapping pathogenic cytokines involved, as well as some different cytokines, but they are both suppressed through the inhibition of TYK2 and JAK1, which our drug does. So, our thesis is to find these highly inflammatory indications, highly inflammatory diseases with high morbidity, which can be expressed in many different organ systems." #PriovantTherapeutics #RareDisease #OrphanIndication #Uveitis #NIU #Dermatomyositis #JAK1 #TYK2 priovanttx.com  Listen to the podcast here

Use AI to Speed up Your Work Flow Ethically and Securely. There are lots of courses on AI out there, but this one is specific only to medical writing and editing.  Access the AIMWE course waitlist. https://www.learnamastyle.com/waitlist/ Leqselvi for Alopecia Areata: The FDA has approved deuruxolitinib (Leqselvi) as a first-line treatment for adults with moderate to severe alopecia areata (AA). Developed by Sun Pharma, this oral selective inhibitor of Janus kinases JAK1 and JAK2 is typically dosed at 8 mg twice daily. The approval, based on the THRIVE-AA1 and THRIVE-AA2 trials, marks an important addition to limited treatment options for AA, which has significant psychological impacts. Femlyv Dissolvable Birth Control: The FDA has approved norethindrone acetate and ethinyl estradiol (Femlyv) as an oral dissolvable birth control pill, expanding access for those who have difficulty swallowing. This form of hormonal birth control, in use since 1968 as a swallowable tablet, also helps manage conditions like endometriosis and PMDD. The approval, based on a study of 743 women, offers a new option with common side effects like headache and nausea. Brineura for Batten Disease: The FDA has expanded the indication for cerliponase alfa (Brineura) to treat neuronal ceroid lipofuscinosis type 2 (CLN2 disease) in children under 3 years of age. Developed by BioMarin Pharmaceutical, this enzyme replacement therapy, initially approved in 2017, is administered by infusion into the brain. The expanded approval was based on a phase 2 trial showing reduced motor function decline and delayed disease onset. Erzofri for Schizophrenia: The FDA has approved paliperidone palmitate (Erzofri) extended-release injectable suspension for treating schizophrenia and schizoaffective disorder in adults. This long-acting injectable (LAI) antipsychotic, administered once a month, improves patient adherence by reducing dosing frequency. Developed by Luye Pharma Group, it was granted a U.S. patent in 2023 and approved under the 505(b)(2) pathway. Eque-cel for MS: The FDA has approved the IND application for equecabtagene autoleucel (Eque-cel) for treating multiple sclerosis (MS). Developed by IASO Biotechnology, this chimeric antigen receptor autologous T cell injection showed promising efficacy in six autoimmune diseases in a Chinese trial. MS, affecting 3.07 million people worldwide, is characterized by CNS demyelination and neuronal injury, with Eque-cel offering a new treatment option. Spravato for TRD: Johnson & Johnson has submitted an sNDA for esketamine (Spravato) as a monotherapy for adults with treatment-resistant depression (TRD). Already approved in combination with an oral antidepressant, esketamine is an NMDA receptor antagonist that rapidly alleviates depressive symptoms. The submission is based on Phase 4 TRD4005 study results, showing rapid improvement in depression scores with a consistent safety profile. ZW191 Anti-Tumor Agent: The FDA has cleared the IND application for ZW191, a novel antibody-drug conjugate (ADC) targeting folate receptor alpha (FR⍺) in cancers like gynecologic and NSCLC. Developed by Zymeworks, this TOPO1i ADC uses a novel payload, ZD06519, showing robust antitumor activity and a tolerable safety profile in preclinical models. Clinical development of ZW191 is planned to begin in the second half of 2024.

Jak II (Review) #jak2 #jak&daxter #gamereview link- https://youtu.be/E4NFhDRMfik HEY GUYS BACK AGAIN FOR ANOTHER VIDEO CHECK IT OUT. ANY AND ALL COPY RIGHTS AND ARTWORK BELONG TO THERE RESPECTFUL OWNERS LINKS DOWN BELOW http://gamsterindustries1.wixsite.com... https://twitter.com/Gamsterwolf92 https://www.facebook.com/Gamster92 https://www.instagram.com https://anchor.fm/gamster-world

Tue, 11 Jun 2024 22:00:00 +0000 https://einfach-beten.podigee.io/289-neue-episode a7e344c5d5558e036f8630851b735fec Für Migranten, die ihre Heimat verlassen mussten. Click to Pray Monatliches Gebet: Liebender Vater, Du nimmst deine Söhne und Töchter auf. Heute bitten wir dich für die Menschen, die vor Krieg und Hunger fliehen. Mögen sie in ihren Aufnahmeländern Akzeptanz und neue Möglichkeiten finden. Denn Gastfreundschaft ist ein Ausdruck der Liebe, jener Dynamik der Offenheit, die uns anspornt, dem anderen Aufmerksamkeit zu schenken, um das Beste für sein Leben zu suchen. Aber wir wissen, dass Migranten als Menschen angesehen werden, die nichts zu bieten haben und das führt zu der vereinfachenden Annahme, dass die Armen gefährlich und nutzlos sind, während die Mächtigen großzügige Wohltäter sind. Lehre uns, eine Kirche zu sein, die ein "Feldlazarett" ist, die stets versucht, andere Menschen besser willkommen zu heißen, eine Willkommenskultur, die schützt und integriert, fördert. Hilf uns, eine offene Welt zu denken und zu entwickeln, nicht die Nützlichkeit der Person zu beurteilen, sondern den Wert in sich zu sehen, den der Mensch darstellt. Hilf, dass die verschiedenen Länder der Welt in der Lage sind, nicht nur als einzelne Länder, sondern auch als Teil der Menschheitsfamilie zu denken, denn nur eine soziale und politische Kultur, die unentgeltliche Akzeptanz beinhaltet, kann eine Zukunft haben. Amen. Aus zu aus einer Ansprache des Papstes In seiner Botschaft zum 105. Welttag des Migranten und Flüchtlings sagte Papst Franziskus: “Es geht nicht nur um Migranten: Es geht auch um unsere Ängste. Die Bosheiten und Widerwärtigkeiten unserer Zeit lassen »unsere Angst vor den „anderen“ wachsen, den Unbekannten, den Ausgegrenzten, den Fremden […] Und das zeigt sich in der heutigen Zeit besonders deutlich angesichts der Ankunft von Migranten und Flüchtlingen, die auf der Suche nach Schutz, Sicherheit und einer besseren Zukunft an unsere Tür klopfen. Das Problem ist nicht, dass wir Zweifel und Ängste haben. Das Problem ist, dass diese unsere Denk- und Handlungsweise so weit konditionieren, dass sie uns intolerant, verschlossen und vielleicht sogar – ohne dass wir es merken – rassistisch machen. Und so beraubt uns die Angst des Wunsches und der Fähigkeit, dem anderen, dem Menschen, der sich von mir unterscheidet, zu begegnen; sie beraubt mich einer Möglichkeit, dem Herrn zu begegnen. (…) Es geht nicht nur um Migranten: Es geht um Nächstenliebe. Durch Werke der Liebe zeigen wir unseren Glauben (vgl. Jak2,18). Und die höchste Form der Nächstenliebe ist diejenige, die denen gegenüber praktiziert wird, die nichts zurückgeben und vielleicht nicht einmal danken können. (…) Es geht nicht nur um Migranten: Es geht um unsere Menschlichkeit. Das Mitleid berührt den sensibelsten Bereich unserer Menschlichkeit und weckt den Drang, denjenigen „zu Nächsten zu werden“, die wir in Schwierigkeiten sehen. Wie Jesus selbst uns lehrt (vgl. Mt 9,35-36; 14,13-14; 15,32-37), bedeutet Mitleid, das Leiden anderer wahrzunehmen und unverzüglich Maßnahmen zur Linderung, Heilung und Rettung zu ergreifen. Mitleid zu haben bedeutet, der Zärtlichkeit Raum zu geben, die zu unterdrücken die heutige Gesellschaft so oft von uns verlangt. (…) Liebe Brüder und Schwestern, die Antwort auf die Herausforderung der gegenwärtigen Migration lässt sich in vier Verben zusammenfassen: aufnehmen, schützen, fördern und integrieren. Aber diese Verben gelten nicht nur bezüglich der Migranten und Flüchtlinge. Sie drücken die Sendung der Kirche zu den Menschen an den Rändern der Existenz aus, die aufgenommen, geschützt, gefördert und integriert werden müssen. Wenn wir diese Verben in die Praxis umsetzen, tragen wir zum Aufbau der Stadt Gottes und des Menschen bei, fördern wir die ganzheitliche menschliche Entwicklung jedes Einzelnen und helfen auch der Weltgemeinschaft, den Zielen nachhaltiger Entwicklung näher zu kommen, die sie sich gesetzt hat und die sonst schwer zu erreichen sein werden. Deshalb geht es nicht nur um die Sache der Migranten, es geht nicht nur um sie, sondern um uns alle, um die Gegenwart und die Zukunft der Menschheitsfamilie. Die Migranten, insbesondere die am meisten Schutzbedürftigen, helfen uns, die „Zeichen der Zeit“ zu erkennen. Durch sie ruft uns der Herr zur Bekehrung auf. Er ruft uns auf, uns vom Exklusivismus, der Gleichgültigkeit und der Wegwerfmentalität zu befreien. Durch diese Menschen lädt der Herr uns ein, unser christliches Leben in seiner Gesamtheit wiederaufzunehmen und – jeder entsprechend seiner eigenen Berufung – zum Aufbau einer Welt beizutragen, die immer mehr dem Plan Gottes entspricht.” full no Jesuiten in Zentraleuropa

In this episode, we discuss the diagnosis and management of Essential Thrombocythemia with Dr. Raajit Rampal. Here are the shownotes:1.     IPSET (revised) system, risk categories are defined by the presence of a prior thrombosis, age, and JAK2 mutation status:·        Very low risk: No prior thrombosis, age ≤60 years, JAK2-unmutated·        Low risk: No prior thrombosis, age ≤60 years, JAK2-mutated·        Intermediate risk: No thrombosis, age >60 years, JAK2-unmutated·        High risk: History of thrombosis (any age/genotype), or age >60 years with JAK2 mutationhttps://ashpublications.org/blood/article/120/26/5128/30914/Development-and-validation-of-an-International                      2.    The MIPSS-ET provides points for:·        Age > 60 years (3 points)·        Adverse mutation (SF3B1/SRSF2/U2AF1/TP53) (2 points)·        Male sex (1 point)·        White blood cell count ≥11 × 10^9/L (1 point)·        https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16380?sid=nlm%3Apubmed 3.    Aspirin o   Is there a benefit of twice-daily aspirin dosing, especially in high-risk or JAK2-mutant disease?https://ashpublications.org/blood/article/136/2/171/454293/A-randomized-double-blind-trial-of-3-aspirin 4.     Cytoreduction in High-risk ET Hydroxyurea: https://www.nejm.org/doi/full/10.1056/NEJM199504273321704 Pegylated interferon alfa MPD-RC 112 Mascarenhas J et al. A randomized phase 3 trial of interferon- α vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood . 2022) https://ashpublications.org/blood/article/139/19/2931/483404/A-randomized-phase-3-trial-of-interferon-vs Anagrelide in EThttps://ashpublications.org/blood/article/121/10/1720/31186/Anagrelide-compared-with-hydroxyurea-in-WHO 5.    Ruxolitinib  In a randomized study phase 2 study (MAJIC-ET), ruxolitinib treatment did not deliver better rates of hematological response than best-available therapy, although symptoms did improve.  ·        MAJIC-ET study which is a randomized phase 2 trial ·        ET patients resistant/intolerant to HU were randomized to receive RUX or standard treatment (HU 71%, anagrelide 48%, IFN 40%). The primary study outcome was CR, defined by normal platelet and white cell counts and normal spleen size.  ·        At 1 year, response was achieved in 46% of patients in the RUX group and in 44% in the standard arm, without statistically significant difference between the two groups.  ·        In addition, no difference was observed in the rates of thrombosis, hemorrhage, and disease transformation after 2 years of follow-up.  ·        MRs were also uncommon. RUX was superior, however, in symptom control. https://ashpublications.org/blood/article/130/17/1889/36509/Ruxolitinib-vs-best-available-therapy-for-ET

Featuring perspectives from Dr Stephen T Oh, including the following topics: Introduction: ASH 2023 Update (0:00)  Case: A woman in her early 70s with symptomatic primary myelofibrosis (MF) receives ruxolitinib — Rao Mushtaq, MD (15:41) Case: A woman in her late 60s, a Jehovah's Witness with multiple comorbidities, presents with splenomegaly and anemia and is diagnosed with primary MF — Bhavana (Tina) Bhatnagar, DO (27:16) Case: A woman in her mid 70s who received pacritinib for 4 years on trial now experiences disease progression with massive splenomegaly and thrombocytopenia (20K-30K) — Neil Morganstein, MD (31:50) Case: A woman in her late 50s with symptomatic primary MF has normal cytogenetics and JAK2 and DNMT3A mutations — Jeanne Palmer, MD (35:45) Case (continued): A woman in her late 50s has progressive MF after ruxolitinib and fedratinib; repeat next-generation sequencing shows JAK2, DNMT3A, IDH2 and TET2 mutations — Dr Palmer (41:09) Case: A woman in her late 60s with primary MF who discontinued ruxolitinib due to onset of congestive heart failure now has possible acute myeloid leukemia transformation — Dr Bhatnagar (50:38) Case: A woman in her late 60s with well controlled MF who has received 10 mg of ruxolitinib twice a day for 3 years develops increasing anemia and splenomegaly — Dr Palmer (52:38) CME information and select publications

BUFFALO, NY- February 7, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma.” In this new paper, researchers Ashley Del Dosso, Elizabeth Tadevosyan, and James R. Berenson from ONCOtherapeutics, Berenson Cancer Center, and Institute for Myeloma and Bone Cancer Research discussed multiple myeloma (MM) — the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM. “The following sections of this article will be focused on studies of RUX [Ruxolitinib] in the preclinical [21–24] and clinical settings [18–20] focused on the treatment of relapsed/refractory (RR) MM.” DOI - https://doi.org/10.18632/oncotarget.28547 Correspondence to - James R. Berenson - jberenson@berensoncancercenter.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28547 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, multiple myeloma, ruxolitinib, JAK/STAT, cytokine, clinical trial About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, 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 Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.20.521329v1?rss=1 Authors: Doggett, K., Keating, N., Dehkhoda, F., Bidgood, G. M., Leong, E., Kueh, A., Nicola, N. A., Kershaw, N. J., Babon, J. J., Alexander, W. S., Nicholson, S. E. Abstract: Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and structural studies have suggested that the SOCS1 kinase inhibitory region (KIR) and Src homology 2 (SH2) domain are important for interaction with and inhibition of the receptor-associated JAK1, JAK2 and Tyk2 tyrosine kinases, which initiate downstream signaling. To investigate the role of the KIR and SH2 domain in SOCS1 function, we independently mutated key conserved residues in each domain and analysed the impact on cytokine signaling, and the in vivo impact on SOCS1 function. Mutation of the SOCS1-KIR or SH2 domain had no impact on the integrity of the SOCS box complex, however, mutation within the phosphotyrosine binding pocket of the SOCS1-SH2 domain specifically disrupted SOCS1 interaction with phosphorylated JAK1. In contrast, mutation of the KIR did not affect the interaction with JAK1, but did prevent SOCS1 inhibition of JAK1 autophosphorylation. In human and mouse cell lines, both mutants impacted the ability of SOCS1 to restrain cytokine signaling, and crucially, Socs1-R105A and Socs1-F59A mice displayed a neonatal lethality and excessive inflammatory phenotype similar to SOCS1 null mice. This study defines a critical and non-redundant role for both the KIR and SH2 domain in endogenous SOCS1 function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Listen as Gabriela Hobbs, MD, clinical director of the leukemia atMass General, talks with Bob Figlin, MD, the Steven Spielberg Family Chair in Hematology Oncology at Cedars-Sinai Cancer in Los Angeles, about the latest progress in the treatment of myelofibrosisand how she both assesses new patients and plans their treatment. New agents, including JAK2 inhibitors,are not curative but can have substantial effects on patients and open up further treatment options. Dr. Hobbs also talks about new drug classes on the horizon and what to expect at the upcoming ASH meeting.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.19.508592v1?rss=1 Authors: Li, F., Oh, I., Kumar, S., Eteleeb, A., Gupta, A., Buchser, W., Xiong, C., Cole, S. F., McDade, E., Karch, C., Harari, O., Payne, P. R., Cruchaga, C. Abstract: The risk of Alzheimer's disease (AD) in women is about 2 times greater than in men. The estrogen hypothesis is being accepted as the essential sex factor causing the sex difference in AD. Also, the recent meta-analysis using large-scale medical records data indicated estrogen replacement therapy. However, the underlying molecular targets and mechanisms explaining this sex difference in AD disease development remain unclear. In this study, we identified that estrogen treatment can strongly inhibition of neuro-inflammation signaling targets, using the systems pharmacology model; and identified ESR1/ESR2 (the receptors of estrogen) are topologically close to the neuroinflammation biomarker genes using signaling network analysis. Moreover, the estrogen level in women decreased to an extremely lower level than in men after age 55. Pooling together the multiple pieces of evidence, it is concluded that the loss of estrogen unleashing neuro-inflammation increases the women's risk of Alzheimer's disease. These analysis results provide novel supporting evidence explaining the potential mechanism of the anti-neuroinflammation role of estrogen causing the sex difference of AD. Medications boosting the direct downstream signaling of ESR1/ESR2, or inhibiting upstream signaling targets of neuroinflammation, like JAK2 inhibitors, on the signaling network can be potentially effective or synergistic combined with estrogen for AD prevention and treatment. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.19.508592v1?rss=1 Authors: Li, F., Oh, I., Kumar, S., Eteleeb, A., Gupta, A., Buchser, W., Xiong, C., Cole, S. F., McDade, E., Karch, C., Harari, O., Payne, P. R., Cruchaga, C. Abstract: The risk of Alzheimer's disease (AD) in women is about 2 times greater than in men. The estrogen hypothesis is being accepted as the essential sex factor causing the sex difference in AD. Also, the recent meta-analysis using large-scale medical records data indicated estrogen replacement therapy. However, the underlying molecular targets and mechanisms explaining this sex difference in AD disease development remain unclear. In this study, we identified that estrogen treatment can strongly inhibition of neuro-inflammation signaling targets, using the systems pharmacology model; and identified ESR1/ESR2 (the receptors of estrogen) are topologically close to the neuroinflammation biomarker genes using signaling network analysis. Moreover, the estrogen level in women decreased to an extremely lower level than in men after age 55. Pooling together the multiple pieces of evidence, it is concluded that the loss of estrogen unleashing neuro-inflammation increases the women's risk of Alzheimer's disease. These analysis results provide novel supporting evidence explaining the potential mechanism of the anti-neuroinflammation role of estrogen causing the sex difference of AD. Medications boosting the direct downstream signaling of ESR1/ESR2, or inhibiting upstream signaling targets of neuroinflammation, like JAK2 inhibitors, on the signaling network can be potentially effective or synergistic combined with estrogen for AD prevention and treatment. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Featuring perspectives from Drs Andrew Armstrong, Alan Bryce and Alicia Morgans, including the following topics: Introduction (0:00) Case: A man in his early 70s with DIPSS low- to intermediate-risk post-essential thrombocythemia myelofibrosis (MF) — Warren S Brenner, MD (5:29) Case: A woman in her late 60s with primary MF who experiences disease progression after 3 years of ruxolitinib — Jeanne Palmer, MD (17:19) Case: A woman in her late 60s with disease progression after multiple regimens for post-polycythemia vera MF — Neil Morganstein, MD (30:51) A woman in her late 70s with post-PV MF with a JAK2 V617F mutation and transfusion dependence — Bhavana (Tina) Bhatnagar, DO (39:33) Case: A man in his mid 60s with primary MF with a JAK2 mutation and recurrent herpes zoster reactivation on ruxolitinib — Niyati A Nathwani, MD (50:23) Case: A man in his early 70s with prefibrotic primary MF with a JAK2 mutation and ruxolitinib-associated HPV reactivation — Susannah Friemel, MD (53:36) Case: A man in his early 20s with myeloproliferative neoplasm with a JAK2 V617F mutation and thrombocytosis — Rajni Sinha, MD, MRCP (57:16) CME information and select publications

Featuring perspectives from Dr John Mascarenhas, including the following topics: Introduction (0:00) Case: A man in his mid 60s with post-PV myelofibrosis (MF) and ASXL1 and SRSF2 mutations — Jeanne Palmer, MD (22:40) Case: A woman in her early 70s with high-risk primary MF and a CALR mutation (28:34) Case: A woman in her mid 70s with primary MF with a JAK2 V617F mutation — Bhavana (Tina) Bhatnagar, DO (40:24) Case: A woman in her early 50s with secondary MF with a JAK2 mutation — G Richard Polkinghorn, MD (43:30) Case: A woman in her mid 80s with primary MF with an MPL mutation — Warren S Brenner, MD (47:01) Case: A woman in her mid 80s with JAK2 mutation-positive primary MF with ASXL1 and U2F2 mutations with severe anemia — Neil Morganstein, MD (53:01) Case: A woman in her mid 80s with MF with a JAK2 mutation and severe anemia — Paul Markowski, MD (56:44) CME information and select publications

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Go online to PeerView.com/CCT860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in dermatology discuss the role of the JAK/STAT pathway in psoriasis, as well as treatment with novel kinase inhibitors for the management of patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe and differentiate targeting of the TYK2, JAK1, JAK2, and JAK3 kinases and the correlation to emerging therapies for the treatment of moderate to severe psoriasis, Summarize recent efficacy and safety data for current and emerging therapies for the treatment of moderate to severe psoriasis, Recommend treatment for patients with moderate to severe psoriasis according to the latest guidelines and clinical evidence, particularly as emerging therapies become available.

Thank you for joining us for our 2nd Cabral HouseCall of the weekend! I'm looking forward to sharing with you some of our community's questions that have come in over the past few weeks…   Jessica: Hi! I'm a 31 yo female. Overall healthy. I developed a rash when I was about 19 that has been biopsied multiple times. Initial few showed generalized inflammation but nothing specific. The most recent was concerning for cutaneous T-cell lymphoma. The physician I saw still decided to label it "parapsoriasis," because "he didn't want to put lymphoma in my chart." Labs have always normal and show no blood involvement. Treatment options are topical steroids (which keep it at bay but have never cleared it completely) and light therapy (which I never had time to commit to 3x per week with work, so I try to get sunlight on my trunk as often as possible). There's not much data I can find from a FM perspective - maybe some data to show clustering of cases which could indicate an environmental trigger. Any suggestions on what the root cause of this could be and options for FM treatments?   Douglas: Hi there! Love all the knowledge you share and I have learned so much from the labs and your podcasts. Thank you for the noble mission you are on. Your life's work is truly inspiring. For the last eight months I have been taking your DNS and Crisp Apple Green supplements. Both are outstanding. So I have a brain injury, 6-7 concussion in my life, low elastase with my pancreas, am 6'5” and 230 pounds. Based on the labs, Ive done a mold detox and cleanse protocol and am feeling like I have more energy. Currently am doing the Healing Gut protocol. For the longest time (20 years) I have been a light weight when drinking any kind of alcohol. I drink maybe a glass of wine or cocktail once a month at most. I instantly feel sleepy when I have a glass. I cant even drink a whole glass sometime as i have the sensation its after midnight and I should be asleep. I do not intend to want to drink more should I fix this, I just want to know in case there is something unhealthy with my body such as missing a key enzyme. What are your thoughts? Thanks! Douglas   Angie: Hello Dr. Cabral! Thank you for all you do, you are truly inspiring! I was diagnosed with hypothyroidism after the birth of my son (the same day I gave birth). I had a miscarriage 3 1/2 years later and was diagnosed with essential thrombocythemia. It's an uncommon disorder with no cure according to my hematologist. I do not have the JAK2 gene mutation but I do have a “less severe” gene mutation that somehow became activated. I did not always have these disorders and was curious if you could make any recommendations on how I can bring my body back into balance for these conditions. I've been seeing a naturopath since I was diagnosed with hypothyroidism and I recently asked her about leaky gut and if there were tests we could run but she wasn't interested in running tests (told me to do a low fodmap diet instead). I'm meeting with a Functional doctor next week and hopefully she will be more open to running tests. In the past I had a food sensitivity test and I'm sensitive to a huge list of foods (top foods are wheat and eggs). I had a hormone test a few years back as well and my progesterone is low and my testosterone is barely registering. Lately I've been very bloated and gassy even when following the low fodmap food list. Thanks so much!! Angie   Thomas: Hey Dr Cabral! I've been listening to your podcasts for about 4 years and share as much of this knowledge as I can remember with others. My wife in particular has experienced more balanced hormones and a better sense of awareness all from your teachings. You are the a saviour and we can't thank you enough. One mystery that I can't seem to pinpoint is her coughing after eating (any meal, spicy, sweet, or salty). Even if it's just cooked vegetables with no oil and very light seasoning. Could eating really cause coughing or do you think it's just a very broad food allergy?   Justin: I've been taking 1 teaspoon of baking soda mixed in 4 to 5 ounces of water almost nightly for the past year. I had heard it keeps you from having to get up frequently to urinate, which has been an issue for me. I also heard that it was good for your kidneys. Sometimes it seems like it helped with frequent urination, and other times not. However I recently heard that frequent consumption of baking soda can neutralize stomach acids, causing a host of problems. What are the benefits of baking soda, and what would be the best dosage for the average person?   Patti: Thank you for significantly helping both myself & my son to live a better life & your team for being so responsive, & helpful. I just listened to the podcast where you answered a question on a hip replacement. What are your thoughts on cortizone shots for pain? Also, antibiotics are recommended for dental work after a joint replacement. What are alternatives? Thank you!   Thank you for tuning into this weekend's Cabral HouseCalls and be sure to check back tomorrow for our Mindset & Motivation Monday show to get your week started off right! - - - Show Notes and Resources: StephenCabral.com/2305 - - - Get a FREE Copy of Dr. Cabral's Book: The Rain Barrel Effect - - - Join the Community & Get Your Questions Answered: CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - Get Your Question Answered On An Upcoming HouseCall: StephenCabral.com/askcabral - - - Would You Take 30 Seconds To Rate & Review The Cabral Concept? The best way to help me spread our mission of true natural health is to pass on the good word, and I read and appreciate every review!

Featuring perspectives from Professor Claire Harrison, including the following topics: Introduction (0:00) Case: A man in his early 70s with DIPSS low- to intermediate-risk post-essential thrombocythemia myelofibrosis (MF) — Warren S Brenner, MD (5:29) Case: A woman in her late 60s with primary MF who experiences disease progression after 3 years of ruxolitinib — Jeanne Palmer, MD (17:19) Case: A woman in her late 60s with disease progression after multiple regimens for post-polycythemia vera MF — Neil Morganstein, MD (30:51) A woman in her late 70s with post-PV MF with a JAK2 V617F mutation and transfusion dependence — Bhavana (Tina) Bhatnagar, DO (39:33) Case: A man in his mid 60s with primary MF with a JAK2 mutation and recurrent herpes zoster reactivation on ruxolitinib — Niyati A Nathwani, MD (50:23) Case: A man in his early 70s with prefibrotic primary MF with a JAK2 mutation and ruxolitinib-associated HPV reactivation — Susannah Friemel, MD (53:36) Case: A man in his early 20s with myeloproliferative neoplasm with a JAK2 V617F mutation and thrombocytosis — Rajni Sinha, MD, MRCP (57:16) CME information and select publications

News: Scientists Say New Treatment Lets Alopecia Patients Regrow Hair | Futurism (01:14) Scientists at Yale announced this week that a common arthritis medication (baricitinib) appears to help alopecia patients regrow their hair. a potential treatment for a widespread autoimmune condition. Baricitinib is used to reduce pain, stiffness, and swelling in adults with rheumatoid arthritis after other treatments have failed. Helps slow the progression of bone and joint damage. It is a Janus kinase (JAK) inhibitor  Janus kinase (JAK) inhibitors are a group of medications that inhibit activity and response of one or more of the Janus kinase enzymes (JAK1, JAK2, JAK3, and TYK2). These enzymes normally promote inflammation and autoimmunity. Alopecia is a common autoimmune disorder that causes hair loss Affects people of all ages, although it most commonly appears in adolescence or early adulthood.  Affects 1 in every 500 to 1,000 people in the United States. There is currently no FDA-approved treatment for the disease. Dr. Brett King, lead author on the study told Yale news:“This is so exciting, because the data clearly show how effective baricitinib is … These large, controlled trials tell us that we can alleviate some of the suffering from this awful disease.” For the study, the researchers conducted two large, randomized trials involving a total of 1,200 people. For 36 weeks, participants were given a daily dose of either 4 milligrams of baricitinib, 2 milligrams of baricitinib, or a placebo. One-third of the patients who received the larger dose grew hair back. The researchers stated that baricitinib thwarts the disease by disrupting the communication of immune cells involved in harming hair follicles.  Hopefully this medication will be proven to be safe & effective and approved by regulators.   Waymo says fully driverless rides are coming to San Francisco | The Verge (06:47) Waymo plans to start offering rides in its fully autonomous vehicles — without human safety drivers behind the wheel — in San Francisco.  They join a waitlist and, once approved, sign non-disclosure agreements to get access to the company's early technology. As of right now it is only available to employees but will soon grow to include members of the company's “Trusted Tester” program. The Trusted Tester program is for customers interested in using Waymo's robotaxis.  The vehicles will be available 24 hours a day, seven days a week, Waymo says. Additionally, Waymo is making moves in Arizona.Growing to include downtown Phoenix after operating exclusively in the exurban towns of Chandler, Gilbert, Mesa, and Tempe for nearly five years. Waymo has been running fully driverless rides without a safety driver in those towns outside of Phoenix for more than a year now.  They must be confident they have enough data to move forward with autonomous taxis.Last year, the company logged the most miles driven autonomously of all the companies permitted to test in the state: 2.3 million miles, a huge increase over 2020, when it had about 629,000 miles driven, and even the pre-pandemic year of 2019, with 1.45 million. The expansion of Waymo's service area in Phoenix and the imminent launch of driverless rides in San Francisco signal the company's sense of confidence that its vehicles can operate safely and efficiently in more dense, urban environments.    Quantum technology could make charging electric cars as fast as pumping gas | Phys.org (12:10) For a long time, batteries had far lower energy density than those offered by hydrocarbons, which resulted in very low ranges of early electric vehicles.Improvements in battery technologies eventually allowed the drive ranges of electric cars to be within acceptable levels However, despite the vast improvements in battery technology, today's consumers of electric vehicles face another difficulty: slow battery charging speed.Takes about 10 hours to fully recharge at home Even the fastest superchargers require up to 20 to 40 minutes to fully recharge This creates additional costs and inconvenience to the customers. To address this problem, scientists looked for answers in the field of quantum physics.Which led to a discovery that quantum technologies may promise new mechanisms to charge batteries at a faster rate.  It was theorized that quantum resources, such as entanglement, can be used to vastly speed up the battery charging process by charging all cells within the battery simultaneously in a collective manner. Conventional batteries collective charging is not possible, where the cells are charged in parallel independently of one another.  In this most recent study, researchers were able to precisely quantify how much charging speed can be achieved with this collective charging scheme vs parallel. The charging speed increases linearly with the number of cells in classical batteries. The study showed, however, that quantum batteries employing global operation can achieve quadratic scaling in charging speed. To illustrate this, consider a typical electric vehicle with a battery that contains about 200 cells. Charging time at home would be cut from 10 hours to about 3 minutes. Quantum charging would lead to a 200 times speedup over classical batteries,  High-speed charging stations, the charge time would be cut from 30 minutes to mere seconds. Of course, quantum technologies are still in their infancy and there is a long way to go before these methods can be implemented in practice. However, this study creates a promising direction and can incentivize the funding agencies and businesses to further invest in these technologies.   HB11's hydrogen-boron laser fusion test yields groundbreaking results | New Atlas (18:24) Australian company HB11 is approaching nuclear fusion from an entirely new angle, using high power, high precision lasers instead of hundred-million-degree temperatures to start the reaction.The 1st demo ​​produced 10 times more fusion reactions than expected The company started tooting their own horn: “the only commercial entity to achieve fusion so far [making it] the global frontrunner in the race to commercialize the holy grail of clean energy." Just to summarize quickly what is required for fusion: Like throwing powerful magnets at each other in space Most companies try to replicate this by magnetically confining hydrogen atoms in a plasma In order to smash atoms together hard enough to make them fuse together and form a new element, you need to overcome the incredibly strong repulsive forces that push two positively-charged nuclei apart.  The Sun accomplishes this by having a huge amount of hydrogen atoms packed into a plasma that's superheated to tens of millions of degrees at its core. HB11 is using a different approach that doesn't require huge amounts of heat, or tricky, radioactive fuels like tritium.Takes advantage of recent advances in ultra-high powered "chirped pulse amplification" lasers that can produce monstrous, unprecedented power levels over 10 petawatts. An HB11 reactor would be a mostly empty metal sphere, with a "modestly sized" boron fuel pellet held in the middle, and apertures in two spots on the sphere for a pair of lasers. One laser, in combination with a capacitive coil, is used to establish a powerful kilotesla magnetic containment field for the plasma. The second is used to massively accelerate hydrogen atoms through the boron sample. The reactor is not heating things up in the hope that they'll smack together at speed.It is aiming the hydrogen right at the boron and using these bleeding-edge lasers to make it go so fast that it'll fuse if it hits a nucleus. Hydrogen-boron fusion doesn't create heat, it merely creates "naked" positively charged helium atoms, or alpha particles They collect that charge to create energy, rather than needing to superheat steam and drive turbines. Initial experiments on laser-triggered chain reactions returned reaction rates a billion times higher than anticipated, and then seem pretty happy about it and a little cocky:“This is many orders of magnitude higher than those reported by any other fusion company, most of which have not generated any reaction despite billions of dollars invested in the field. The results show great potential for clean energy generation: hydrogen-boron reactions use fuels that are safe and abundant, don't create neutrons in the primary reaction so cause insignificant amounts of short-lived waste, and can provide large-scale power for base-load grid electricity or hydrogen generation." Mitochondrial transplants between living cells could save dying organs | ETH News (23:53) In a technological breakthrough, researchers at ETH Zurich have announced the development of a new technique that can transplant mitochondria.Mitochondria are the tiny powerhouses of the cell where the processes of cellular respiration take place In their research, recently published in the journal PLOS Biology, the group successfully used a ‘nanosyringe' they had previously developed to transplant mitochondria from one living cell to another. In more detail:These cylindrical nanosyringes were specially developed for this study, the researchers pierced the cell membrane and sucked up the spherical mitochondria. They then pierced the membrane of a different cell and pumped the mitochondria back out of the nanosyringe into the recipient cell. The position of the nanosyringe is controlled by laser light from a converted atomic force microscope. A pressure regulator adjusts the flow, allowing scientists to transfer incredibly small volumes of fluid in the femtoliter range (millionths of a millionth of a milliliter) during organelle transplants The transplanted mitochondria have a high survival rate – more than 80 percent. The injected mitochondria begin to fuse with the filamentous network of the new cell 20 minutes after transplantation. The technique could be deployed as a way of treating diseased organs, but may also find use in the realm of anti-aging, rejuvenating stem cells that deteriorate in metabolic activity as we grow older.

Featuring perspectives from Dr Srdan Verstovsek, including the following topics: Introduction (0:00) Case: A man in his early 70s with JAK2-positive intermediate-risk myelofibrosis (MF), a CALR mutation and multiple comorbidities — Amany R Keruakous, MD, MS (11:52) Case: A woman in her mid 70s with JAK2 V617F-positive primary MF treated with ruxolitinib — Bhavana (Tina) Bhatnagar, DO (22:51) Case: A woman in her early 80s with primary MF and pancytopenia (Hb 7.2 g/dL, platelets 30,000uL) — Jeanne Palmer, MD (28:49) Case: A man in his mid 60s with JAK2-positive primary MF and pancytopenia who develops recurrent herpes zoster on ruxolitinib — Niyati A Nathwani, MD (35:05) Case: A man in his mid 60s with an unspecified myeloproliferative neoplasm, pancytopenia and a JAK2 mutation — Dr Bhatnagar (40:03) Case: A man in his mid 60s with post-polycythemia vera MF and ASXL1, SRSF2 mutations — Dr Palmer (55:25) CME information and select publications

Featuring an interview with Dr Ruben Mesa, including the following topics: Management of myeloproliferative neoplasms (MPNs) (0:00) Case: A man in his early 40s with MPN with a JAK2 mutation (27:17) Case: A man in his mid-50s with disease exacerbation 14 years after diagnosis of polycythemia vera (PV) (28:24) Case: A man in his mid-70s with post-PV myelofibrosis and resistance to ruxolitinib (30:50) CME information and select publications

Enjoy this Curbsiders classic and stay tuned this Wednesday, August 25, 2021 for a brand new CBC Abnormalities Triple Distilled episode. Take a deep dive into common CBC abnormalities. We recorded LIVE at joint grand rounds between Walter Reed NMMC and Uniformed Services University with hematologist, Dr. Mary Kwok MD. Topics include: which parts of the complete blood count (CBC) are most important, interpreting the differential, when to order flow cytometry, who needs a hematology consult and simplified approaches to patients with leukocytosis, leukopenia, erythrocytosis and thrombocytopenia. Episodes | Subscribe | Spotify | Swag! | Top Picks | Mailing List | thecurbsiders@gmail.com Credits Written, Produced and Edited by: Matthew Watto MD, FACP Cover Art and Infographic by: Matthew Watto MD, FACP Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP Guest: Mary Kwok MD Sponsor: American College of Physicians acponline.org/100curb ACP CME 100 virtual video package includes 75 hours of practice-changing updates by expert faculty from Internal Medicine Meeting 2021 acponline.org/100CURB. Plus enjoy an exclusive: 25 bonus CME sessions and access until June 1, 2024! Sponsor: Birch by Helix birchliving.com/curb Birch is giving $200 dollars off ALL mattresses and 2 free eco-rest pillows at birchliving.com/curb   Time Stamps* Time Stamps refer to ad-free version 00:00 Intro; Paul shame's the audience; Guest bio 03:17 Guest one-liner, book recommendation* –Emperor of All Maladies (book) by Siddhartha Mukherjee, When Breath Becomes Air (book) by Paul Kalanithi; Career advice -set goals for whatever you're learning. 08:43 Picks of the week: John Wick 3 (film); The Movies That Made Me (podcast) by Joe Dante; The Tim Ferriss Podcast with Julie Rice of Soul Cycle; Infinity Chamber (film) by Travis Milloy 11:50 A case of asymptomatic leukocytosis; Red flags; Repeat the CBC until it's normal 17:30 The peripheral smear; Leukemoid reaction 20:00 The physical exam; When to send flow cytometry? 22:18 A case of lymphopenia; benign ethnic neutropenia; What to look for in the history 27:10 A case of erythrocytosis; Checking EPO levels; JAK2 mutation; Differential Diagnosis; Therapeutic Phlebotomy; Physical findings of Polycythemia Vera 36:53 A case of thrombocytopenia; Lab workup; Differential diagnosis; Pathophysiology; Culprit meds 45:35 Advice for internists 46:36 Take Home Points 47:46 Dr. Kwok's disclaimer 48:10 Outro and post credit scene

In this week’s episode, we consider the role of MYC and BCL2 copy number variants in double-hit diffuse large B-cell lymphoma, explore megakaryocyte-biased stem cells in JAK2-mutated myeloproliferative neoplasms, and finally, we look at long-term outcomes with emicizumab prophylaxis in patients with hemophilia, which are even better than in the first reports.

In this episode, Amy E. DeZern, MD, MHS, and Srdan Verstovsek, MD, provide medical oncology and hematology perspectives on new data from ASH 2020 in MDS and MPNs, with topics including:3-year OS results with RIC allogeneic transplantation in patients with higher-risk MDS in the BMT CTN 1102 studyA post hoc analysis of phase II data on the addition of pevonedistat to azacitidine in higher-risk MDS patients5-year results of ropeginterferon α-2b in polycythemia vera from the CONTINUATION-PV studyPhase II results of luspatercept for anemia in patients with myelofibrosis who are transfusion dependentAnalysis of clinical benefit in patients with myelofibrosis and OS benefit from imetelstat.Presenters:Amy E. DeZern, MD, MHSAssociate ProfessorOncology and MedicineThe Johns Hopkins University School of MedicineBaltimore, MarylandSrdan Verstovsek, MD, PhDZProfessorDivision of Cancer MedicineDepartment of LeukemiaThe University of Texas MD Anderson Cancer CenterHouston, TexasContent supported by educational grants from Amgen; AstraZeneca; Bristol-Myers Squibb; Epizyme, Inc; GlaxoSmithKline; Incyte Corporation; Janssen Biotech; Karyopharm Therapeutics Inc; Novartis; PharmaEssentia Corp; Seattle Genetics; and Takeda Oncology.Link to full program and Capsule Summary downloadable slidesets:http://bit.ly/3tyQ9nG

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, the MPN Hub spoke to Jyoti Nangalia, University of Cambridge, Cambridge, UK. We asked, Should we consider early testing and treatment for driver mutations acquired in childhood? In this podcast, Jyoti Nangalia reports results from a study using next-generation sequencing to trace acquired MPN mutations in hematopoietic stem cells taken from patients with varying stages of disease presentation. Nangalia discusses unexpected results, such as the acquisition of key driver mutations (JAK2 and DNMT3A) very early in life. She also discusses results observing a variation in the growth rate of cancer cell clones between patients, as well as the correlation of growth rate with disease presentation. Nangalia concludes with possible future applications of these methods in the early detection and prevention of MPN. Hosted on Acast. See acast.com/privacy for more information.

MECP2, RAS, and TP53. JAK2, RET, and BCR-ABL. Genetics is full of abbreviated names, pedigrees, and surprisingly, math. Not to worry, though - genetics TA Aaron D'Souza shares best practices to succeed in this class.

CME credits: 0.50 Valid until: 19-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/part-2-improving-quality-care-and-shared-decision-making-myelofibrosis/12004/ The only potentially curative therapy for Myelofibrosis (MF) is hematopoietic stem cell transplantation (HSCT), applicable only to patients with a compatible donor, and of suitable age and functional status to withstand treatment-related toxicity. The JAK inhibitor ruxolitinib has been the mainstay of MF treatment since it was approved in 2011, and until recently was the only targeted agent approved by the US Food & Drug Administration for management of MPNs. The recent addition of a novel JAK inhibitor, the JAK2-selective fedratinib, is a significant milestone in the therapeutic landscape of MF. Despite this critical advancement, MF management is suboptimal, owing to a lack of clinician awareness of the substantial symptom burden and quality-of-life impact of MF. The development of individualized care concepts have changed with increasing understanding of the role of HSCT, JAK inhibitors, and other patient-/disease-specific factors in the treatment paradigm for MF. This activity will review recent advances and critical concepts that affect outcomes, including symptom burden, molecular diagnostics, prognostic risk stratification scores, and the treatment and management of MF. A patient and clinician SDM support tool will be provided to help foster discussion and dialogue that will result in improved SDM ...

CME credits: 0.50 Valid until: 19-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/part-1-improving-quality-care-and-shared-decision-making-myelofibrosis/11997/ The only potentially curative therapy for Myelofibrosis (MF) is hematopoietic stem cell transplantation (HSCT), applicable only to patients with a compatible donor, and of suitable age and functional status to withstand treatment-related toxicity. The JAK inhibitor ruxolitinib has been the mainstay of MF treatment since it was approved in 2011, and until recently was the only targeted agent approved by the US Food & Drug Administration for management of MPNs. The recent addition of a novel JAK inhibitor, the JAK2-selective fedratinib, is a significant milestone in the therapeutic landscape of MF. Despite this critical advancement, MF management is suboptimal, owing to a lack of clinician awareness of the substantial symptom burden and quality-of-life impact of MF. The development of individualized care concepts have changed with increasing understanding of the role of HSCT, JAK inhibitors, and other patient-/disease-specific factors in the treatment paradigm for MF. This activity will review recent advances and critical concepts that affect outcomes, including symptom burden, molecular diagnostics, prognostic risk stratification scores, and the treatment and management of MF.

CME credits: 0.50 Valid until: 19-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/part-2-improving-quality-care-and-shared-decision-making-myelofibrosis/12004/ The only potentially curative therapy for Myelofibrosis (MF) is hematopoietic stem cell transplantation (HSCT), applicable only to patients with a compatible donor, and of suitable age and functional status to withstand treatment-related toxicity. The JAK inhibitor ruxolitinib has been the mainstay of MF treatment since it was approved in 2011, and until recently was the only targeted agent approved by the US Food & Drug Administration for management of MPNs. The recent addition of a novel JAK inhibitor, the JAK2-selective fedratinib, is a significant milestone in the therapeutic landscape of MF. Despite this critical advancement, MF management is suboptimal, owing to a lack of clinician awareness of the substantial symptom burden and quality-of-life impact of MF. The development of individualized care concepts have changed with increasing understanding of the role of HSCT, JAK inhibitors, and other patient-/disease-specific factors in the treatment paradigm for MF. This activity will review recent advances and critical concepts that affect outcomes, including symptom burden, molecular diagnostics, prognostic risk stratification scores, and the treatment and management of MF. A patient and clinician SDM support tool will be provided to help foster discussion and dialogue that will result in improved SDM ...

CME credits: 0.50 Valid until: 19-11-2021 Claim your CME credit at https://reachmd.com/programs/cme/part-1-improving-quality-care-and-shared-decision-making-myelofibrosis/11997/ The only potentially curative therapy for Myelofibrosis (MF) is hematopoietic stem cell transplantation (HSCT), applicable only to patients with a compatible donor, and of suitable age and functional status to withstand treatment-related toxicity. The JAK inhibitor ruxolitinib has been the mainstay of MF treatment since it was approved in 2011, and until recently was the only targeted agent approved by the US Food & Drug Administration for management of MPNs. The recent addition of a novel JAK inhibitor, the JAK2-selective fedratinib, is a significant milestone in the therapeutic landscape of MF. Despite this critical advancement, MF management is suboptimal, owing to a lack of clinician awareness of the substantial symptom burden and quality-of-life impact of MF. The development of individualized care concepts have changed with increasing understanding of the role of HSCT, JAK inhibitors, and other patient-/disease-specific factors in the treatment paradigm for MF. This activity will review recent advances and critical concepts that affect outcomes, including symptom burden, molecular diagnostics, prognostic risk stratification scores, and the treatment and management of MF.

Episode 347 is an updated guide to somatropic hormone and GOD did I go crazy on this one! I honestly want to know more about growth hormone than anyone alive and thus, begins this string of GH based guides! I DID finally discuss the MoA for how GH causes localized fat loss which really had me excited since no one in our industry has EVER talked about this so that definitely was an interesting avenue to go down! Below I am going to reference a lot of the literature for this hormone that I was read through over the past few years on this topic so please DO NOT TAKE MY WORD FOR THIS - READ THESE YOURSELF! Keep in mind this is a brief snippet of every bit of literature on the topic however. REFERENCES   Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989;10:68–91. [PubMed] [Google Scholar] Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16:3–34. [PubMed] [Google Scholar] Le Roith D, Bondy C, Yakar S, Liu JL, Butler A. The somatomedin hypothesis: 2001. Endocr Rev. 2001;22:53–74. [PubMed] [Google Scholar] Melmed S. Endocrinology. 5th edn. Philadelphia: Elsevier Saunders; 2006. pp. 411–428. [Google Scholar] Fain, J. N., García‐Sáinz, JA. (1983) Adrenergic regulation of adipocytes metabolism. J Lipid Res 24: 945– 966. CAS PubMed Web of Science®Google Scholar  Gilman, AG. (1987) G protein: transducer of receptor‐generated signals. Annu Rev Biochem 56: 615– 649. Crossref CAS PubMed Web of Science®Google Scholar  Jimenez, M., Lèger, B., Canola, K., et al (2002) Beta(1)/beta(2)/beta(3)‐adrenoceptor knockout mice are obese and cold‐sensitive but have normal lipolytic responses to fasting. FEBS Lett 530: 37– 40. Wiley Online Library CAS PubMed Web of Science®Google Scholar  Birnbaumer, L., Abramowitz, J., Brown, AM. (1990) Receptor‐effector coupling by G proteins. Biochim Biophys Acta 1031: 163– 224. Crossref CAS PubMed Web of Science®Google Scholar  Spiegel, A. M., Shenker, A., Weinstein, LS. (1992) Receptor‐effector coupling by G‐protein: implications for normal and abnormal signal transduction. Endocr Rev 13: 536– 565. Crossref CAS PubMed Web of Science®Google Scholar  Beebe, S. J., Holloway, R., Rannels, R. S., Corbin, JD. (1984) Two classes of cAMP analogs which are selective for the two different cAMP‐binding sites of type II protein kinase demonstrate synergism when added together to intact adipocytes. J Biol Chem 269: 3539– 3547. PubMed Google Scholar Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350:48–58. [PubMed] [Google Scholar] Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science. 2003;299:1346–1351. [PubMed] [Google Scholar] Ibrahim YH, Yee D. Insulin-like growth factor-I and cancer risk. Growth Horm IGF Res. 2004;14:261–269. [PubMed] [Google Scholar] Laban C, Bustin SA, Jenkins PJ. The GH-IGF-I axis and breast cancer. Trends Endocrinol Metab. 2003;14:28–34. [PubMed] [Google Scholar] Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–928. [PubMed] [Google Scholar] Mayo KE. A little lesson in growth regulation. Nat Genet. 1996;12:8–9. [PubMed] [Google Scholar] Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev. 1994;15:369–390. [PubMed] [Google Scholar] Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, Rundle AC, Wells JA, Carlsson LM. Mutations of the growth hormone receptor in children with idiopathic short stature. The Growth Hormone Insensitivity Study Group. N Engl J Med. 1995;333:1093–1098. [PubMed] [Google Scholar] Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349:2211–2222. [PubMed] [Google Scholar] Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996;335:1363–1367. [PubMed] [Google Scholar] Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol. 2001;229:141–162. [PubMed] [Google Scholar] Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, Gillett N, Stewart TA. IGF-I is required for normal embryonic growth in mice. Genes Dev. 1993;7:2609–2617. [PubMed] [Google Scholar] Sotiropoulos A, Ohanna M, Kedzia C, Menon RK, Kopchick JJ, Kelly PA, Pende M. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proc Natl Acad Sci U S A. 2006;103:7315–7320. [PMC free article] [PubMed] [Google Scholar] Fernandez AM, Dupont J, Farrar RP, Lee S, Stannard B, Le Roith D. Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle. J Clin Invest. 2002;109:347–355. [PMC free article] [PubMed] [Google Scholar] Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ. Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem. 1995;270:12109–12116. [PubMed] [Google Scholar] Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci U S A. 1998;95:15603–15607. [PMC free article] [PubMed] [Google Scholar] Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol. 2001;3:1014–1019. [PubMed] [Google Scholar] Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001;27:195–200. [PubMed] [Google Scholar] Barton ER, Morris L, Musaro A, Rosenthal N, Sweeney HL. Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J Cell Biol. 2002;157:137– 148. [PMC free article] [PubMed] [Google Scholar] Caroni P, Schneider C. Signaling by insulin-like growth factors in paralyzed skeletal muscle: rapid induction of IGF1 expression in muscle fibers and prevention of interstitial cell proliferation by IGF-BP5 and IGF-BP4. J Neurosci. 1994;14:3378–3388. [PMC free article] [PubMed] [Google Scholar] Edwall D, Schalling M, Jennische E, Norstedt G. Induction of insulin-like growth factor I messenger ribonucleic acid during regeneration of rat skeletal muscle. Endocrinology. 1989;124:820–825. [PubMed] [Google Scholar] DeVol DL, Rotwein P, Sadow JL, Novakofski J, Bechtel PJ. Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth. Am J Physiol. 1990;259:E89–E95. [PubMed] [Google Scholar] Carson JA, Nettleton D, Reecy JM. Differential gene expression in the rat soleus muscle during early work overload-induced hypertrophy. FASEB J. 2002;16:207–209. [PubMed] [Google Scholar] Waters MJ, Hoang HN, Fairlie DP, Pelekanos RA, Brown RJ. New insights into growth hormone action. J Mol Endocrinol. 2006;36:1–7. [PubMed] [Google Scholar] Herrington J, Carter-Su C. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol Metab. 2001;12:252–257. [PubMed] [Google Scholar] Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord. 2006;7:225–235. [PubMed] [Google Scholar] Rotwein P, Thomas MJ, Harris DM, Gronowski AM, LeStunff C. Nuclear actions of growth hormone: an in vivo perspective. J Anim Sci. 1997;75:11–19. [Google Scholar] Herrington J, Smit LS, Schwartz J, Carter-Su C. The role of STAT proteins in growth hormone signaling. Oncogene. 2000;19:2585–2597. [PubMed] [Google Scholar] Levy DE, Darnell JEJ. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–662. [PubMed] [Google Scholar] Gronowski AM, Rotwein P. Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. J Biol Chem. 1994;269:7874–7878. [PubMed] [Google Scholar] Gronowski AM, Zhong Z, Wen Z, Thomas MJ, Darnell JEJ, Rotwein P. In vivo growth hormone treatment rapidly stimulates the tyrosine phosphorylation and activation of Stat3. Mol Endocrinol. 1995;9:171–177. [PubMed] [Google Scholar] Ram PA, Park SH, Choi HK, Waxman DJ. Growth hormone activation of Stat 1, Stat 3, and Stat 5 in rat liver. Differential kinetics of hormone desensitization and growth hormone stimulation of both tyrosine phosphorylation and serine/threonine phosphorylation. J Biol Chem. 1996;271:5929–5940. [PubMed] [Google Scholar] Campbell GS, Meyer DJ, Raz R, Levy DE, Schwartz J, Carter-Su C. Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. J Biol Chem. 1995;270:3974–3979. [PubMed] [Google Scholar] Smit LS, Vanderkuur JA, Stimage A, Han Y, Luo G, Yu-Lee LY, Schwartz J, Carter-Su C. Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B. Endocrinology. 1997;138:3426–3434. [PubMed] [Google Scholar] Smit LS, Meyer DJ, Billestrup N, Norstedt G, Schwartz J, Carter-Su C. The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. Mol Endocrinol. 1996;10:519–533. [PubMed] [Google Scholar] Gebert CA, Park SH, Waxman DJ. Regulation of signal transducer and activator of transcription (STAT) 5b activation by the temporal pattern of growth hormone stimulation. Mol Endocrinol. 1997;11:400–414. [PubMed] [Google Scholar] Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell. 1998;93:841–850. [PubMed] [Google Scholar] Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A. 1997;94:7239–7244. [PMC free article] [PubMed] [Google Scholar] Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349:1139–1147. [PubMed] [Google Scholar] Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, Berberoglu M, Rosenfeld RG. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab. 2005;90:4260–4266. [PubMed] [Google Scholar] Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends Endocrinol Metab. 2007;18:134–141. [PubMed] [Google Scholar] Thompson BJ, Shang CA, Waters MJ. Identification of genes induced by growth hormone in rat liver using cDNA arrays. Endocrinology. 2000;141:4321–4324. [PubMed] [Google Scholar] Flores-Morales A, Stahlberg N, Tollet-Egnell P, Lundeberg J, Malek RL, Quackenbush J, Lee NH, Norstedt G. Microarray analysis of the in vivo effects of hypophysectomy and growth hormone treatment on gene expression in the rat. Endocrinology. 2001;142:3163–3176. [PubMed] [Google Scholar] Rowland JE, Lichanska AM, Kerr LM, White M, d'Aniello EM, Maher SL, Brown R, Teasdale RD, Noakes PG, Waters MJ. In vivo analysis of growth hormone receptor signaling domains and their associated transcripts. Mol Cell Biol. 2005;25:66–77. [PMC free article] [PubMed] [Google Scholar] Huo JS, McEachin RC, Cui TX, Duggal NK, Hai T, States DJ, Schwartz J. Profiles of growth hormone (GH)-regulated genes reveal time-dependent responses and identify a mechanism for regulation of activating transcription factor 3 by GH. J Biol Chem. 2006;281:4132–4141. [PubMed] [Google Scholar] Vidal OM, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia DJ, Woelfle J, Ono M, Lenhard B, Norstedt G, Rotwein P, Flores-Morales A. In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. Mol Endocrinol. 2007;21:293–311. [PubMed] [Google Scholar] Clodfelter KH, Holloway MG, Hodor P, Park SH, Ray WJ, Waxman DJ. Sex-dependent liver gene expression is extensive and largely dependent upon signal transducer and activator of transcription 5b (STAT5b): STAT5b-dependent activation of male genes and repression of female genes revealed by microarray analysis. Mol Endocrinol. 2006;20:1333–1351. [PubMed] [Google Scholar] Jorgensen JO, Jessen N, Pedersen SB, Vestergaard E, Gormsen L, Lund SA, Billestrup N. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. Am J Physiol Endocrinol Metab. 2006;291:E899–E905. [PubMed] [Google Scholar] Nielsen C, Gormsen LC, Jessen N, Pedersen SB, Moller N, Lund S, Jorgensen JO. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J Clin Endocrinol Metab. 2008;93:2842–2850. [PubMed] [Google Scholar] Waxman DJ, O'Connor C. Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol. 2006;20:2613–2629. [PubMed] [Google Scholar] Wauthier V, Waxman DJ. Sex-specific early growth hormone response genes in rat liver. Mol Endocrinol. 2008;22:1962–1974. [PMC free article] [PubMed] [Google Scholar] Ahluwalia A, Clodfelter KH, Waxman DJ. Sexual dimorphism of rat liver gene expression: regulatory role of growth hormone revealed by deoxyribonucleic Acid microarray analysis. Mol Endocrinol. 2004;18:747–760. [PubMed] [Google Scholar] Zhou YC, Waxman DJ. Cross-talk between janus kinase-signal transducer and activator of transcription (JAK-STAT) and peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling pathways. Growth hormone inhibition of pparalpha transcriptional activity mediated by stat5b. J Biol Chem. 1999;274:2672–2681. [PubMed] [Google Scholar] Zhou YC, Waxman DJ. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 transactivation domain. J Biol Chem. 1999;274:29874–29882. [PubMed] [Google Scholar] Ono M, Chia DJ, Merino-Martinez R, Flores-Morales A, Unterman TG, Rotwein P. Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone. Mol Endocrinol. 2007;21:1443–1457. [PubMed] [Google Scholar] Murphy LJ. Insulin-like growth factor-binding proteins: functional diversity or redundancy? J Mol Endocrinol. 1998;21:97–107. [PubMed] [Google Scholar] Barthel A, Schmoll D, Unterman TG. FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab. 2005;16:183–189. [PubMed] [Google Scholar] Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–426. [PubMed] [Google Scholar] Rotwein P. Contemporary endocrinology: the IGF system. Totowa: Humana Press; 1999. Molecular biology of IGF-I and IGF-II; pp. 19–35. [Google Scholar] Hall LJ, Kajimoto Y, Bichell D, Kim SW, James PL, Counts D, Nixon LJ, Tobin G, Rotwein P. Functional analysis of the rat insulin-like growth factor I gene and identification of an IGF-I gene promoter. DNA Cell Biol. 1992;11:301–313. [PubMed] [Google Scholar] Adamo ML, Ben-Hur H, Roberts CTJ, LeRoith D. Regulation of start site usage in the leader exons of the rat insulin-like growth factor-I gene by development, fasting, and diabetes. Mol Endocrinol. 1991;5:1677–1686. [PubMed] [Google Scholar] Shimatsu A, Rotwein P. Mosaic evolution of the insulin-like growth factors. Organization, sequence, and expression of the rat insulin-like growth factor I gene. J Biol Chem. 1987;262:7894–7900. [PubMed] [Google Scholar] Kim SW, Lajara R, Rotwein P. Structure and function of a human insulin-like growth factor-I gene promoter. Mol Endocrinol. 1991;5:1964–1972. [PubMed] [Google Scholar] Kavsan VM, Koval AP, Grebenjuk VA, Chan SJ, Steiner DF, Roberts CTJ, LeRoith D. Structure of the chum salmon insulin-like growth factor I gene. DNA Cell Biol. 1993;12:729–737. [PubMed] [Google Scholar] Hoyt EC, Van Wyk JJ, Lund PK. Tissue and development specific regulation of a complex family of rat insulin-like growth factor I messenger ribonucleic acids. Mol Endocrinol. 1988;2:1077–1086. [PubMed] [Google Scholar] Woelfle J, Billiard J, Rotwein P. Acute control of insulin-like growth factor-1 gene transcription by growth hormone through STAT5B. J Biol Chem. 2003;278:22696–22702. [PubMed] [Google Scholar] Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. J Biol Chem. 2003;278:51261–51266. [PubMed] [Google Scholar] Bichell DP, Kikuchi K, Rotwein P. Growth hormone rapidly activates insulin-like growth factor I gene transcription in vivo. Mol Endocrinol. 1992;6:1899–1908. [PubMed] [Google Scholar] Thomas MJ, Kikuchi K, Bichell DP, Rotwein P. Characterization of deoxyribonucleic acid-protein interactions at a growth hormone-inducible nuclease hypersensitive site in the rat insulin-like growth factor-I gene. Endocrinology. 1995;136:562–569. [PubMed] [Google Scholar] An MR, Lowe WLJ. The major promoter of the rat insulin-like growth factor-I gene binds a protein complex that is required for basal expression. Mol Cell Endocrinol. 1995;114:77–89. [PubMed] [Google Scholar] Mittanck DW, Kim SW, Rotwein P. Essential promoter elements are located within the 5' untranslated region of human insulin-like growth factor-I exon I. Mol Cell Endocrinol. 1997;126:153–163. [PubMed] [Google Scholar] Wang L,Wang X, Adamo ML. Two putative GATA motifs in the proximal exon 1 promoter of the rat insulin-like growth factor I gene regulate basal promoter activity. Endocrinology. 2000;141:1118–1126. [PubMed] [Google Scholar] Wang X, Talamantez JL, Adamo ML. A CACCC box in the proximal exon 2 promoter of the rat insulin-like growth factor I gene is required for basal promoter activity. Endocrinology. 1998;139:1054–1066. [PubMed] [Google Scholar] Wang Y, Jiang H. Identification of a distal STAT5-binding DNA region that may mediate growth hormone regulation of insulin-like growth factor-I gene expression. J Biol Chem. 2005;280:10955–10963. [PubMed] [Google Scholar] Chia DJ, Ono M, Woelfle J, Schlesinger-Massart M, Jiang H, Rotwein P. Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. J Biol Chem. 2006;281:3190–3197. [PubMed] [Google Scholar] Eleswarapu S, Gu Z, Jiang H. Growth hormone regulation of insulin-like growth factor-I gene expression may be mediated by multiple distal signal transducer and activator of transcription 5 binding sites. Endocrinology. 2008;149:2230–2240. [PMC free article] [PubMed] [Google Scholar] Björntorp, P. (1992) Biochemistry of obesity in relation to diabetes. In: KGMM Alberti RA DeFronzo H Keen P Zimmet eds. International Textbook of Diabetes Mellitus 551– 568. John Wiley & Sons Ltd London, United Kingdom. Google Scholar  Björntorp, P. (1992) Hormonal effects on fat distribution and its relationship to health risk factors. Acta Paediatr Suppl 383: 59– 60. CAS PubMed Google Scholar  Rosèn, T., Bosaeus, I., Tolli, J., Lindstedt, G., Bengtsson, BA. (1993) Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 38: 63 Wiley Online Library PubMed Web of Science®Google Scholar  Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) Cell. 1993;75:59–72. [PubMed] [Google Scholar] Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse) Proc Natl Acad Sci U S A. 1997;94:13215–13220. [PMC free article] [PubMed] [Google Scholar] Sims NA, Clement-Lacroix P, Da Ponte F, Bouali Y, Binart N, Moriggl R, Goffin V, Coschigano K, Gaillard-Kelly M, Kopchick J, Baron R, Kelly PA. Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. J Clin Invest. 2000;106:1095–1103. [PMC free article] [PubMed] [Google Scholar] Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D. Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest. 2002;110:771–781. [PMC free article] [PubMed] [Google Scholar] Miyakoshi N, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S. Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology. 2001;142:4349–4356. [PubMed] [Google Scholar] Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–1441. [PubMed] [Google Scholar] Ishizuya T, Yokose S, Hori M, Noda T, Suda T, Yoshiki S, Yamaguchi A. Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells. J Clin Invest. 1997;99:2961–2970. [PMC free article] [PubMed] [Google Scholar] McCarthy TL, Centrella M, Canalis E. Parathyroid hormone enhances the transcript and polypeptide levels of insulin-like growth factor I in osteoblast-enriched cultures from fetal rat bone. Endocrinology. 1989;124:1247–1253. [PubMed] [Google Scholar] Zhao G, Monier-Faugere MC, Langub MC, Geng Z, Nakayama T, Pike JW, Chernausek SD, Rosen CJ, Donahue LR, Malluche HH, Fagin JA, Clemens TL. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology. 2000;141:2674–2682. [PubMed] [Google Scholar] Bengtsson, BÅ, Edén, S., Lönn, L., et al (1993) Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 76: 309– 317. Crossref CAS PubMed Web of Science®Google Scholar  Al‐Shoumer, K. A. S., Page, B., Thomas, E., Murphy, M., Beshyah, S. A., Johnston, DG. (1996) Effects of four years’ treatment with biosynthetic human growth hormone (GH) on body composition in GH‐deficient hypopituitary adults. Eur Endocrinol 135: 559– 567. Crossref CAS PubMed Web of Science®Google Scholar  Li, C. H., Simpson, M. E., Evans, HM. (1949) Influence of growth and adrenocorticotropic hormone on the body composition of hypophysectomized rats. Endocrinology 44: 71– 75. Crossref CAS PubMed Web of Science®Google Scholar  Scow, RO. (1959) Effects of growth hormone and thyroxine on growth and chemical composition of muscle, bone and other tissues in thyroidectomized‐hypophysectomized rats. Am J Physiol 196: 859– 865. CAS PubMed Web of Science®Google Scholar  Lee, M. O., Schaffer, NK. (1934) Anterior pituitary growth hormone and the composition of growth. J Nutr 7: 337– 363. Crossref CAS Web of Science®Google Scholar  Goodman, H. M., Schwartz, J. (1974) Growth hormone and lipid metabolism. In: E Enobil WH Sawyer eds. Handbook of Physiology, Part 2 IV: 211– 232. American Physiological Society Washington DC. Google Scholar  Bengtsson, BÅ, Brummer, R. J. M., Edén, S., Rosèn, T., Sjöström, L. (1992) Effects of growth hormone on fat mass and fat distribution. Acta Paediatr Suppl 383: 62– 65. PubMed Google Scholar  Tanner, J. M., Hughes, P. C. R., Whitehouse, RH. (1977) Comparative rapidity of response of height, limb muscle and limb fat to treatment with human growth hormone in patients with and without growth hormone deficiency. Acta Endocrinol (Copenh) 84: 53– 57. Google Scholar  Goodman, H. M., Gorin, E., Honeyman, TW. (1988) Biochemical basis for the lipolytic activity of growth hormone. In: LE Underwood eds. Human Growth Hormone: Progress and Challenges 75– 111. Marcel Dekker Inc New York. Google Scholar  Bonnet, F., Vanderschueren‐Lodeweyckx, M., Echels, R., Malvaux, P. (1974) Subcutaneous adipose tissue and lipids in blood in growth hormone deficiency before and after treatment with human growth hormone. Pediatr Res 8: 800– 805. Crossref CAS PubMed Web of Science®Google Scholar  van Vliet, G, Bosson, D., Craen, M., Caju, NVLD, Malvaux, P., Vanderschueren‐Lodeweyckx, M. (1987) Comparative study of the lipolytic potencies of pituitary‐derived and biosynthetic human growth hormone in hypopituitary children. J Clin Endocrinol Metab 65: 876– 879. Crossref PubMed Web of Science®Google Scholar  Beauville, M., Harent, I., Crampes, F., Riviere, D., Tauber, M. T., Tauber, J. P., Garrigues, M. (1992) Effect of long‐term rhGH administration in GH‐deficient adults on fat cell epinephrine response. Am J Physiol 263: E467– E472. Crossref CAS PubMed Web of Science®Google Scholar  Vernon, R. G., Flint, DJ. (1989) Role of growth hormone in the regulation of adipocyte growth and function. In: RB Heap, C Prosser GE Lamming eds. Biotechnology in Growth Regulation 57– 71. Butterworths London, United Kingdom. Crossref Web of Science®Google Scholar  Harant, I., Beauville, M., Crampes, F., et al (1994) Response of fat cells to growth hormone (GH): effect of long term treatment with recombinant human GH in GH‐deficient adults. J Clin Endocrinol Metab 78: 1392– 1395. Crossref PubMed Web of Science®Google Scholar  Marcus, C., Bolme, P., Micha‐Johansson, G., Margery, V., Brönnegård, M. (1994) Growth hormone increases the lipolytic sensitivity from catecholamines in adipocytes from healthy adults. Life Sci 54: 1335– 1341. Crossref CAS PubMed Web of Science®Google Scholar  Yang, S., Björntorp, P., Liu, X., Edén, S. (1996) Growth hormone treatment of hypophysectomized rats increases catecholamine‐induced lipolysis and the number of β‐adrenergic receptors in adipocytes: no differences in the effects of growth hormone on different fat depots. Obes Res 4: 471– 478. Wiley Online Library CAS PubMed Web of Science®Google Scholar  Watt, P. W., Finley, E., Cork, S., Legg, R. A., Vernon, RG. (1991) Chronic control of the β‐ and α2‐adrenergic systems of sheep adipose tissue by growth hormone and insulin. Biochem J 273: 39– 42. Crossref CAS PubMed Web of Science®Google Scholar  Arner, P. (1992) Adrenergic receptor function in fat cells. Am J Clin Nutr 55: 228S– 236S. Crossref CAS PubMed Web of Science®Google Scholar  Arner, P., Hellmér, J., Wennlund, A., Östman, J., Engfeldt, P. (1988) Adrenoceptor occupancy in isolated human fat cells and its relationship with lipolysis rate. Eur J Pharmacol 146: 45– 56. Crossref CAS PubMed Web of Science®Google Scholar  Davidson, MB. (1987) Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 8: 115– 131. Crossref CAS PubMed Web of Science®Google Scholar  Ottosson, M., Lönnroth, P., Björntorp, Edén S. (2000) Effects of cortisol and growth hormone on lipolysis in human adipose tissue. J Clin Endocrinol Metab 85: 799– 803. Crossref CAS PubMed Web of Science®Google Scholar  Pierlussi, J., Pierlussi, R., Aschcroft, SJH. (1980) Effects of growth hormone on insulin release in the rat. Diabetologia 19: 391– 396. Crossref PubMed Web of Science®Google Scholar  Roupas, P., Ghou, S. T., Towns, R. J., Kostyo, JL. (1991) Growth hormone inhibits activation of phosphatidylinositol phospholipase C in adipose plasma membranes: evidence for a growth hormone‐induced change in G protein function. Physiol Pharmacol 88: 1691– 1695. CAS PubMed Web of Science®Google Scholar  72 Slavin, B. G., Ong, J. M., Kern, P. (1994) Hormonal regulation of hormone‐sensitive lipase activity and mRNA levels in isolated rat adiposities. J Lipid Res 35: 1535– 1541. CAS PubMed Web of Science®Google Scholar  Sheridan, MK. (1986) Effects of thyroxin, cortisol, growth hormone, and prolactin on lipid metabolism of coho salmon, oncorhynchus kisutch, during smoltification. Gen Comp Endocrinol 64: 220– 238. Crossref CAS PubMed Web of Science®Google Scholar  Dietz, J., Schwartz, J. (1991) Microdetermination of long chain fatty acids in plasma and tissue. J Biol Chem 235: 2595– 2599. PubMed Web of Science®Google Scholar Yang, S., Xu, X., Björntorp, P., Edén, S. (1995) Additive effects of growth hormone and testosterone on lipolysis in adipocytes of hypophysectomized rats. J Endocrinol 147: 147– 152. Crossref CAS PubMed Web of Science®Google Scholar  Lands, A. M., Arnold, A., McAuliff, J. P., Bron, TG. (1967) Differentiation of receptor systems activated by sympathetic amines. Nature 214: 597– 598. Crossref CAS PubMed Web of Science®Google Scholar  Stiles, G. L., Caron, M. G., Lefkowitz, RJ. (1984) β‐Adrenergic receptors: biochemical mechanisms of physiological regulation. Physiol Rev 64: 661– 743. Crossref CAS PubMed Web of Science®Google Scholar  Emorine, L. J., Marullo, S., Briend‐Sutren, M. M., et al (1989) Molecular characterization of human β3‐adrenergic receptor. Science 245: 1118– 1121. Crossref CAS PubMed Web of Science®Google Scholar  Ahquist, RP. (1948) A study of the adrenotropic receptors. Am J Physiol 153: 586– 600. PubMed Web of Science®Google Scholar  Honnor, R. C., Dhillon, G. S., Londos, C. (1985) cAMP‐dependent protein kinase and lipolysis in rat adipocytes. I. Cell preparation, manipulation and predictability in behavior. J Biol Chem 260: 15122– 15129. CAS PubMed Web of Science®Google Scholar  Honnor, R. C., Dhillon, G. S., Londos, C. (1985) cAMP‐dependent protein kinase and lipolysis in rat adipocytes. II. Definition of steady‐state relationship with lipolytic and antilipolytic modulators. J Biol Chem 260: 15130– 15138. CAS PubMed Web of Science®Google Scholar  Corbin, J. D., Cobb, C. E., Beebe, S. J., et al (1988) Mechanism and function of cAMP‐ and cGMP‐dependent protein kinases. Adv Second Messenger Phosphoprotein Res 21: 75– 86. CAS PubMed Web of Science®Google Scholar  Londos, C., Brasaemle, D. L., Schultz, C. J., Segrest, J. P., Kimmel, AR. (1999) Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Semin Cell Dev Biol 10: 51– 58. Crossref CAS PubMed Web of Science®Google Scholar  Holm, C., Osterlund, T., Laurell, H., Contreras, JA. (2000) Molecular mechanisms regulating hormone‐sensitive lipase and lipolysis. Annu Rev Nutr 20: 365– 393. Crossref CAS PubMed Web of Science®Google Scholar  Brasaemle, D. L., Rubin, B., Harten, I. A., Gruia‐Gray, J., Kimmel, A. R., Londos, C. (2000) Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem 275: 38486– 38493. Crossref CAS PubMed Web of Science®Google Scholar  Tansey, J. T., Huml, A. M., Vogt, R., et al (2003) Functional studies on native and mutated forms of perilipins. A role in protein kinase A‐mediated lipolysis of triacylglycerols. J Biol Chem 278: 8401– 8406. Crossref CAS PubMed Web of Science®Google Scholar  Strålfors, P., Björgell, P., Belfrage, P. (1984) Hormone regulation of hormone‐sensitive lipase in intact adipocytes: Identification of phosphorylated sites and effects of the phosphorylation by lipolytic hormone and insulin. Proc Natl Acad Sci U S A 81: 3317– 3321. Crossref CAS PubMed Web of Science®Google Scholar  Egan, J. J., Greenberg, A. S., Chang, M. K., Wek, SA Moos JMC, Londos, C. (1992) Mechanism of hormone‐stimulated lipolysis in adipocytes: translocation of hormone‐sensitive lipase to the lipid storage droplet. Proc Natl Acad Sci U S A 89: 8537– 8541. Crossref CAS PubMed Web of Science®Google Scholar  Anthonsen, M. W., Ronnstrand, L., Wernstedt, C., Degerman, E., Holm, C. (1998) Identification of novel phosphorylation sites in hormone‐sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J Biol Chem 273: 215– 221. Crossref CAS PubMed Web of Science®Google Scholar  Sztalryd, C., Xu, G., Dorward, H., et al (2003) Perilipin A is essential for the translocation of hormone‐sensitive lipase during lipolytic activation. J Cell Boil 161: 1093– 1103. Crossref CAS PubMed Web of Science®Google Scholar  Smith, PE. (1930) Hypophysectomy and replacement therapy in the rat. Am J Anat 45: 205– 273. Wiley Online Library Web of Science®Google Scholar  Edén, S., Jansson, J. O., Oscarsson, J. (1987) Sexual dimorphism of growth hormone secretion. In: O Isaksson C Binder K Hall B Hökfelt eds. Growth Hormone—Basic and Clinical Aspects 129– 151. Elsevier Science Publishers B.V Amsterdam. Google Scholar  Frohman, L. A., Bernardis, LL. (1970) Growth hormone secretion in rat: metabolic clearance and secretion rates. Endocrinology 86: 305– 312. Crossref CAS PubMed Google Scholar  Jansson, J. O., Albertsson‐Wikaland, K., Edén, S., Thorngren, K. G., Isaksson, O. (1982) Circumstantial evidence for a role of the secretory pattern of growth hormone in control of body growth. Acta Endocrinol 99: 24– 30. CAS PubMed Web of Science®Google Scholar  Björntorp, P., Karlsson, M., Pertoft, H., Pettersson, P., Sjöström, L., Smith, U. (1978) Isolation and characterization of cells from rat adipose tissue developing into adipocytes. J Lipid Res 19: 316– 324. CAS PubMed Web of Science®Google Scholar  Lowry, O. H., Rosebrough, N. J., Farr, A. L., Randall, RJ. (1951) Protein measurements with the folin phenol reagent. J Biol Chem 193: 265– 275. CAS PubMed Web of Science®Google Scholar  Rebuffé‐Scrive, M. (1987) Sex steroid hormones and adipose tissue metabolism in adrenalectomized and ovariectomized rats. Acta Physiol Scand 129: 471– 477. Wiley Online Library CAS PubMed Web of Science®Google Scholar  Laurell, S., Tibbling, G. (1966) An enzymatic fluorometric micromethod for the determination of glycerol. Clin Chim Acta 13: 317– 322. Crossref CAS PubMed Web of Science®Google Scholar  Dole, V. P., Meinertz, H. (1960) Microdetermination of long chain fatty acids in plasma and tissues. J Biol Chem 235: 2595– 2599. CAS PubMed Web of Science®Google Scholar  Smith, U., Sjöström, L., Björntorp, P. (1972) Comparison of two methods of determining human adipose cell size. J Lipid Res 13: 822– 824. CAS PubMed Web of Science®Google Scholar  Östman, J., Arner, P., Kimura, H., Wahrenberg, H., Engfeldt, P. (1984) Influence of fasting on lipolytic response to adrenergic agonists and on adrenergic receptors in subcutaneous adipocytes. Eur J Clin Invest 14: 383– 391. Wiley Online Library PubMed Web of Science®Google Scholar  Steiner, A. L., Pagliara, A. S., Chase, L. R., Kipnis, DM. (1972) Radioimmunoassay for cyclic nucleotides. II. Adenosine 3′, 5′‐monophosphate and guanosine 3′, 5′‐monophosphate in mammalian tissues and body fluids. J Biol Chem 247: 1114– 1120. CAS PubMed Web of Science®Google Scholar  Steiner, A. L., Parker, C. W., Kipnis, DM. (1972) Radioimmunoassay for cyclic nucleotides. I. Preparation of antibodies and iodinated cyclic nucleotides. J Biol Chem 247: 1106– 1113. CAS PubMed Web of Science®Google Scholar  McKenzie, FR. (1988) Basic techniques to study G‐protein function. In: G Milligan eds. Signal Transduction—A Practical Approach, Part 2 31– 56. Oxford University Press New York. Google Scholar  Solomon, S. S., Sibley, S. D., Dismukes, J.R. (1991) Growth hormone‐enhanced lipolysis in the spontaneously diabetic BB rat. J Lab Clin Med 118: 99– 105. CAS PubMed Web of Science®Google Scholar  Nam, S. Y., Marcus, C. (2000) Growth hormone and adipocyte function in obesity. Horm Res 53: (Suppl 1), 87– 97. Crossref CAS PubMed Web of Science®Google Scholar  Bahouth, S. W., Malbon, CC. (1988) Subclassification of β‐adrenergic receptors of rat fat cells: a re‐evaluation. Mol Pharmacol 34: 318– 326. CAS PubMed Web of Science®Google Scholar  Granneman, J. G., Lahners, K. N., Chaudhry, A. (1992) Molecular cloning and expression of the rat β3‐adrenergic receptor. Mol Pharmacol 40: 895– 899. Web of Science®Google Scholar  Hollenga, C. H., Zaagsma, J. (1989) Direct evidence for the atypical nature of functional β‐adrenoceptors in rat adipocytes. Br J Pharmacol 98: 1420– 1424. Wiley Online Library CAS PubMed Web of Science®Google Scholar  Lacasa, D., Agli, B., Giudicelli, Y. (1985) Direct assessment of β‐adrenergic receptors in intact rat adipocytes by binding of [3H]CGP 12177. Eur J Biochem 146: 339– 346. Wiley Online Library CAS PubMed Web of Science®Google Scholar  Umekawa, T., Yoshida, T., Sakane, N., Kondo, M. (1996) Effect of CL316, 243, a highly specific β3‐adrenoceptor agonit, on lipolysis of human and rat adipocytes. Horm Metab Res 28: 394– 396. Crossref CAS PubMed Web of Science®Google Scholar  Bojanic, D., Nahorski, SR. (1983) Identification and subclassification of rat adipocyte β‐adrenoceptors using (±)‐[125I]cyanopindolol. Eur J Pharmacol 93: 235– 243. Crossref CAS PubMed Web of Science®Google Scholar  Langin, D., Portillo, M., Saulnier‐Blache, J. S., Lafontan, M. (1991) Coexistence of three beta‐adrenergic receptor subtypes in white fat cells of various mammalian species. Eur J Pharmacol 199: 291– 301. Crossref CAS PubMed Web of Science®Google Scholar   •••WANT YOUR QUESTION ANSWERED?••• Create a free account at www.theprepcoachforum.com and post up your question in the Mike Arnold PED Q&A open threat!    •••SUPPORT OUR PEPTIDE/RESEARCH CHEMS SPONSORS•••   (RESEARCH CHEMS) www.maresearchchems.net___use discount code “alex15” to save off your order!   (SPECIALTY SUPPS) www.masupps.com___use discount code “alex20” to save off your order!   (BEEF) www.skinnybeef.com___use discount code “alex10” to save off your order!   •••FIND THE EPISODES•••   ITUNES:https://itunes.apple.com/us/podcast/beastfitness-radios-podcast/id1065532968   LIBSYN:http://beastfitnessradio.libsyn.com   VIMEO: www.vimeo.com/theprepcoach        •••PREP COACH APPAREL•••   https://teespring.com/stores/the-prep-coach-apparel    

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.13.246454v1?rss=1 Authors: Schmalohr, B. F., Mustafa, A.-H. M., Krämer, O., Imhof, D. Abstract: Janus kinase 2 (JAK2) is the most important signal transducing tyrosine kinase in erythropoietic precursor cells. Its malfunction drives several myeloproliferative disorders. Heme is a small metal ion-carrying molecule, which is incorporated into hemoglobin in erythroid precursor cells to transport oxygen. In addition, heme is a signaling molecule and regulator of various biochemical processes. Here we show that heme exposure leads to hyperphosphorylation of JAK2 in a myeloid cancer cell line. Two peptides identified in JAK2 represent heme-regulatory motifs and show low micromolar affinities for heme. These peptides map to the kinase domain of JAK2, which is essential for downstream signaling. We suggest these motifs to be the interaction sites of heme with JAK2, which drive the heme-induced hyperphosphorylation. The results presented herein may facilitate the development of heme-related pharmacological tools to combat myeloproliferative disorders. Copy rights belong to original authors. Visit the link for more info

Guest Name and Bio: Suneer “Sunny” Jain, M.S., Chief Executive Officer, Sun Genomics. Mr. Jain earned his Bachelor of Science (B.S.) degree from the University of Iowa in 1999. He went on to graduate with a Masters in Anatomy and Cell Biology from the Department of Anatomy and Cell Biology at the University of Iowa in 2004, where he conducted research in the field of Microbiology and Gene Therapy. Following graduation, Mr. Jain began his career as a Research and Development Supervisor for Pathway Diagnostics. Here he developed new molecular biomarker assays for clinical trials and out-licensing opportunities, planned and performed studies for the development and optimization of molecular assay(s) such as RNA/DNA extractions, (q)RT-PCR, PCR, SNP genotyping, Indel detection, gene rearrangement, and mutation status. Mr. Jain focused his career in 2007 towards clinical patient testing while working for LabCorp in the molecular oncology laboratory. During his time at LabCorp, Sunny participated in the development and launch of new lymphoma and leukemia molecular assays such as T-Cell GR, BCR/ABL, improved and troubleshooted existing assays such as Jak2, FLT3, IgVh somatic hypermutation, B-Cell GR, and MSI; he also reviewed and oversaw the scheduling and completion of Proficiency testing for CAP and NYS, and submitted validations and received approval from the New York State DOH on multiple assays. In 2009, Mr. Jain began working as a Lab Manager and Technical Supervisor in a Clinical Services Laboratory for industry leader, Illumina. At Illumina, Sunny managed the world’s first CLIA Whole Genome Sequencing Lab at Illumina for seven (7) years and was a part of the team that established the Illumina Clinical Services Laboratory and the first Clinical Laboratory to sequence the whole human genome in a CLIA-certified, CAP-accredited laboratory introducing NGS technology into a clinical setting. Additionally, he led a zero deficiency CAP inspection as acting quality manager/general supervisor/technical supervisor from 2011-2015, authored state of the art assay validation studies for Whole Genome Sequencing as an LDT, managed site relocation, re-verification studies, and HiSeq 2000 validations for Whole Genome Sequencing, and restructured payment processing workflow in a SAP for a laboratory generating over $5 Million per year. What you will learn from this episode: 1) What is a precision probiotic? 2) Can probiotics help and how? 3) What is the best way to sequence the gut microbiome 4) How to take a highly personalized approach to gut health 5) Understanding how to optimize gut health How to learn more about our guest: https://sungenomics.com/ https://www.instagram.com/sungenomics/ https://www.facebook.com/sungenomics/ https://www.linkedin.com/company/sungenomics/ https://twitter.com/sungenomics?lang=en Please enjoy, share, rate and review our podcast and help us bring the message about precision health care to the world!

In Episode 2 we explore the most rare of the myeloproliferative neoplasms, Myelofibrosis. Donal McLornan joins us to discuss diagnosis, patient experience and options available to treat this bone marrow scarring disease, including JAK2 inhibitors and stem cell transplantation.

Take a deep dive into common CBC abnormalities. We recorded LIVE at joint grand rounds between Walter Reed NMMC and Uniformed Services University with hematologist, Dr. Mary Kwok MD. Topics include: which parts of the complete blood count (CBC) are most important, interpreting the differential, when to order flow cytometry, who needs a hematology consult and simplified approaches to patients with leukocytosis, leukopenia, erythrocytosis and thrombocytopenia.  Full show notes at https://thecurbsiders.com/podcast. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Credits Written, Produced and Edited by: Matthew Watto MD, FACP Cover Art and Infographic by: Matthew Watto MD, FACP Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP Guest: Mary Kwok MD   Sign Up for a course w/our Chief of POCUS, Dr. Renee Dversdal! ACP - acponline.org/pocus AIUM - Check out https://aium.org for upcoming events.  TRUST (Train the Ultrasound Trainers) https://www.ultrasoundtraining.com.au/courses/category/train-the-ultrasound-trainer-trust Time Stamps 00:00 Intro; Paul shame’s the audience; Guest bio 03:17 Guest one-liner, book recommendation* -Emperor of All Maladies (book) by Siddhartha Mukherjee, When Breath Becomes Air (book) by Paul Kalanithi; Career advice -set goals for whatever you’re learning. 08:43 Picks of the week: John Wick 3 (film); The Movies That Made Me (podcast) by Joe Dante; The Tim Ferriss Podcast with Julie Rice of Soul Cycle; Infinity Chamber (film) by Travis Milloy 11:50 A case of asymptomatic leukocytosis; Red flags; Repeat the CBC until it’s normal 17:30 The peripheral smear; Leukemoid reaction 20:00 The physical exam; When to send flow cytometry? 22:18 A case of lymphopenia; benign ethnic neutropenia; What to look for in the history 27:10 A case of erythrocytosis; Checking EPO levels; JAK2 mutation; Differential Diagnosis; Therapeutic Phlebotomy; Physical findings of Polycythemia Vera 36:53 A case of thrombocytopenia; Lab workup; Differential diagnosis; Pathophysiology; Culprit meds 45:35 Advice for internists 46:36 Take Home Points 47:46 Dr. Kwok’s disclaimer 48:10 Outro and post credit scene

A virtual roundtable discussion with noted investigators Prof Claire Harrison and Dr John Mascarenhas for a review of recent innovations in the treatment of myeloproliferative neoplasms. Biology of myeloproliferative neoplasms (MPN); mutational landscape and implications for prognosis and therapy (00:00) Diagnosis and risk stratification of MPN (3:34) Pathophysiology of MPN and therapeutic approach to patients with MPN (6:41) Case (Prof Harrison): A man in his early 60s with symptomatic primary myelofibrosis (MF) and mutations in JAK2, ASXL1, EZH2 and TET2 receives ruxolitinib as first-line therapy (9:39) Dosing and quality of life with ruxolitinib (11:58) Case (Dr Mascarenhas): A man in his early 60s receives ruxolitinib for symptomatic primary MF and experiences a return of symptoms 3 years later (14:14) Bone pain associated with MF; use of bone marrow biopsy to monitor disease progression (16:41) Design, eligibility criteria and results of the Phase III COMFORT-I and COMFORT-II studies evaluating ruxolitinib for patients with MF (21:16) A pooled analysis of overall survival in the COMFORT-I and COMFORT-II trials of ruxolitinib for the treatment of MF (23:53) Predictors of overall survival benefit with ruxolitinib (26:01) Biologic rationale for the survival benefit with ruxolitinib in MF (28:50) Perspective on the use of ruxolitinib in patients with MF in the absence of symptoms (32:56) Side-effect profile of ruxolitinib (36:36) Management of cytopenias associated with ruxolitinib (40:33) Potential correlation between JAK inhibitor therapy and second primary cancers (42:13) Spectrum of activity and ongoing investigation of novel JAK inhibitors in MF (45:21) Efficacy of fedratinib, pacritinib and momelotinib in patients with MF (48:08) Activity and tolerability of fedratinib for MF (50:45) Results of the single-arm, Phase II JAKARTA-2 study evaluating fedratinib in patients with MF previously treated with ruxolitinib (52:51) Response to fedratinib in the JAKARTA-2 study; ongoing Phase III studies of fedratinib in the second-line setting for MF (55:49) Case (Prof Harrison): A man in his late 60s with triple-negative primary MF experiences a good response to fedratinib as second-line therapy on the JAKARTA-2 trial (1:00:13) Case (Dr Mascarenhas): A man in his early 70s with primary MF and cytopenias experiences an improvement in symptoms and reduction in spleen size after treatment with pacritinib on the PERSIST-2 study (1:03:23) Potential role of fedratinib, pacritinib and momelotinib in the management of MF (1:05:11) Ongoing investigation of erythroid maturation agents in patients with MF (1:09:09) Perspective on the role of luspatercept and sotatercept in the management of MF (1:11:09) Case (Prof Harrison): A man in his late 50s with severe pruritus associated with polycythemia vera (PV) experiences a dramatic relief of symptoms with ruxolitinib (1:13:11) Efficacy of ruxolitinib in managing pruritus associated with PV (1:15:39) Case (Dr Mascarenhas): A woman in her late 60s with essential thrombocythemia (ET) refuses cytoreductive therapy (1:18:24) Effect of age and mutational status on the decision to treat ET (1:21:18) CME information and select publications  

Novel and Emerging Therapeutic Strategies in the Management of Hematologic Disorder-Related Anemia — Part 1: Our interview with Dr Komrokji highlights the following topics and cases from his practice. Approved and emerging therapies for patients with transfusion-dependent myelodysplastic syndromes (MDS); mechanism of action of the investigational erythroid maturation agent (EMA) luspatercept (00:00) Design, entry criteria and outcomes of the Phase III MEDALIST trial of luspatercept for the treatment of anemia in patients with very low-, low- or intermediate-risk MDS with ring sideroblasts who require red blood cell (RBC) transfusions (2:10) Clinical experience with the EMAs luspatercept and sotatercept (6:03) Potential FDA approval of luspatercept for the management of low-risk MDS (9:11) Ongoing investigation of luspatercept-based strategies for MDS (12:25) Investigation of venetoclax in combination with a hypomethylating agent for higher-risk MDS (16:00) Role of luspatercept in myelofibrosis; predictors of benefit from luspatercept (18:24) Case: A man in his mid-70s presents with fatigue and dyspnea and is diagnosed with lower-risk MDS with ring sideroblasts (21:17) Initial workup and diagnosis for patients with MDS (23:58) Risk stratification in MDS and therapeutic options for patients at lower versus higher risk (25:52) Clinical experience with EMAs for lower-risk, RBC transfusion-dependent MDS (29:42) Monitoring and management of iron overload in patients with lower-risk, RBC transfusion-dependent MDS (32:30) Case: A man in his early 60s with lenalidomide-refractory, lower-risk MDS and a del(5q) mutation receives the telomerase inhibitor imetelstat on a clinical trial (36:09) Case: A man in his mid-70s with postpolycythemia vera myelofibrosis with anemia and splenomegaly receives initial ruxolitinib therapy (40:49) Activity and tolerability of JAK1/2 inhibitors in myelofibrosis (45:09) Case: A woman in her mid-70s with myelofibrosis and a JAK2 mutation presents with progressive splenomegaly and anemia and receives ruxolitinib (48:31) Novel agents and strategies under investigation for myeloproliferative neoplasms (MPNs) (50:40) Incidence of IDH1/2 mutations in patients with MPNs; responses to IDH1/2 inhibitors and ongoing clinical investigations (53:13) Activity of the antifibrotic immunomodulator PRM-151 in patients with myelofibrosis (56:04) Common misconceptions about the use of erythropoietin-stimulating agents (57:45) Perspective on the appropriate choice of therapy for patients with intermediate-2 or high-risk myelofibrosis (1:01:41) Lack of correlation between JAK2 mutation status and response to ruxolitinib (1:03:19) Select publications  

Myeloproliferative Neoplasms Update — Part 2: Our interview with Dr Gerds highlights the following topics and cases from his practice: Common misconceptions about MPNs (0:00) Alterations of the JAK-STAT signaling pathway in MPNs (1:43) Case: A 61-year-old woman with primary MF and mutations in JAK2, EZH2 and CALR receives ruxolitinib (4:29) Prognostic significance of the JAK2, EZH2 and CALR mutations associated with MF (7:20) Dosing and activity of ruxolitinib for MF (8:53) Management of ruxolitinib-associated cytopenias and effect of ruxolitinib on disease pathogenesis (12:19) Evolution of clinical research with the selective JAK2 inhibitor fedratinib for MF (15:32) Association between fedratinib and thiamine levels; cytopenias associated with fedratinib (17:20) Efficacy of fedratinib as second-line treatment for patients with disease progression on ruxolitinib (18:38) Risks and benefits associated with pacritinib therapy (20:00) Case: A 66-year-old man who presents with anemia is diagnosed with MF and a Type 1 CALR mutation (21:48) Risk of infections associated with ruxolitinib (23:12) Evaluation of ruxolitinib for the treatment of graft-versus-host disease (27:05) Activity of the JAK1/2 inhibitor momelotinib in patients with MF (28:23) Hepcidin suppression and improvement of anemia in patients with MF; effect of novel JAK inhibitors, including fedratinib and momelotinib (30:03) Results of the SIMPLIFY 2 study evaluating momelotinib versus best available therapy for patients with MF previously treated with ruxolitinib (32:28) Use of JAK inhibitors for rheumatoid arthritis (35:29) Novel agents and approaches under investigation for MPNs (36:48) Perspective on the potential role of venetoclax for patients with MPNs (40:30) Case: A 75-year-old woman previously diagnosed with ET and a JAK2 V617F mutation is found to have disease transformation to PV on reassessment 12 years later (43:34) Efficacy and side effects of the MDM2 antagonist idasanutlin in the treatment of PV (47:36) Importance of maintaining hematocrit control in patients with PV (50:15) Role of ruxolitinib for patients with PV (51:55) Case: A 45-year-old woman with persistent headaches is diagnosed with ET and a JAK2 V617F mutation (54:08) Therapeutic options for patients with ET (56:47) Perspective on the need for aspirin for ET (59:17) Role of interferon and PI3-kinase inhibitors in the treatment of MPNs (1:00:37) Select publications

Dr Jimena Ferraris of the Karolinska Institute and the University of Buenos Aires talks with NEN about her recently published work in Neuroendocrinology on the identification of signal transduction pathways that may play a role in the pathogenesis of prolactinomas. Interview by Dr. Julie Ann Lough de Dios, N., Orrillo, S.J., Irizarri, M., Theas, M., Boutillon, F., Candolfi, M., Seilicovic, A., Goffin, V., Pisera, D., Ferraris, J. (2018). JAK2/STAT5 pathway mediates prolactin-induced apoptosis of lactotropes. Neuroendocrinology, doi: 10.1159/000494975.

Dr Mascarenhas speaks with ecancertv at ASH 2016 about pacritinib, an oral kinase inhibitor against JAK2, FLT3, IRAK1, and CSF1R. He describes the patient response to pacritinib, with a direct comparison to ruxolitinib (a JAK1/2 inhibitor) being of significant interest, and weighs measuring spleen volume reduction against other endpoints. Pacritinib is currently on full clinical hold by the FDA following deaths and cardiac events in PERSIST-1, which Dr Mascarenhas considers against the toxicity profile in this trial.

Kris Wood discusses two new studies that reveal potential ways to overcome drug resistance in cancer.

Keqiang Ye discusses a small molecule inhibitor of the kinase JAK2 that blocks proliferation of glioblastoma cells.

Dr Ross Levine presented results from a study on targeting the JAK-STAT pathway in myeloproliferative neoplasms at the EHA 2013. Myeloproliferative neoplasms (MPN) are clonal blood disorders characterised by excessive production of mature blood cells. The identification of somatic mutations in JAK2, MPL and LNK in the majority of MPN patients led to the development of JAK kinase inhibitors. JAK1/2 inhibitors improve splenomegaly and systemic symptoms, however the mechanism by which this occurs in patients has not been elucidated.

We present a case of a 42-year old female with the rare diagnosis of a myeloproliferative syndrome harboring both a BCR-ABL transclocation and a JAK2V617F mutation.Initially diagnosed with a CML, the patient underwent treatment with imatinib followed by dasatinib. Despite a major molecular response, the patient developed a thrombocytosis. Molecular analyses revealed a heterozygous JAK2V617F mutation, which was detected retrospectively in the bone marrow at the time of CML diagnosis.This case underlines the complexity of MPS pathogenesis. For the clinician, a JAK2 mutational screening should be performed in CML patients without hematological response in the absence of BCR-ABL.

Srdan Verstovsek, MD PhD, associate professor of Medicine, department of Leukemia, at the university of texas, MD anderson cancer center, discussing observations and results of a randomised trial using Jak2 inhibitors in Myelofibrosis.

Srdan Verstovsek, MD PhD, associate professor of Medicine, department of Leukemia, at the university of texas, MD anderson cancer center, discussing observations and results of a randomised trial using Jak2 inhibitors in Myelofibrosis.

By Reed Drews. This JCO Podcast provides observations and commentary on the JCO article, "Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis" by authors Animesh Pardanani, et al.

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORtextgreekgt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1textgreekb, IL6, IL21 and IL23. Recent studies indicate that TGFtextgreekb is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFtextgreekb reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

Die akute Pankreatitis beginnt in den Azinuszellen, allerdings bestimmen die sich anschließenden außerazinären, immunologischen Geschehnisse den Schweregrad der Erkrankung. Diese immunologische Reaktion wird über Zytokine vermittelt, die hauptsächlich von Immunzellen, zusätzlich aber auch von Pankreasazinuszellen selbst sezerniert werden. In dieser Arbeit wurde untersucht, ob Pankreasazinuszellen in der Lage sind, auf autokrin oder parakrin freigesetzte Zytokine zu reagieren. Der JAK/STAT-Signaltransduktionsweg, eine Phosphorylierungskaskade, die von Oberflächenrezeptoren initiierte Signale in den Zellkern weiterleitet, stellt den Haupteffektor der meisten Zytokine dar. Wir konnten mittels Immunopräzipitation und Western-Blot die meisten JAK und STAT Proteine in Pankreasazinuszellen nachweisen (JAK1, JAK2 und TYK2 sowie STAT1, STAT2, STAT3, STAT5 und STAT6). Darüber hinaus konnten wir zeigen, dass einige dieser Proteine in Pankreasazinustellen durch physiologische (Zytokine), aber auch unphysiologische (Stress) Stimuli phosphoryliert und damit aktiviert werden. Dies belegt neben der Expression zusätzlich eine Regulation dieser Proteine und damit eine funktionelle Rolle des JAK/STATSignaltransduktionsweges im Pankreas. Exemplarisch wurde mitttels Immunhistochemie gezeigt, dass IFN-