Podcasts about cd4 t

Description: Co-hosts Ryan Piansky, a graduate student and patient advocate living with eosinophilic esophagitis (EoE) and eosinophilic asthma, and Holly Knotowicz, a speech-language pathologist living with EoE who serves on APFED's Health Sciences Advisory Council, interview Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital. Dr. Shreffler is also an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative. His research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy. This interview covers the results of a research paper on The Intersection of Food Allergy and Eosinophilic Esophagitis, co-authored by Dr. Shreffler. Disclaimer: The information provided in this podcast is designed to support, not replace the relationship that exists between listeners and their healthcare providers. Opinions, information, and recommendations shared in this podcast are not a substitute for medical advice. Decisions related to medical care should be made with your healthcare provider. Opinions and views of guests and co-hosts are their own.   Key Takeaways: [:50] Co-host Ryan Piansky introduces the episode, brought to you thanks to the support of Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron. Ryan introduces co-host, Holly Knotowicz.   [1:15] Holly introduces today's topic, the intersection of food allergy and eosinophilic esophagitis.   [1:26] Holly introduces today's guest, Dr. Wayne Shreffler, Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital and an investigator at The Center for Immunology and Inflammatory Disease and The Food Allergy Science Initiative.   [1:43] Dr. Shreffler's research is focused on understanding how adaptive immunity to dietary antigens is both naturally regulated and modulated by therapy in the context of food allergy.   [1:54] Holly welcomes Dr. Shreffler to Real Talk. When Holly moved to Maine, she sent her patients to Dr. Shreffler at Mass General.   [2:25] Dr. Shreffler trained in New York on a Ph.D. track. He was interested in parasitic diseases and the Th2 immune response. Jane Curtis, a program director at Albert Einstein College of Medicine, encouraged him to consider MD/PhD programs. He did.   [3:31] Jane Curtis connected him to Hugh Sampson, who was working with others to help understand the clinical prevalence of food allergy and allergens.   [3:51] As a pediatric resident, Dr. Shreffler had seen the burden of allergic disease, caring for kids in the Bronx with asthma. His interest in Th2 immunity, the clear and compelling unmet clinical need, and the problem of food allergy guided his career.   [4:31] Dr. Shreffler's wife has food allergies and they were concerned for their children. Fortunately, neither of them developed food allergies.   [5:21] Dr. Shreffler thinks the food allergy field has a lot of people who gravitate toward it for personal reasons.   [5:53] Food allergy is an adverse response to food that is immune-mediated. There is still uncertainty about this but Dr. Shreffler believes that a large percentage of patients with EoE have some triggers that are food antigens.   [6:27] The broad definition of food allergy would include things like food protein-induced enterocolitis syndrome (FPIES).   [6:47] The way we use the term food allergy in the clinic, there are two forms: IgE-mediated allergies and non-IgE-mediated allergies, including EoE.   [7:40] Some patients have food-triggered eczema, some have FPIES.   [8:04] In 2024, Dr. Shreffler and Dr. Caitlin Burk released a paper that looked at the triggers of EoE, particularly the intersection of IgE-mediated food allergy and EoE.   [8:41] Dr. Caitlin Burk joined the group as they were publishing papers on IG food allergy and EoE. It was a moment where things unexpectedly came together.   [9:17] Adaptive immunity to food proteins comes from antibodies that cause milk allergy, egg allergy, peanut allergy, or multiple allergies. The IgE has specificity.   [9:40] T cells also are specific to proteins. They express a host of receptors that recognize almost anything the immune system might encounter. They have a long memory like B-cells.   [10:09] The overlap in these two threads of research was regarding a population of T cells that are important for mediating chronic inflammation at epithelial sites, including the gut.   [10:36] These T cells have been described in the airways in asthma, in the skin in eczema, and the GI tract. Researchers years ago had also described them as being associated with IgE food allergy. People with IgE food allergies avoid allergens.   [11:13] T cells, being associated with chronic allergic inflammation, now being associated with food allergies which are not having chronic exposures to the allergen, was interesting and surprising.   [11:30] Dr. Shreffler and his group found the T cell subset in patients who don't do well with Oral Immunotherapy (OIT) and patients who have EoE with immediate symptoms.   [12:01] Dr. Shreffler notes differences. There are immediate symptoms of IgE food allergy. There is a subset of patients with EoE who have immediate symptoms that are not fully understood. Maybe IgE plays a role there.   [12:28] There are different mechanisms for how symptoms are caused and so different ways of making a diagnosis. A food allergy with an IgE antibody can be measured through skin tests and blood tests. This can help identify which foods are the trigger.   [12:57] This common T cell subset that we see in EoE and food allergy, helps to explain why IgE alone is not always a very specific marker for identifying people who will have immediate reactions when they're exposed to the food.   [13:17] For patients who react at low levels, it's not just that they have more or better IgE but they also have an expansion of these T cells that are common between EoE and other chronic forms of allergy and IgE food allergy.   [13:41] There's a lot to learn that might be relevant for patients about this T cell subset.   [14:23] These T cells are a specific subset of the group of Th2 T cells, which are a subset of all CD4 T cells. Some CD4 T cells are important for responding to viruses and tumors. Others are important for responding to outside allergens.   [15:01] In an allergy or a parasite infection, Th2 T cells are important. There is a subset of T cells that is driven by repetitive and chronic exposure to the triggering protein, antigen, or allergen.   [15:47] Most antigens are proteins that trigger an immune response. An antigen that elicits an allergic response is an allergen. [16:30] A food trigger is a protein antigen that is an allergen. In IgE, food allergies, milk, and eggs are prevalent triggers early in life. For reasons not well understood, a lot of people outgrow them. In older patients, peanut and tree nut allergies are prevalent.   [17:01] In EoE, milk is one of the most common dietary triggers into adulthood. Some patients with IgE allergy to milk can tolerate it if it's well cooked. Patients with EoE are less likely to be able to get away with regular and ongoing exposure to milk protein.   [17:54] Milk, eggs, and nuts are common triggers in both conditions. There can also be rare food allergy triggers. That's part of the early evidence that the adaptive immune response was likely to be involved. It can be so specific for some people to rare things.   [18:20] Hallmarks of something being immune-mediated are that it is reproducibly demonstrable as a trigger. It's going to be long-lived. It's going to be generally relatively small amounts. The immune system is good at detecting small exposures.   [19:07] EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.   [20:14] A history of having blood in the stools can be milk-allergen-driven and was associated with a diagnosis of EoE in those kids when they're older.   [20:26] There are a lot of commonalities in the allergens but it's not always obvious clinically.   [22:40] A challenge in diagnosing EoE is that providers have to be on guard against their biases. They have to give a patient good advice. In EoE there is no test to identify triggers, except rigorous introduction, elimination, reintroduction, and endoscopies.   [24:18] For some of Dr, Shreffler's patients, it becomes less important to know their dietary triggers. They gravitate toward an approved form of treatment that may, if successful, allow them to have a more normal diet because of effective medication.   [24:50] Dr. Shreffler thinks there are other triggers, including pollens. There is evidence of seasonality of active EoE in patients shown to have allergic sensitization to pollens. That's indirect evidence. If the body is making IgE, it's likely making other responses.   [25:32] There are questions about how large the population of patients is who have EoE that may be more intrinsically than extrinsically driven because of genetic variations.   [25:54] Dr. Shreffler believes that EoE in some patients is allergen-driven and in some patients EoE is food-driven. Food is a trigger for the majority of pediatric patients and a large percentage of adult patients but not necessarily the exclusive trigger.   [27:04] If a patient is motivated to learn what dietary triggers may be at play, Dr. Shreffler often makes assessments outside of pollen season for allergens to which the patient has demonstrated positivity.   [28:09] Looking at the epidemiology, both EoE and food allergy are atopic disorders. You see an increased prevalence of asthma, hay fever, eczema, and even allergic proctocolitis in infancy. You see an enrichment of one disorder to another.   [28:29] The overlap of food allergy to EoE is stronger than you might expect. About 30 to 40% of patients with EoE will also have IgE food allergy. A higher rate will have IgE positivity, whether or not that food is a trigger of immediate symptoms.   [28:48] Patients with food allergies are about four times more likely to have EoE than the general population. That's a stronger association than the risk of eczema or other atopic conditions to EoE.   [30:09] There are differences between IgE food allergy and EoE. The presence of IgE gives a useful tool for identifying the food trigger in food allergy, but not in EoE. Identifying rare triggers in EoE patients is done by clinical observation.   [31:46] Epinephrine and antihistamines are not useful in treating EoE. Blocking IgE with Omalizumab has not been effective in trials in treating EoE. PPIs, topical steroids, and dupilumab are helpful for many EoE patients.   [32:38] Dupilumab has been evaluated a bit in food allergy in combination with OIT, and there was no statistically significant benefit from dupilumab in food allergy.   [33:25] A group in Pennsylvania has been evaluating epicutaneous immunotherapy as a modality to treat EoE. It's also being evaluated for IgE food allergy. Dr. Shreffler thinks it's something to keep an eye on.   [33:40] The oral route for immunotherapy can drive EoE for patients. As they become less sensitive from an immediate reactivity viewpoint, a significant percentage of patients develop GI symptoms. This has also been observed with sublingual therapy.   [34:14] Iatrogenic EoE, caused by the treatment, may resolve on the cessation of the immunotherapy treatment.   [36:25] Dr. Shreffler says in some cases, the shared decision is a decision where he has a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally supported by what we know right now.   [36:57] We've said that EoE is a contraindication for OIT. There is a shift happening. Dr. Shreffler sits with families and has a conversation about restricting diet or trying chronic therapy and keeping an ad-lib diet.   [37:38] What about doing the same thing by treating the immediate-type food allergy with chronic allergen exposure and then ameliorating the effects of EoE if it emerges, with another therapy? A hundred providers would have a diversity of responses.   [38:19] When there is a history of EoE in a family, Dr. Shreffler advocates for getting a baseline scope. It becomes an important “ground zero.”   [38:28] The goal is to have less invasive ways to monitor these conditions.   [39:32] Chronic inflammation, which is the hallmark of EoE, is well-targeted by therapies like PPIs and steroids. Steroids don't help with IgE-related food allergies. They're not effective at blocking the IgE-driven immediate response.   [41:13] Until recently, IgE food allergy has only been managed with avoidance. We have some other tools now. Xolair is not effective in EoE but is effective in two-thirds to three-quarters of patients with immediate-type food allergies for preventing anaphylaxis.   [41:45] Dr. Shreffler refers to an upcoming study on the effectiveness of Xolair in treating people with food allergies. Those who were able to tolerate a minimum amount were allowed to begin consuming allergen. We'll get insight into how those patients did.   [43:08] Food-induced immediate response of the esophagus (FIRE) is immediate discomfort with exposure to some allergens. Dr. Shreffler explains it. Data supports that these patients are experiencing an IgE-mediated but local response to those triggers.   [44:59] If FIRE is IgE-mediated, it may be that Xolair would help suppress it in these patients. It's worth looking at Xolair for this subset of EoE patients.   [45:20] Ryan invites any listeners who want to learn more about FIRE to check out episode #34 with Dr. Nirmala Gonsalvez.   [45:37] In the paper, Dr. Shreffler wrote about what he hopes will be the practical usefulness of the finding, the intersection between IgE food allergy and EoE.   [45:56] A subset of Th2 T cells express a protein called GPR15. It appears to be a marker for the subset of cells that are playing a role in the EoE.   [46:36] Caitlin Burk's work now is looking at their activation status in active disease and post-diet elimination and remission. She is developing a data set that is leading us toward the possibility of focusing on that cell subset and techniques to adopt in clinics.   [47:12] She is also working out more advanced techniques to look at the receptors. Dr. David Hill at CHOP is working on similar research. This research has the potential to lead to the development of better tests for EoE.   [47:44] Holly tells Dr. Shreffler this has been such an informative episode with so many tidbits of things to help patients advocate for themselves. Holly thanks him for sharing all of that.   [48:12] Dr. Shreffler is trying to see what can be utilized from their research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. He sees it as a huge unmet need.   [48:31] Ryan thanks Dr. Shreffler for joining us. For our listeners who would like to learn more about eosinophilic disorders, including EoE, please visit APFED.org and check out the links in the show notes.   [48:41] If you're looking to find a specialist who treats eosinophilic disorders, we encourage you to use APFED's Specialist Finder at APFED.org/specialist.   [48:50] If you'd like to connect with others impacted by eosinophilic diseases, please join APFED's online community on the Inspire Network at APFED.org/connections.   [49:00] Ryan thanks Dr. Shreffler for joining us today for this interesting conversation. Holly also thanks APFED's Education Partners Bristol Myers Squibb, GSK, Sanofi, and Regeneron for supporting this episode.   Mentioned in This Episode: Dr. Wayne Shreffler, MD, Ph.D., Chief of Pediatric Allergy and Immunology and Co-Director of The Food Allergy Center at Massachusetts General Hospital “Triggers for eosinophilic esophagitis (EoE): The intersection of food allergy and EoE” Dr. Caitlin Burk Dr. David A. Hill   APFED on YouTube, Twitter, Facebook, Pinterest, Instagram Real Talk: Eosinophilic Diseases Podcast apfed.org/specialist apfed.org/connections   Education Partners: This episode of APFED's podcast is brought to you thanks to the support of Bristol Myers Squibb, GSK, Sanofi, and Regeneron.   Tweetables:   “This fascinating problem of food allergy: why does the immune system do that for some people — recognize what should be nutritive and innocuous sources of energy as an immunological trigger? ” — Dr. Wayne Shreffler   “A food allergy; because there is this IgE antibody, we can do skin tests. We can measure that in the blood. It's a useful marker for helping to identify which foods are the trigger.” — Dr. Wayne Shreffler   “EoE is tricky because there's not that clear and easy temporal association between an offending allergen exposure for most people and their symptoms. People don't associate the symptoms with the triggers.” — Dr. Wayne Shreffler   “Everything is shared decision-making. In some cases, it's a shared decision where I have a strong evidence-based opinion. In some cases, there's a lot more room for a range of clinical decisions that could be equally justified.” — Dr. Wayne Shreffler   “Steroids don't help with IgE-related food allergy. They're not effective at blocking that IgE-driven immediate response.” — Dr. Wayne Shreffler   “I'm trying to see what we can utilize from our research to make non-invasive tests to identify food allergen triggers for patients so they don't have to go through so many endoscopies. I think that's a huge unmet need.” — Dr. Wayne Shreffler  

Morbidity & Mortality (M & M) are common case conferences to learn from unfortunate cases to improve care in the future. This episode looks at two recently published case reports. 1. Fatal tumor lysis syndrome following a lack of venetoclax ramp-up in AML: https://www.jhoponline.com/issue-archive/2024-issues/december-2024-vol-14-no-6/rapid-onset-of-fatal-tumor-lysis-syndrome-in-a-patient-with-acute-myeloid-leukemia-receiving-azacitidine-and-venetoclax-without-a-ramp-up-schedule-a-case-report 2. CD4+ T-cell lymphoma harboring a CAR integration into TP53: https://www.nejm.org/doi/full/10.1056/NEJMoa2411507

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

This week, Jonathan is joined by Dr Shahram Kordasti, Associate Professor in Applied Cancer Immunopathology at King's College London, UK. In this episode, Dr Kordasti discusses the immunobiology of Myelodysplastic syndrome and Aplastic anaemia, the role of CD4+ T cells in myeloid malignancies, and how cutting-edge computational tools are enhancing treatment strategies.   Timestamps:  (00:00)-Introduction  (01:23)-Hodgkin's lymphoma origin   (04:21)- Immunobiology of diseases  (08:55)-Plasticity of T cells   (13:42)-Computational biology and multiomics for patient stratification  (21:00)-Standardising immune monitoring  (25:41)- Pretreatment with systemic agents  (27:55)- Myeloproliferative neoplasms  (31:48)-Synthetic data generation   (36:22)-Exciting developments on the horizon   (39:16)-Three wishes for healthcare  

The immune system adapts to various threats through innate and adaptive responses, utilizing epigenetic mechanisms to regulate gene activity without changing DNA sequences. These mechanisms help maintain long-term immune phenotypes, allowing the immune system to respond to changing environments. In innate immunity, epigenetic changes enable immediate pathogen responses, while in adaptive immunity, they create memory cells that remember past infections for quicker, stronger reactions. This adaptability ensures ongoing protection and highlights the potential for developing targeted therapies to modulate the immune response, offering more effective treatments for various diseases.In this week's episode of the Everything Epigenetics podcast, join me and Dr. Andrew DiNardo as we explore the complexities of the immune system. Dr. DiNardo shares his journey from internal medicine to addressing global health issues like tuberculosis and his latest research on the impact of school deworming initiatives on vaccine efficacy in children with schistosomiasis.We dive into how the immune system interacts with DNA, focusing on CD4 T cells and DNA methylation, and discuss Dr. DiNardo's pioneering use of single-cell technology to study immune responses. This technology highlights both the benefits of vaccines and the risks posed by severe infections to our genetic makeup. Our conversation also covers the potential of manipulating these immune responses to develop new treatments and the challenges posed by high-resolution analyses in this field.Wrapping up, we reflect on the dual role of mTOR in modulating the immune response and influencing DNA methylation patterns. Dr. DiNardo's insights emphasize the complex interplay between genetic regulation and immune function, emphasizing the need for comprehensive data repositories to advance infectious disease research. In this episode of Everything Epigenetics, you'll learn about: Current research on co-infection and immunityImmunity through the lens of epigeneticsAnalyzing immune cell subsets in epigenetic studiesThe double-edged sword of epigenetic immune modificationsThe impact of tuberculosis on epigenetic agingDNA methylation, cellular senescence and premature epigenetic agingManipulating metabolism to improve epigeneticsmTOR and its role in immune responseThe potential of carotenoids in preventing epigenetic changesMetformin studies in infectious diseasesThe power of food in improving healthCutaneous spectrometersWhere to find Andrew: Baylor College of Medicine profileAndrew attended Wayne State School of Medicine from 2003 to 2007. His internship and residency in global health and Internal medicine was completed at the Hospital of the University of Pennsylvania in Philadelphia from 2007 to 2010.Support the Show.Thank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how.

Rabies is a vaccine-preventable, zoonotic, viral disease affecting the central nervous system. Once clinical symptoms appear, rabies is virtually 100% fatal, and treatment is typically supportive. It causes tens of thousands of deaths every year, mainly in Asia and Africa. Currently, there is no validated treatment in humans that prevents death following symptomatic rabies, however my guest today and his colleagues at the Uniformed Services University (USU) have made a significant breakthrough which may have changed that. Joining me today to discuss this rabies therapy is Brian Schaefer PhD, Dr Schaefer is a Professor in the Department of Microbiology and Immunology at the Uniformed Services University (USU) in Bethesda, MD. He also holds secondary appointments as Professor in the following USU graduate (Ph.D.) programs: Emerging Infectious Diseases; Molecular and Cell Biology; and Neuroscience. The study: mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.28.550550v1?rss=1 Authors: Andrews, T. S., Nakib, D., Perciani, C., Ma, X. Z., Liu, L., Winter, E., Camat, D., Chung, S., Manuel, J., Mangroo, S., Hansen, B., Arpinder, B., Thoeni, C., Sayed, B., Feld, J., Gehring, A., Gulamhusein, A., Hirschfield, G. M., Rciutto, A., Bader, G. D., McGilvray, I. D., MacParland, S. A. Abstract: Background: Primary sclerosing cholangitis (PSC) is a serious immune-mediated cholestatic liver disease characterized by bile retention, biliary tree destruction, and progressive fibrosis leading to end stage liver disease and transplantation. There is an unmet need to understand the cellular composition of the PSC liver and how it underlies disease pathogenesis. As such, we generated a comprehensive atlas of the PSC liver and a reference healthy liver dataset using multiple multi-omic modalities with functional validation. Methods: In this work, we employed single-cell (12,000 cells), single-nuclei (23,000 nuclei) and spatial transcriptomics (1 sample by 10x Visium and 3 samples with multi-region profiling by Nanostring GeoMx DSP) to profile the cellular ecosystem in 5 patients with PSC. Transcriptomic profiles were compared to 100k single cell transcriptomes and spatial transcriptomics controls from 24 healthy neurologically deceased donor (NDD) livers. Flow cytometry and intracellular cytokine staining was performed to validate PSC-specific differences in immune phenotype and function. Results: PSC explants with cirrhosis of the liver parenchyma and prominent periductal fibrosis were associated with a unique population of hepatocytes which transformed to a cholangiocyte-like phenotype. Those hepatocytes were surrounded by diverse immune cell populations, including monocyte-like macrophages, liver-resident and circulating natural killer (NK) cells. Cytokines released by inflamed cholangiocytes and fibrosis-resident hepatic stellate cells and endothelial cells recruited CD4+T-cells, dendritic cells, and neutrophils to PSC liver tissues. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional inflammatory response to LPS and IFN-{gamma} stimulation. Conclusions: We present the first comprehensive atlas of the PSC liver and demonstrate hyper-activation and exhaustion-like phenotypes of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.01.547333v1?rss=1 Authors: Fong, H., Mendel, M., Jascur, J., Najmi, L., Kim, K., Lew, G., Garimalla, S., Schock, S., Hu, J., Villegas, A., Conway, A., Fontenot, J., Zompi, S. Abstract: iPSCs can serve as a renewable source of a consistent edited cell product, overcoming limitations of primary cells. While feeder-free generation of clinical grade iPSC-derived CD8 T cells has been achieved, differentiation of iPSC-derived CD4sp and regulatory T cells requires mouse stromal cells in an artificial thymic organoid. Here we report a serum- and feeder-free differentiation process suitable for large-scale production. Using an optimized concentration of PMA/Ionomycin, we generated iPSC-CD4sp T cells at high efficiency and converted them to Tregs using TGF{beta} and ATRA. Using zinc finger nucleases, we demonstrated high non-viral, targeted integration of an HLA-A2 CAR in iPSCs. iPSC-Tregs +/- HLA-A2 CAR phenotypically, transcriptionally and functionally resemble primary Tregs and suppress T cell proliferation in vitro. Our work is the first to demonstrate an iPSC-based platform amenable to manufacturing CD4 T cells to complement iPSC-CD8 oncology products and functional iPSC-Tregs to deliver Treg cell therapies at scale. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

On episode #29 of the Infectious Disease Puscast, Daniel and Sara review the infectious disease literature for the weeks of 5/11 – 5/23/23. Hosts: Daniel Griffin and Sara Dong Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of Puscast! Links for this episode Harmonie phase IIIb study trial results of nirsevimab against RSV lower respiratory tract infection hospitalization for infants (ESPID) Mogamulizumab for treatment of HTLV-1 associated Myelopathy/Tropical Spastic Paraparesis (IDSA) Revised protocol for secondary prevention of congenital cytomegalovirus infection with valaciclovir (IDSA) Increase in false positive fourth generation HIV tests in patients with COVID-19 (CID) Implementation of an antibiotic stewardship initiative in a large urgent care network (JAMA) Clindamycin + vancomycin versus linezolid for treatment of necrotizing soft tissue infection (OFID) Assessing empiric antimicrobial therapy with the dundee classification for skin and soft tissue infections (OFID) Combination of amoxicillin 3000mg and probenecid vs 1500mg amoxicillin monotherapy for treating syphilis in patients with HIV (CID) The sympathetic nervous system is necessary for development of CD4+ T cell memory following Staphylococcus aureus infection (JID) Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with infections caused by Acinetobacter baumannii-calcoaceticu complex (The Lancet) First reported US cases of tinea caused by Trichophyton indotineae (CDC) How to use direct microscopy for diagnosing fungal infections (CMI) Limited Cutaneous Leishmaniasis as Ulcerated Verrucous Plaque on leg (EID) Can Ivermectin kill Sarcoptes scabiei during the molting process? (PLOS) The Infectious Diseases Specialist, at risk of extinction (JID) Ticks harbor and excrete chronic wasting disease prions (NIH) Music is by Ronald Jenkees

Check out "Heard on the Street" recorded during the IDS Paris 2023 Day 1 Poster session. Hear from Dr. Maria Bettini from University of Utah as she discusses recruitment of stem-like T cells and exhaustion resistance support CD4 T cells in autoimmunity.

In pursuit of mechanisms and evidence-based approaches, gut health has been revealed as a critical cornerstone of neurological health. In this episode, we're going into detail on what the gut layers are. I hope this video will help someone else who's trying to understand how the gut works for purposes of biohacking with functional medicine, nutrition, supplements, etc. For any intervention, is there evidence of a relationship, and is there data that it worked in other humans? We talk about: what the gut mucus is made out of elements of the gut barrier - the many ways the body keeps microbes and partially digested food away kinds of intestinal epithelial cells (Goblet cells, Paneth cells, M cells, etc.) and their functions types of gut associated lymphoid tissue (GALT) and their distinctions - lamina propria, Peyer's patches, lymph nodes the enteric nervous system and enteroendocrine cells different types of CD4+ T cells: Th1, Th2, Th17, and Treg, what they respond to, and their major outputs the mechanism of nutrient absorption the mechanism of leaky gut (paracellular transport through tight junctions) Here's the video: https://youtu.be/sIn_VxH6zDA Transcript of the video, for those who are pressed for time: https://www.brainforest.org/post/leaky-gut-anatomy I hope this helps someone understand their gut a little better on the path to health. Stay tuned for our next podcast on the relationship between leaky gut and aging. Share this resource with others who are studying gut anatomy on the path to health!

4.07 Polymyositis and Dermatomyositis MSK/Rheum review for the USMLE Step 1 Exam Polymyositis and dermatomyositis are autoimmune inflammatory myopathies. They are caused by abnormal activation of T cells that attack skeletal muscle and both cause proximal muscle weakness, especially of the shoulders and pelvic girdle muscles. Polymyositis develops when there is abnormal activation of CD8 T cells, while dermatomyositis is primarily attacked by CD4 T cells. Both are diagnosed through a muscle biopsy and the presence of elevated CK levels and several different autoantibodies. Dermatomyositis includes dermatologic manifestations, such as gottron papules, heliotrope rash, and shawl rash. Both are associated with MI, interstitial lung disease, and various types of cancer (dermatomyositis more so). Both diseases require prompt treatment with steroids and immunosuppressive agents.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.05.535697v1?rss=1 Authors: Zheng, J., Wang, L., Zhao, S., Zhang, W., Chang, Y., Dheer, A., Gao, S., Xu, S., Ayasoufi, K., Al-kharboosh, R., Xie, M., Johnson, A. J., Dong, H., Wu, L.-J. Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2-/- mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2+. Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4+ T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4+ T cell response against gliomas. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.02.530914v1?rss=1 Authors: Van Gulck, E., Pardons, M., Nijs, E., Verheyen, N., Dockx, K., Van Den Eynde, C., Battivelli, E., Vega, J., Florence, E., Autran, B., Archin, N., Margolis, D. M., Katlama, C., Hamimi, C., Van Den Wyngaert, I., Eyassu, F., Vandekerckhove, L., Boden, D. Abstract: A major barrier to HIV-1 cure is caused by the pool of latently infected CD4 T-cells that persist under combination antiretroviral therapy (cART). This latent reservoir is capable of producing replication-competent infectious virus once prolonged suppressive cART is withdrawn. Inducing the reactivation of HIV-1 gene expression in T-cells harboring a latent provirus in people living with HIV-1 under cART will likely result in depletion of this latent reservoir due to cytopathic effects or immune clearance. Studies have investigated molecules that reactivate HIV-1 gene expression but to date no latency reversal agent has been identified to eliminate latently infected cells harboring replication-competent HIV in cART treated individuals. Stochastic fluctuations in HIV-1 tat gene expression have been described and hypothesized to allow the progression into proviral latency. We hypothesized that exposing latently infected CD4+ T-cells to Tat would result in effective latency reversal. Our results indicate the capacity of a truncated Tat protein and mRNA to reactivate HIV-1 in latently infected T-cells ex vivo to a similar degree as the protein kinase C agonist: Phorbol 12-Myristate 13-Acetate, without T-cell activation nor any significant transcriptome perturbation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Tanvi Ahluwalia (voice), Chelsea Klein (post-production), and Amanda Bruce (post-production) from the Translational Molecular Medicine program at the University of Ottawa interview Ph.D. student Rafael Silva Lima from the Cell-Cell Interaction Lab at the Federal University of Minas Gerais in Belo Horizonte, Brazil. Rafael works on the characterization of the intestinal microbiota and the expression and methylation profile in CD4 + T cell differentiation genes in childhood and juvenile obesity. In this episode, Rafael shares with us his research on COVID-19 and how obesity interplays with the immune system to foster a severe immune response and contribute to severe COVID-19. Learn more: https://labicufmg.wixsite.com/labic/alunos?lang=en 0:00 - Introduction1:30 - What is covid-19?5:00 - How does obesity provide higher susceptibility to COVID-19 symptoms?6:15 - Immunology & Obesity Research7:15- Why obesity?8:00 - How did you select papers for the review? 9:00 - Upregulated Genes in Obesity10:30 - Next steps in obesity research & COVID-19 research12:15 - Differences in immune response between COVID-19 variants

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519463v1?rss=1 Authors: Vangansewinkel, T., Lemmens, S., Tiane, A., Geurts, N., Dooley, D., Vanmierlo, T., Pejler, G., Hendrix, S. Abstract: Traumatic spinal cord injury (SCI) most often leads to permanent paralysis due to the inability of axons to regenerate in the adult mammalian central nervous system (CNS). In the past, we have shown that mast cells (MCs) improve the functional outcome after SCI by suppressing scar tissue formation at the lesion site via mouse mast cell protease 6 (mMCP6). In this study, we investigated whether recombinant mMCP6 can be used therapeutically to improve the functional outcome after SCI. Therefore, we applied mMCP6 locally via an intrathecal catheter in the subacute phase after a spinal cord hemisection injury in mice. Our findings showed that hind limb motor function was significantly improved in mice that received recombinant mMCP6 compared to the vehicle-treated group. In contrast to our previous findings in mMCP6 knockout mice, the lesion size and expression levels of the scar components fibronectin, laminin, and axon growth-inhibitory chondroitin sulfate proteoglycans were not affected by the treatment with recombinant mMCP6. Surprisingly, no difference in infiltration of CD4+ T cells and reactivity of Iba-1+ microglia/macrophages at the lesion site was observed between the mMCP6 treated mice and control mice. Additionally, local protein levels of the pro- and anti inflammatory mediators IL-1{beta}, IL-2, IL-4, IL-6, IL 10, TNF-, IFN{gamma}, and MCP-1 were comparable between the two treatment groups, indicating that locally applied mMCP6 did not affect inflammatory processes after injury. However, the increase in locomotor performance in mMCP6-treated mice was accompanied by reduced demyelination and astrogliosis in the perilesional area after SCI. Consistently, we found that TNF-a/IL-1B-astrocyte activation was decreased, and that oligodendrocyte precursor cell (OPC) differentiation was increased after recombinant mMCP6 treatment in vitro. Mechanistically, this suggests effects of mMCP6 on reducing astrogliosis and improving (re)myelination in the spinal cord after injury. In conclusion, these data show for the first time that recombinant mMCP6 is therapeutically active in enhancing recovery after SCI. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Episode 120: Immune Reconstitution Inflammatory Syndrome (IRIS) Abeda Faharti and Dr. Schlaerth present the definition, diagnosis, and treatment of IRIS. Moderated by Dr. Arreaza. Written by Abeda Farhati, MS4, Ross University School of Medicine. Editing and comments by Katherine Schlaerth, MD, and Hector Arreaza, MD.You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.Definition.Have you heard of IRIS? No, not the color portion of our eyes. IRIS is short for Immune Reconstitution Inflammatory Syndrome. This condition occurs in immunocompromised patients with HIV/AIDS due to an overactive inflammatory response. In most cases, it occurs after initiating antiretroviral therapy (ART). To understand IRIS in HIV patients, we must first understand HIV.HIV.The Human Immunodeficiency Virus (HIV) infection was first reported in 1981. The virus attacks the immune system, destroying white blood cells called CD4+ T lymphocytes, which are part of our body's defense mechanism. These cells are also known as "helper T cells" and are responsible for destroying viruses, bacteria, and other germs that make us sick.When your CD4+ count is low, you are more likely to get serious infections from viruses, bacteria, and fungi, which usually do not cause problems in otherwise healthy individuals. These infections are called Opportunistic infections, and they can be deadly. To restore CD4+ T lymphocytes, HIV patients are started on ART to normalize their immune response to pathogens. As a result of these treatments, HIV patients' lives have been significantly improved and prolonged. [Comment by Dr. Arreaza: It is paradoxical, but some HIV patients are among the healthiest patients I have seen.]Despite this, no treatment is guaranteed to be without side effects. Increases in CD4+ T lymphocytes trigger the immune system to respond to any persisting antigen, regardless of whether it is fragments or intact organisms. As a result, a hyperinflammatory response may occur.Diagnosis.There are no established criteria for diagnosing IRIS. It is generally accepted that IRIS requires the worsening of an existing infection or an unrecognized, preexisting infection in the context of improved immune function. For a diagnosis to be made, most, if not all of the following features must be present:The presence of a low CD4 count (less than 100 cells) before initiating treatment with ART (Except IRIS secondary to preexisting TB infection can occur with CD4 counts >200 cells).The presence of an inflammatory condition, especially after ART is initiated.The absence of drug-resistant infection, bacterial superinfection, drug allergy, or other adverse drug reactions.The absence of patient noncompliance or reduced drug levels due to drug-drug interactions or malabsorption.Clinical Manifestations.IRIS can be presented in patients in 2 ways:Patient's with a preexisting infectious disease that has NOT been treated, getting paradoxically worse after initiating treatment with ART ---this is known as “unmasking IRIS” ORPatient's with a preexisting infectious disease that has been previously diagnosed and treated but regained capacity after treatment with ART, causing it to mount an inflammatory response – this is known as “paradoxical IRIS.”In summary: Unmasking IRIS and paradoxical IRIS.Patients with IRIS have clinical features that vary widely. The presentations are strongly dependent on the type of preexisting opportunistic infection. For example, about 75% of patients with a mycobacterial or cryptococcal-related infection will develop a fever. In contrast, fever is rarely seen in cytomegalovirus (CMV) infections.Risk & Prevention.Researchers have found that lower CD4 cell counts or high HIV RNA levels at the time of anti-retroviral treatment initiation increase the risk of developing IRIS. One way to prevent IRIS development is to treat opportunistic infections prior to starting ART. Although this reduces the risk of IRIS development, it does not guarantee it.Treatment.In “unmasking IRIS,” patients can be treated with antibiotics, antivirals, or antifungals against the underlying infectious organism. In severe cases, steroids can also be used to suppress inflammation until the infection has been eradicated. Unfortunately, there is no treatment for paradoxical IRIS. Most patients who experience “paradoxical IRIS” reactions will get better spontaneously without additional therapy.Incidence of IRIS.The overall incidence of IRIS is unknown; however, studies have shown that anywhere from 25 to 30% of HIV patients who start antiretroviral treatment develop IRIS in the first six months. You may ask, which preexisting infections can lead to patients developing IRIS?Pathogens associated with IRIS.Different pathogens have been associated with the development of IRIS. The leading pathogens include:Mycobacterium tuberculosisMycobacterium avium complexCytomegalovirusCryptococcus neoformansPneumocystis jiroveciiHerpes simplex virusHepatitis B virusHuman herpes virus 8 (associated with Kaposi sarcoma)Non-HIV etiologies.IRIS can also be seen in other immunocompromised conditions, such as:Solid organ transplant recipients Postpartum period – 3 to 6 weeks after giving birthNeutropenic patients – with an absolute neutrophil count of less than 500Patients on Tumor Necrosis Factor Antagonists (TNF antagonists)- are used to treat chronic conditions such as ulcerative colitis, Crohn's disease, or sarcoidosis.In summary, Immune Reconstitution Inflammatory Syndrome (IRIS) is a hyper-inflammatory state seen after initiating ART in HIV patients whose improved immune system responds to previously acquired opportunistic infection, whether treated or not.The treatment is directed to the unmasked specific opportunistic infection or support therapy if no active infection is found.____________________________Conclusion: Now we conclude episode number 121, “Immune Reconstitution Inflammatory Syndrome (IRIS).” This syndrome presents in about 30% of HIV patients when they start ART. A stronger immune system means a stronger immune reaction. So, keep in mind this diagnosis when your HIV patients get sicker when they are supposed to get better after starting ART. This week we thank Hector Arreaza, Abeda Farhati, and Katherine Schlaerth. Audio edition by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________Links:“CD4 Lymphocyte Count: MedlinePlus Medical Test.” Medlineplus.gov, accessed on November 4, 2022.https://medlineplus.gov/lab-tests/cd4-lymphocyte-count/#:~:text=A%20CD4%20count%20is%20mostly,have%20trouble%20fighting%20off%20infections.Sun HY, Singh N. Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients. Curr Opin Infect Dis. 2009 Aug;22(4):394-402. doi: 10.1097/QCO.0b013e32832d7aff. PMID: 19483618. https://pubmed.ncbi.nlm.nih.gov/19483618/Thapa, Sushma, and Utsav Shrestha. “Immune Reconstitution Inflammatory Syndrome.” PubMed, StatPearls Publishing, 2022, www.ncbi.nlm.nih.gov/books/NBK567803/.Wolfe, Cameron. Immune reconstitution inflammatory syndrome, UpToDate. ww.uptodate.com, https://www.uptodate.com/contents/immune-reconstitution-inflammatory-syndrome. Accessed November 14, 2022.Royalty-free music used for this episode: “Keeping Watch,” New Age Landscapes. Downloaded on October 13, 2022, from https://www.videvo.net/royalty-free-music-albums/new-age-landscapes/. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.22.517543v1?rss=1 Authors: Gallups, N. J., Childers, G. M., Webster, J. M., Yang, Y.-T., Zane, A., Mudium, N., Manfredsson, F., Kordower, J., Harms, A. S. Abstract: Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of GCI pathology, however it is not known what specifically drives disease pathogenesis. Recently in a mouse model of MSA, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs also remains unclear. In this study we use genetic and pharmacological approaches in a novel model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFN{gamma}) drives neuroinflammation and demyelination. Furthermore, using an IFN{gamma} reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFN{gamma} in response to -syn overexpression in oligodendrocytes. Results from these studies indicate that IFN{gamma} expression in CD4 T cells drives -syn-mediated neuroinflammation and demyelination, and strategies to target IFN{gamma} expression may be a potential disease modifying therapeutic strategy for MSA. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511960v1?rss=1 Authors: Schonhoff, A. M., Figge, D. A., Jurkuvenaite, A. J., Gallups, N. J., Childers, G. M., Webster, J. A., Standaert, D. G., Goldman, J. E., Harms, A. S. Abstract: Dopaminergic cell loss due to the accumulation of -syn is a core feature of PD pathogenesis. Neuroinflammation specifically induced by -syn has been shown to exacerbate neurodegeneration, yet the role of CNS resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating -syn related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response. Surprisingly, the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, -syn expression led to an expansion in BAM numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that BAMs played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, BAMs were identified in post-mortem PD brain in close proximity to T cells. These results point to a critical role for BAMs in mediating PD pathogenesis through their essential role in the orchestration of the -syn-mediated neuroinflammatory response. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Guar Gum may be a potent Immune regulator Diets high in guar gum, a common food additive and dietary fibre, limited inflammation and delayed the onset of multiple sclerosis (MS) symptoms in mice, according to new research by members of the University of British Columbia (UBC) Microbiology and Immunology department. #guargum #ms # neuroinflammation Fettig NM, Robinson HG, Allanach JR, Davis KM, Simister RL, Wang EJ, Sharon AJ, Ye J, Popple SJ, Seo JH, Gibson DL, Crowe SA, Horwitz MS, Osborne LC. Inhibition of Th1 activation and differentiation by dietary guar gum ameliorates experimental autoimmune encephalomyelitis. Cell Rep. 2022 Sep 13;40(11):111328. doi: 10.1016/j.celrep.2022.111328. PMID: 36103823. Guar gum, fiber, fibre, autoimmune, neuroinflammation, th1, autoimmune encephalomyelitis, dietary fiber, microbiota, experimental autoimmune encephalomyelitis, EAE, multiple sclerosis, MS, CD4+ T cells --- Support this podcast: https://anchor.fm/ralph-turchiano/support

Guar Gum may be a potent Immune regulator Diets high in guar gum, a common food additive and dietary fibre, limited inflammation and delayed the onset of multiple sclerosis (MS) symptoms in mice, according to new research by members of the University of British Columbia (UBC) Microbiology and Immunology department. #guargum #ms # neuroinflammation Fettig NM, Robinson HG, Allanach JR, Davis KM, Simister RL, Wang EJ, Sharon AJ, Ye J, Popple SJ, Seo JH, Gibson DL, Crowe SA, Horwitz MS, Osborne LC. Inhibition of Th1 activation and differentiation by dietary guar gum ameliorates experimental autoimmune encephalomyelitis. Cell Rep. 2022 Sep 13;40(11):111328. doi: 10.1016/j.celrep.2022.111328. PMID: 36103823. Guar gum, fiber, fibre, autoimmune, neuroinflammation, th1, autoimmune encephalomyelitis, dietary fiber, microbiota, experimental autoimmune encephalomyelitis, EAE, multiple sclerosis, MS, CD4+ T cells --- Support this podcast: https://anchor.fm/ralph-turchiano/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.01.505977v1?rss=1 Authors: Giachino, C., Tirolo, C., Caniglia, S., Serapide, M. F., L'Episcopo, F., Bertoli, F., Giuliano, C., Mearelli, M., Jakobi, M., Schneiderhan-Marra, N., Deleidi, M., Marchetti, B. Abstract: Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). The incomplete penetrance of LRRK2 mutations suggest that additional hits are required for disease onset. We hypothesized that chronic low-grade inflammation interacts with LRRK2 G2019S, the most frequent PD-associated mutation, to activate peripheral and central immune reactions and drive age-dependent neurodegeneration. Methods and Results: We exposed wild-type and LRRK2 G2019S mice to a low chronic dose of lipopolysaccharide, and we performed a longitudinal analysis of central and peripheral immune reactions and neurodegeneration. Low-dose inflammation triggered nigrostriatal degeneration, macrophage/monocyte brain infiltration, and astro-/microgliosis. LRRK2 G2019S mice showed an early dysregulation of peripheral cytokines, increased CD4+ T-cell infiltration and -synuclein aggregation in the colon. Interestingly, peripheral immune activation and colonic -synuclein aggregation precede astro-/microgliosis and neurodegeneration. Conclusions: Our study suggests an early role of the peripheral immune system and the gut in LRRK2 PD and provides a novel model to study early therapeutic immune targets and biomarkers. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

In this week's episode we review a novel approach to generating autologous CD7-specific CAR T therapy for patients with T-cell malignancies that overcomes a key limitation: target-driven fratricide. We'll also learn about new research pinpointing a key subset of exhausted CD4+ T cells in B- ALL, which also provides a rationale for combining tyrosine kinase inhibitors and PD-L1 blockers to reverse exhaustion and enhance leukemia clearance. Finally, we'll discuss studies in a mouse model of acute ischemic stroke, showing that inhibiting phosphorylation of a tight junction protein in endothelial cells reduces risk of intracranial hemorrhage after treatment with recombinant tissue plasminogen activator.

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late.  So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out.      Disclosures:  Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Vedanta Biosciences  Consulting or Advisory Role (Immediate family member): Shionogi  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences  Research Funding (Inst.): Zucero Therapeutics  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:   Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine  Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Measurement of CD4 T cell-mediated immunity requires functional tests to be conducted with viable peripheral blood mononuclear cells, PBMC. Recently, scientists at CTL successfully developed a positive control that not only verifies the functionality of CD4 T cells in PBMC, but also that the antigen-presenting cell compartment is unimpaired in the test sample as well.

Alex Berenson Substack Article China's CoronaVac shot caused people to make far more T-cells targeting the coronavirus than those who received Pfizer's mRNA shot, scientists in Hong Kong have found. Though it is only one datapoint, the study hints the Chinese shot - which is based on older, well understood principles of vaccinology - may ultimately provide longer-lasting protection than the hastily developed mRNA jabs from Pfizer and Moderna. The study was published in a peer-reviewed journal called Respirology in November, but has (unsurprisingly) received no attention. It offers a rare head-to-head look at the immune-system effects of the Chinese and Pfizer Covid vaccines, which work in very different ways. “Humoral responses” are antibodies, the body's first-line defense against infection; the mRNA vaccines are known to produce supra-natural levels of antibodies, giving rise to short-term protection that fades within months. T-cells are a part of the immune system crucial for producing long-term immunity and reducing severe disease in people who are infected. The mRNA jabs have been shown to produce relatively limited T-cell protection, but this study appears to have been the first time anyone directly compared them to the Chinese vaccine. As expected, they found very high levels of anti-spike protein antibodies in people who received the mRNA shot. The mRNA jabs force our cells to make large amounts of the spike protein that sticks out of the shell of the coronavirus. Those proteins then cause the immune system to produce antibodies against it. The CoronaVac recipients had lower levels of anti-spike protein antibodies. But they also had antibodies to other parts of the coronavirus. Even more importantly, when the scientists ran further tests on a smaller group of about 100 people, they found the CoronaVac shot had sharply increased the level of their coronavirus-targeting T-cells, which last far longer than antibodies. The new T-cells targeted both the spike protein and another important part of the virus. They included both CD4+ T-cells - which stimulate the overall immune response to infection - and CD8+ T-cells - which directly attack infected cells. Meanwhile, the mRNA jab produced an equally good response in only one of those four types of T-cell. “The average magnitude of post-vaccination responses was higher in CoronaVac subjects for structural and S-specific T-cell responses,” the researchers explain. CoronaVac's advantage in producing a T-cell response probably occurs because it presents the body with an invader that is far more like the actual coronavirus than the mRNA shots do. The CoronaVac shot is a traditional “inactivated virus” vaccine. It contains whole Sars-Cov-2 particles grown in kidney cells and chemically treated so they cannot reproduce. They are then injected alongside an “adujvant” meant to boost the immune response. In short-term trials, the mRNA vaccines reduced infections far more than the CoronaVac and a second Chinese vaccine called Sinopharm BIBP, which is also an inactivated virus vaccine. The early results led to considerable chest-pounding about the superiority of Western vaccines and biotechnology in general. But the real-world data from the last year has made clear that the mRNA shots lose their protective effect quickly. Because they focus the body's immune response on a small part of the coronavirus, they are also very vulnerable to new variants such as Omicron, even after a third “booster” dose. J Fallon Apple Music J Fallon Spotify --- Send in a voice message: https://anchor.fm/jason-fallon/message

Merhaba! Daha önceden HIV enfeksiyonunun seyri ve profilaksi üzerine ilk yazıyı paylaşmıştık. Bu yazıda ise HIV enfeksiyonuna ait çeşitli komplikasyonlar ile acil servise başvuran hastaların yönetimi üzerinde duracağız.​1​ ​2​ ​3​ Unutulmamalıdır ki antiretroviral tedaviye uyum gösteren hastalar, saptanamayan viral yüke, iyileştirilmiş yaşam kalitesine ve normal yaşam beklentisine ulaşabilir. Tedavi uyumsuzluğu olan veya henüz tanı almamış hastalar fırsatçı enfeksiyonlara ve ateş, kilo kaybı, yorgunluk ve halsizlik gibi sistemik semptomlara daha yatkın olabilir. HIV ile yaşayan bireyler için en önemli başvuru nedenlerinden biri ateştir.​4​ Bu hastaların fırsatçı enfeksiyonlara yakalanma ihtimalini ise en çok CD4+ T lenfosit sayısı değiştirir. Genel olarak, CD4+ T lenfosit değerleri

Why do some patients experience low CD4 T-cell counts? Join our expert faculty to find out. Credit available for this activity expires: 1/4/2023 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/965495?src=mkm_podcast_addon_965495

1 Aralık Dünya AIDS Günü nedeniyle HIV hakkında farkındalık yaratmak ve bilgilerimizi tazelemek adına bu yazıyı kaleme almak istedim. HIV + bireylerin acil servise başvuru nedenleri üzerine ikinci bir yazıyı ilerleyen tarihlerde sizinle paylaşacağım. Keyifli okumalar dilerim! Tanımlar ve Genel Bilgiler HIV yani Human immunodeficiency virus, lentivirüs ailesinde yer alan bir retrovirüstür. CD4+ T lenfositlerini hedef alarak immün sisteme zarar verir. Korunmasız cinsel ilişkiyle, kan yoluyla, anneden bebeğe (gebelik, doğum ve emzirme ile) bulaşır. HIV ter, tükürük, idrar, göz yaşı gibi vücut sıvılarıyla, hapşurma ya da öksürmeyle, aynı tabak, çatal, bıçak, havlu kullanımıyla, aynı tuvalet ve duşun kullanımıyla, sivrisinek, böcek ve diğer hayvan ısırıklarıyla, tokalaşma, sarılma, öpüşme, aynı ortamda bulunma gibi sosyal davranışlarla bulaşmaz. AIDS yani Edinilmiş Bağışıklık Yetersizliği Sendromu ise HIV enfeksiyonunun etkin tedavi almamış kişilerde görülen ileri evresi olarak adlandırılır. Günümüzde HIV ile yaşayan bireyler tedavi ile enfeksiyonun kontrol altına alınması halinde standart yaşam sürelerini HIV kaynaklı bir sağlık sorunu olmaksızın yaşayabilmektedir. Bu nedenle HIV + bireylerin çeşitli nedenlerle sağlık bakımından uzak kalmamaları oldukça önemlidir. Ülkemizde HIV bildirimi zorunlu hastalıklar listesinde yer almakta olup 1985 yılındaki ilk vaka bildiriminden bu yana sürveyansı yürütülmektedir.​1​ HIV konusunda toplumda farkındalığın düşük olması nedeniyle ve bireylerin ayırımcılık ve damgalanmaya uğramalarına engel olmak amacıyla HIV enfeksiyonunun bildiriminde hastaların güvenliği ve kişilik haklarına zarar verilmemesi esastır. Bu nedenle HIV nedeniyle sağlık kuruluşlarına başvuran, tedavi ve testlerini yaptıran hastaların veya yeni tespit edilen HIV + bireylerin kimliği ile ilgili bilgiler kodlanarak bildirilir. Ülkemizde HIV ile ilgili yıllık sayısal verilere Halk Sağlığı Genel Müdürlüğü'nün ilgili sayfasından ulaşılabilir. HIV Enfeksiyon Evreleri ​2​ ​3​ 1. Primer HIV enfeksiyonu: Virüs bulaşı sonucu ilk belirtilerin ortaya çıktığı akut HIV enfeksiyonu (1-6 hafta) ve serokonversiyonla (6-12 hafta) birlikte immün restorasyonun sağlanmaya başlandığı erken dönem HIV enfeksiyonudur. Akut dönemde klinik bulgular, HIV infeksiyonuna özgü değildir ve değişkendir. Sıklıkla görülen bulgular ateş, lenfadenopati, cilt döküntüleri, miyalji ve eklem ağrıları, ishal, baş ağrısı, bulantı, hepatosplenomegali ve oral aftlardır. 2. Kronik HIV enfeksiyonu: Persistan, asemptomatik, latent ya da inaktif dönem olarak da bilinir. Bu dönemde virüsün replikasyon hızı ve CD4+ T lenfosit kaybı azalır. Bu dönemde kişilerde belirti yoktur ama bulaştırıcıdırlar. Asemptomatik dönem ortalama 8-10 yıl sürer. Ancak vakaların %20 ila 30'unda ortalama 1.5-5 yıl içerisinde bir sonraki döneme geçiş olabilir. Asemptomatik süre hastaya ait faktörler ve HIV virülansı ile değişir. 3. İleri evre hastalık/AIDS: Tedavi edilmeyen HIV olgularının çoğunluğunda virüsün edinilmesinden ortalama 8-10 yıl sonra AIDS açığa çıkar. AIDS, CD4+ T lenfositi sayısının

On the World HTLV Day (10th November), we focus on how the Human T leukaemia virus affects people, and review new developments in HTLV treatment and vaccination medicine. HTLV is a retrovirus similar to HIV which incorporates its DNA indefinitely into the human CD4 T lymphocytes. It is predominantly transmitted through condomless sex, but also from mother-to-child and through contact with HTLV positive blood. Unlike HIV, HTLV causes severe disease only in about 5% of PLHTLV, so it is easy for HTLV transmission to go unnoticed. The two dominant HTLV associated diseases are Adult T cell leukaemia (ATL) and HTLV-1 associated myelopathy (HAM/TSP). Participants: STI's Podcast Editor, Dr Fabiola Martin, interview Ms Kristy Blakeborough, Lived experience and UK patient rep; Prof Yoshihisa Yamano, Neurologist St Marianna University Japan; A/P Keith Chappell, University of Queensland. Read the blog post: https://blogs.bmj.com/sti/2021/11/10/world_htlv_day/ Other relevant links: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2818%2930974-7/fulltext https://gvn.org/who/ https://pubmed.ncbi.nlm.nih.gov/27965813/ https://pubmed.ncbi.nlm.nih.gov/33250897/ https://www.htlvaware.com

Dr. Dario Vignali is the Frank Dixon Chair in Cancer Immunology and Vice Chair and Professor of Immunology at University of Pittsburgh School of Medicine.  His lab studies various aspects of T cell regulation, and recently generated a new mouse model to target conventional CD4 T cells.

Macrophage polarization and differentiation works in conjunction with CD4+ T lymphocyte differentiation into Th1 and Th2 subclasses and both NK and B cell activities. The aging human loses feedback control over the pro-inflammatory and anti-inflammatory pathways from these classical cellular differentiations contributing to hyperinflammation and/or hypoinflammatory responses ultimately resulting in pathological cell degeneration or proliferation, morbidity and death. Dr. Daniel J. Guerra Authentic Biochemistry Production. 18.9.21. Reference Nature Immunology June 2018 19: 561–570 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

A few people are asking about the need to vaccinate if you have already had COVID natural illness. What is the story here? Hot off of the press from Cell Reports Medicine, we see: "Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients." (Cohen et. al. 2021) Read more for COVID #41......https://www.salisburypediatrics.com/patient-education/dr-magryta-s-newsletter/988-volume-11-letter-33-coronavirus-update-42 Read more for COVID #42......https://www.salisburypediatrics.com/patient-education/dr-magryta-s-newsletter/994-coronavirus-update-42 Happy listening Dr. M

Dr. Marc Jenkins is a Regents and Distinguished McKnight University Professor in the Department of Microbiology and Immunology and the Director of the Center for Immunology at the University of Minnesota. Dr. Jenkins discovered that CD4+ T cells require CD28 as well as TCR to produce IL-2. The Jenkins lab is focused on the basic biology of CD4+ T lymphocytes.

Cranberry Powder Attenuates Benign Prostatic Hyperplasia University of Suwon (South Korea), June 21, 2021   Cranberry powder (CR) is reported to be effective against lower urinary tract symptoms (LUTS) and recurrent urinary tract infections. Benign prostatic hyperplasia (BPH) in men older than 50 years is a common cause of LUTS. Here, we attempted to evaluate if CR is also effective for treating BPH using a BPH-induced rat model, which was orally administered CR. Male Sprague-Dawley rats weighing 200–250 g were randomly divided into the following six groups (n = 9): noncastration group; castration group; BPH group; BPH and cranberry for 8-week (CR8W) group; BPH and cranberry for 4-week (CR4W) group; and BPH and saw palmetto group (saw palmetto). Compared with the BPH group, the CR8W group showed a significant decrease in prostate weight (by 33%), dihydrotestosterone (DHT) levels (by 18% in serum and 28% in prostate), 5-alpha reductase levels (18% reduction of type 1 and 35% of type 2), and histological changes. These results indicate that CR could attenuate BPH by inhibiting 5-alpha reductase and by reducing other biomarkers such as prostate weight and DHT levels. Thus, CR may be an effective candidate for the development of a functional food for BPH treatment. IACUC (USW-IACUC-R-2015-004).   In our investigation, the administration of CP significantly prevented the progression of BPH by reducing the 5AR levels, and consequently reducing DHT levels in the serum and prostate, along with reduction of the prostate size. This study demonstrated that CR exerts positive effects against BPH, based on biochemical and histological changes in BPH-induced rats. Although further investigation and validation is required, our study provides evidence, for developing a potential treatment for BPH from natural products.     Psychedelic spurs growth of neural connections lost in depression Yale University, July 5, 2021 The psychedelic drug psilocybin, a naturally occurring compound found in some mushrooms, has been studied as a potential treatment for depression for years. But exactly how it works in the brain and how long beneficial results might last is still unclear. In a new study, Yale researchers show that a single dose of psilocybin given to mice prompted an immediate and long-lasting increase in connections between neurons. The findings are published July 5 in the journal Neuron. "We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well," said Yale's Alex Kwan, associate professor of psychiatry and of neuroscience and senior author of the paper. Previous laboratory experiments had shown promise that psilocybin, as well as the anesthetic ketamine, can decrease depression. The new Yale research found that these compounds increase the density of dendritic spines, small protrusions found on nerve cells which aid in the transmission of information between neurons. Chronic stress and depression are known to reduce the number of these neuronal connections. Using a laser-scanning microscope, Kwan and first author Ling-Xiao Shao, a postdoctoral associate in the Yale School of Medicine, imaged dendritic spines in high resolution and tracked them for multiple days in living mice. They found increases in the number of dendritic spines and in their size within 24 hours of administration of psilocybin. These changes were still present a month later. Also, mice subjected to stress showed behavioral improvements and increased neurotransmitter activity after being given psilocybin. For some people, psilocybin, an active compound in "magic mushrooms," can produce a profound mystical experience. The psychedelic was a staple of religious ceremonies among indigenous populations of the New World and is also a popular recreational drug. It may be the novel psychological effects of psilocybin itself that spurs the growth of neuronal connections, Kwan said. "It was a real surprise to see such enduring changes from just one dose of psilocybin," he said. "These new connections may be the structural changes the brain uses to store new experiences."   How long can a person live? The 21st century may see a record-breaker University of Washington, July 2, 2021 The number of people who live past the age of 100 has been on the rise for decades, up to nearly half a million people worldwide. There are, however, far fewer "supercentenarians," people who live to age 110 or even longer. The oldest living person, Jeanne Calment of France, was 122 when she died in 1997; currently, the world's oldest person is 118-year-old Kane Tanaka of Japan. Such extreme longevity, according to new research by the University of Washington, likely will continue to rise slowly by the end of this century, and estimates show that a lifespan of 125 years, or even 130 years, is possible. "People are fascinated by the extremes of humanity, whether it's going to the moon, how fast someone can run in the Olympics, or even how long someone can live," said lead author Michael Pearce, a UW doctoral student in statistics. "With this work, we quantify how likely we believe it is that some individual will reach various extreme ages this century." Longevity has ramifications for government and economic policies, as well as individuals' own health care and lifestyle decisions, rendering what's probable, or even possible, relevant at all levels of society. The new study, published June 30 in Demographic Research, uses statistical modeling to examine the extremes of human life. With ongoing research into aging, the prospects of future medical and scientific discoveries and the relatively small number of people to have verifiably reached age 110 or older, experts have debated the possible limits to what is referred to as the maximum reported age at death. While some scientists argue that disease and basic cell deterioration lead to a natural limit on human lifespan, others maintain there is no cap, as evidenced by record-breaking supercentenarians. Pearce and Adrian Raftery, a professor of sociology and of statistics at the UW, took a different approach. They asked what the longest individual human lifespan could be anywhere in the world by the year 2100. Using Bayesian statistics, a common tool in modern statistics, the researchers estimated that the world record of 122 years almost certainly will be broken, with a strong likelihood of at least one person living to anywhere between 125 and 132 years. To calculate the probability of living past 110 -- and to what age -- Raftery and Pearce turned to the most recent iteration of the International Database on Longevity, created by the Max Planck Institute for Demographic Research. That database tracks supercentenarians from 10 European countries, plus Canada, Japan and the United States. Using a Bayesian approach to estimate probability, the UW team created projections for the maximum reported age at death in all 13 countries from 2020 through 2100. Among their findings: Researchers estimated near 100% probability that the current record of maximum reported age at death -- Calment's 122 years, 164 days -- will be broken; The probability remains strong of a person living longer, to 124 years old (99% probability) and even to 127 years old (68% probability); An even longer lifespan is possible but much less likely, with a 13% probability of someone living to age 130; It is "extremely unlikely" that someone would live to 135 in this century. As it is, supercentenarians are outliers, and the likelihood of breaking the current age record increases only if the number of supercentenarians grows significantly. With a continually expanding global population, that's not impossible, researchers say. People who achieve extreme longevity are still rare enough that they represent a select population, Raftery said. Even with population growth and advances in health care, there is a flattening of the mortality rate after a certain age. In other words, someone who lives to be 110 has about the same probability of living another year as, say, someone who lives to 114, which is about one-half. "It doesn't matter how old they are, once they reach 110, they still die at the same rate," Raftery said. "They've gotten past all the various things life throws at you, such as disease. They die for reasons that are somewhat independent of what affects younger people. "This is a very select group of very robust people."     Dried Plum Consumption Improves Total Cholesterol and Antioxidant Capacity and Reduces Inflammation in Healthy Postmenopausal Women San Diego State University, June 27, 2021 Dried plums contain bioactive components that have demonstrated antioxidant and anti-inflammatory effects. The objective of this study was to determine if dried plum consumption reduces the risk factors for cardiovascular disease (CVD) in postmenopausal women, specifically examining lipid profiles, oxidative stress, antioxidant capacity, and inflammation in a dose-dependent manner. We conducted a 6-month, parallel-design controlled clinical trial, where 48 postmenopausal women were randomly assigned to consume 0, 50, or 100 g of dried plum each day. After 6 months of intervention, total cholesterol (TC) in the 100 g/day treatment group (P = .002) and high-density lipoprotein cholesterol in the 50 g/day treatment group (P = .005) improved significantly compared to baseline. Inflammatory biomarkers interleukin-6 (P = .044) and tumor necrosis factor-α (P = .040) were significantly lower after 6 months within the 50 g/day dried plum group compared to baseline. Moreover, total antioxidant capacity increased significantly within the 50 g/day group (P = .046), and superoxide dismutase activity increased significantly within both 50 and 100 g/day groups (P = .044 and P = .027, respectively) after 6 months compared to baseline. In addition, plasma activities of alanine transaminase (P = .046), lactate dehydrogenase (P = .039), and creatine kinase (P = .030) were significantly lower after 6 months in the 50 g/day dried plum group. These findings suggest that daily consumption of 50–100 g dried plum improves CVD risk factors in postmenopausal women as exhibited by lower TC, oxidative stress, and inflammatory markers with no clear dose dependence.     Regular physical activity linked to more 'fit' preteen brains   Childrens Hospital Boston, July 2, 2021 We know exercise has many health benefits. A new study from Boston Children's Hospital adds another benefit: Physical activity appears to help organize children's developing brains. The study, led by Dr. Caterina Stamoulis, analyzed brain imaging data from nearly 6,000 9- and 10-year-olds. It found that physical activity was associated with more efficiently organized, robust, and flexible brain networks. The more physical activity, the more "fit" the brain. "It didn't matter what kind of physical activity children were involved in," says Dr. Stamoulis, who directs the Computational Neuroscience Laboratory at Boston Children's. "It only mattered that they were active." Crunching the data Dr. Stamoulis and her trainees, Skylar Brooks and Sean Parks, tapped brain imaging data from the Adolescent Brain Cognitive Development (ABCD) study, a long-running study sponsored by the National Institutes of Health. They used functional magnetic resonance imaging (fMRI) data to estimate the strength and organizational properties of the children's brain circuits. These measures determine how efficiently the brain functions and how readily it can adapt to changes in the environment. "The preteen years are a very important time in brain development," notes Dr. Stamoulis. "They are associated with a lot of changes in the brain's functional circuits, particularly those supporting higher-level thought processes. Unhealthy changes in these areas can lead to risky behaviors and long-lasting deficits in the skills needed for learning and reasoning." The team combined these data with information on the children's physical activity and sports involvement, supplied by the families, as well as body mass index (BMI). Finally, they adjusted the data for other factors that might affect brain development, such as being born before 40 weeks of gestation, puberty status, sex, and family income. Healthy brain networks Being active multiple times per week for at least 60 minutes had a widespread positive effect on brain circuitry. Children who engaged in high levels of physical activity showed beneficial effects on brain circuits in multiple areas essential to learning and reasoning. These included attention, sensory and motor processing, memory, decision making, and executive control (the ability to plan, coordinate, and control actions and behaviors). In contrast, increased BMI tended to have detrimental effects on the same brain circuitry. However, regular physical activity reduced these negative effects. "We think physical activity affects brain organization directly, but also indirectly by reducing BMI," Dr. Stamoulis says. Analyzing brain effects In the analyses, the brain was represented mathematically as a network of "nodes": a set of brain regions linked by connections of varying strength. Physical activity had two kinds of positive effects: on the efficiency and robustness of the network as a whole, and on more local properties such as the number and clustering of node connections. "Highly connected local brain networks that communicate with each other through relatively few but strong long-range connections optimizes information processing and transmission in the brain," explains Dr. Stamoulis. "In preteens, a number of brain functions are still developing, and they can be altered by a number of risk factors. Our results suggest that physical activity has a positive protective effect across brain regions."   Could Sumac Be Effective on COVID-19 Treatment? Fırat University Medicine Faculty (Turkey), June 11, 2021 Sumac is an herbal product, commonly consumed as a spice and was used for medical treatment for centuries. The phytochemical structure of Sumac was studied extensively, and it was established that the herb contained tannins, polyphenols, flavonoids, organic acids, and essential oils. Various scientific studies demonstrated that Sumac had a free oxygen radical-scavenging effect, a protective effect against liver damage, antihemolytic, leukopenia, and antifibrogenic effects, along with its antiviral, antimicrobial, anti-inflammatory, and antioxidant properties. Recently, several scientific studies described the pathophysiology, clinical course, and the treatment of COVID-19 infection. The examination of the characteristics of COVID-19 infection revealed via the clinical studies suggests that Sumac extract could be useful in the treatment of COVID-19. Given the scientific studies focusing on the beneficial effects of Sumac, the present review aims to provide an encouraging viewpoint to investigate whether Sumac is effective in treating COVID-19 infection. Antiviral Effect SARS-CoV2 virus, which causes COVID-19 infection, is a highly infectious RNA virus. There are no scientific studies on whether Sumac is effective against the SARS-CoV2 virus. On the contrary, the medications currently being used for treatment were directly administered in clinics, without scrutinizing whether they were effective against the novel coronavirus. Subsequently, several medications were identified to be useful during the clinical course of the disease. Yet, there are scientific in vitro and in vivo studies that investigated the antiviral effects of Sumac against several viruses. In a study, bioflavonoids isolated from Sumac were evaluated for their antiviral activities. Sumac presented inhibitory activities against respiratory viruses (influenza A, influenza B, and measles) and herpes viruses (HSV-1, HSV-2, and varicella zoster virus [VZV]).2 Another study found that Sumac extract exhibited significant antiviral activity against fish pathogenic infectious hematopoietic necrosis virus, and viral hemorrhagic septicemia virus. Furthermore, it was considered that Sumac was a potential antiviral therapeutic against fish viral diseases.3 In a study conducted in 2015, it was established that urushiol obtained from Sumac exhibited reverse transcriptase inhibitory activity for human immunodeficiency virus type 1 (HIV-1). It was specified that Sumac could be used as a biological resource due to such inhibitory activity.4 Another study focusing on HIV found that Sumac extracts exhibited anti-HIV activity due to inhibiting the HIV-1 reverse transcriptase and protease activity. It was also demonstrated that Sumac inhibited the viral load in HIV-infected CEM-GFP (a CD4+ T-lymphocytic reporter cell line expressing green fluorescent protein [GFP] under HIV-1 LTR promoter) cells and human peripheral blood lymphocytes.5 Another study reported that Sumac extract presented strong antiviral activity against HSV-1 and HSV-2. The study also revealed that Sumac extract did not only interact with the viral envelope but also interacted with the surface of the host cells of the viruses, thus, disrupted the ability of the virus to adsorb and penetrate the host cells.6 The above-mentioned studies indicated the antiviral effects of Sumac extracts. The review of the viruses, on which Sumac is effective, such as influenza, HSV-1, HSV-2, VZV, and HIV-1 demonstrated that the common point between these viruses was the fact that they are all enveloped viruses, contain dense lipids in their envelopes, and are sensitive to ether.7 Coronaviruses share the same common features.7 Sumac is likely to affect the lipid layer in the virus envelope, disrupting the adsorption to the host cell and preventing the virus from penetrating the host cell, positively contributing to the infection. Naturally, this hypothesis should be evidenced in future studies. However, its effectiveness on the novel coronavirus (SARS-CoV2) should be clarified first through animal testing and subsequently should be tested through human subjects. Conclusion An evaluation of the up to date knowledge, revealed by the clinical studies, on the characteristics of COVID-19 infection, its pathophysiology, clinic, and treatment, suggests that the use of Sumac extracts could be beneficial. Based on the beneficial effects indicated by the scientific studies on Sumac extracts, the present review could be encouraging to investigate its effectiveness for COVID-19 treatment. The authors of the present study believe that the benefits of Sumac extract can be tested by adding the adverse-effect-free Sumac extract to treatment and protecting the existing treatment protocols.   Sugar intake during pregnancy is associated with allergy and allergic asthma in children University of Bristol (UK), July 5, 2021 High maternal sugar intake during pregnancy may increase the risk of allergy and allergic asthma in the offspring, according to an early study led by Queen Mary University of London (QMUL) involving almost 9,000 mother-child pairs. While some research has reported an association between a high consumption of sugar-containing beverages and asthma in children, the relation between maternal sugar intake during pregnancy and allergy and asthma in the offspring has been little studied. The team, which included researchers from University of Bristol, used data from a world-leading birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC), also known as 'Children of the 90s'. The cohort recruited mothers who were pregnant in the 1990s and has been following up their offspring ever since. The current study, which is published in the European Respiratory Journal, analysed associations between maternal intake of free sugars in pregnancy and allergy (defined by positive skin tests to common allergens, namely dust mite, cat and grass) and asthma at seven years of age. While there was only weak evidence for a link between free sugar intake in pregnancy and asthma overall, there were strong positive associations with allergy and allergic asthma (where the child was diagnosed with asthma and had positive skin tests to allergens). When comparing the 20 per cent of mothers with the highest sugar intake versus the 20 per cent of mothers with the lowest sugar intake, there was an increased risk of 38 per cent for allergy in the offspring (73 per cent for allergy to two or more allergens) and 101 per cent for allergic asthma. The team found no association with eczema or hay fever. Lead researcher Professor Seif Shaheen from QMUL said: "We cannot say on the basis of these observations that a high intake of sugar by mothers in pregnancy is definitely causing allergy and allergic asthma in their offspring. However, given the extremely high consumption of sugar in the West, we will certainly be investigating this hypothesis further with some urgency. "The first step is to see whether we can replicate these findings in a different cohort of mothers and children. If we can, then we will design a trial to test whether we can prevent childhood allergy and allergic asthma by reducing the consumption of sugar by mothers during pregnancy. In the meantime, we would recommend that pregnant women follow current guidelines and avoid excessive sugar consumption." The team speculate that the associations may be explained by a high maternal intake of fructose causing a persistent postnatal allergic immune response leading to allergic inflammation in the developing lung. The researchers controlled for numerous potential confounders in their analyses, such as background maternal characteristics, social factors and other aspects of maternal diet, including foods and nutrients that have been previously linked to childhood asthma and allergy. Importantly, the offspring's free sugar intake in early childhood was found to have no association with the outcomes seen in the analysis. As the study is observational, it does not prove a causal link between maternal sugar intake and allergies or asthma. A randomised controlled trial would be needed to definitively test causality.

Listen to the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 10. View the complete issue: https://www.oncotarget.com/archive/v12/i10/ COVER PAPER: “Inhibitory effects of Tomivosertib in acute myeloid leukemia” https://doi.org/10.18632/oncotarget.27952 EDITORIAL: “Raman spectroscopy determination of the mineral characteristics of microcalcifications in breast cancer, a way towards an improved screening approach” https://doi.org/10.18632/oncotarget.27912 (PDF Download) EDITORIAL: “Reactive oxygen species in leukemias: maintaining cancer cell proliferation via redox signaling and changing metabolic homeostasis” https://doi.org/10.18632/oncotarget.27913 (PDF Download) RESEARCH PAPER: “Genome wide DNA methylation landscape reveals glioblastoma’s influence on epigenetic changes in tumor infiltrating CD4+ T cells” https://doi.org/10.18632/oncotarget.27955 RESEARCH PAPER: “Association between miRNA signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity” https://doi.org/10.18632/oncotarget.27953 RESEARCH PAPER: “Perioperative changes in the plasma metabolome of patients receiving general anesthesia for pancreatic cancer surgery” https://doi.org/10.18632/oncotarget.27956 RESEARCH PAPER: “Transcriptome analyses of urine RNA reveal tumor markers for human bladder cancer: validated amplicons for RT-qPCR-based detection” https://doi.org/10.18632/oncotarget.27954 Keywords - acute myeloid leukemia, breast cancer, bladder cancer, leukemia, DNA methylation, tumor, glioblastoma, miRNA, skin toxicity, pancreatic cancer, cancer, science, research, oncology About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals, LLC. Please visit https://www.impactjournals.com/ or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Merhabalar. Bilindiği üzere, glukokortikoid için kritik olan ve olmayan hastalarda çeşitli kullanım alanları mevcut. ARDS, septik şok, toplum kaynaklı pnömoni gibi ciddi hallerde ise rolü tartışmalı. Bunun sebebi ise genellikle hastalıkların patogenezinin ve konağın glukokortikoidlere yanıtının hastadan hastaya değişmesi. Bugün glukokortikoidlerin kritik bakımdaki kullanımı ile ilgili bulduğum 90 sayfalık bir kaynağı​1​ özetlemeye çalışacağım. Kortizol üretimi emosyonel ve fiziksel streslerle tetiklenmekle birlikte, bazal olarak gece git gide artan ve sabah uyanmaya yakın saatte pik yapan bir sirkadyen ritmi izler. Gün içerisinde ise kortizol düzeyleri giderek azalır. Bu düzen, hipotalamusun suptakiazmatik çekirdeği tarafından kontrol edilir. Mekanizma Glukokortikoidler birtakım genleri aktive ederek veya baskılayarak immunsupresyon oluşturur.Bu etki birkaç basamakta meydana gelir ve etki başlangıç süresi 4-24 saat arasında değişir.Ekstraselüler alanda, glukokortikoidlerin çoğunluğu kortikosteroid bağlayıcı globüline bağlı ve inaktif halde bulunur.Bağlı olmayan glukokortikoidler ise plazma membranından geçerek sitoplazmadaki glukokortikoid reseptörü ile bir araya gelir.Glukokortikoid ile bağlı olmadığı zamanlarda, glukokortikoid reseptörü sitoplazma içerisinde çeşitli şaperon moleküllerine (ısı şok proteinleri, immunofilinler) bağlı halde inaktif halde bulunur.Glukokortikoidlerin glukokortikoid reseptörleri ile bağlanması sonucu şaperon moleküller reseptörden ayrılır ve glukokortikoid-reseptör kompleksi çekirdek içerisine girerek belirli genleri aktive veye suprese eder. Glukokortikoidlerin dokulara geçişi çeşitli faktörlere bağlıdır. Örneğin, glukokortikoidlerin plazma proteinlerine bağlanması, beyin omurilik sıvısına geçişini etkiler. Prednizolonun proteine bağlanması konsantrasyon bağımlı olup %60-95 arasında değişmekteyken deksametazon daha sabit olarak %70 oranında proteine bağlanır. Buna göre, deksametazonun daha uzun yarı ömrüne ek olarak BOS geçişi daha iyidir. Glukokortikoid Kullanımın Genel Olarak Kabul Gördüğü Akut ve Kronik Hastalıklar : Bu hastalıklarda glukokortikoid kullanılmasında herkes hemfikir. Astım ve KOAH Alevlenmeleri Astım veya KOAH alevlenmesinde olan hastalar için glukokortikoidler hayat kurtarıcı olabilir.Ciddi astım tedavisinde 125 mg iv başlangıç dozunu takiben (GINA kılavuzuna göre 60-80 mg), hasta yanıtına göre her 6-12 saatte bir 60 mg oral metilprednizolon, toplam 5-10 gün süresince önerilir.KOAH alevlenmesinde, kısa süreli glukokortikoid kullanımının faydalı olduğu gösterilmiş.Glukokortikoid tedavisinin yardımlı ventilasyon ihtiyacı olmayan hastalarda havayolu obstrüksiyonu ve semptomlarda daha hızlı iyileşme, daha az tedavi başarısızlığı ve daha kısa hastane yatış süreleri ile ilişkili olduğu gösterilmiş. Bunun yanı sıra, glukokortikoidlerin oral veya iv yoldan verilmesinin tedavi başarısında, relaps veya mortalitede bir fark yaratmadığı da gösterilmiş​2​.KOAH alevlenmesi nedeniyle yoğun bakımda takip edilen 17.239 hastalık gözlemsel bir çalışmada, günlük 240 mg veya daha düşük dozda metilprednizolon verilmesinin, günlük 240 mg’dan daha yüksek dozda verilmesiyle mortaliteya katkısı açısından farkı olmadığı, bunun yanı sıra, düşük doz grubunun daha kıza yoğun bakım yatışı ve mekanik ventilasyon süresi ile ilişkili olduğu görülmüş​3​. Pnömosistoz Pneumocystis Jiroveci’nin neden olduğu, CD4+ T hücre sayısı< 200/mm3 olan veya intrinsik T hücre disfonksiyonu olan, sitotoksik kemoterapi veya uzamış yüksek doz glukokortikoid kullananlar gibi immunkompromize hastalarda meydana gelen bir enfeksiyondur.Tedavi seçenekleri arasında trimetoprim-sulfometaksazol, pentamidin, dapson+trimetoprim veya klindamisin+primakin bulunur.Pnömosistoz tedavisi alan HIV-pozitif hastalarda prednizon tedavisi eklenmesinin erken dönemde solunumsal kötüleşmeyi ve mortaliteyi azalttığı gösterilmiş. Bunun muhtemel sebebinin anti-pnömosistoz tedavisinin sonucunda ortaya çıkan inflamatuvar yanıt...

Merhabalar. Bilindiği üzere, glukokortikoid için kritik olan ve olmayan hastalarda çeşitli kullanım alanları mevcut. ARDS, septik şok, toplum kaynaklı pnömoni gibi ciddi hallerde ise rolü tartışmalı. Bunun sebebi ise genellikle hastalıkların patogenezinin ve konağın glukokortikoidlere yanıtının hastadan hastaya değişmesi. Bugün glukokortikoidlerin kritik bakımdaki kullanımı ile ilgili bulduğum 90 sayfalık bir kaynağı​1​ özetlemeye çalışacağım. Kortizol üretimi emosyonel ve fiziksel streslerle tetiklenmekle birlikte, bazal olarak gece git gide artan ve sabah uyanmaya yakın saatte pik yapan bir sirkadyen ritmi izler. Gün içerisinde ise kortizol düzeyleri giderek azalır. Bu düzen, hipotalamusun suptakiazmatik çekirdeği tarafından kontrol edilir. Mekanizma Glukokortikoidler birtakım genleri aktive ederek veya baskılayarak immunsupresyon oluşturur.Bu etki birkaç basamakta meydana gelir ve etki başlangıç süresi 4-24 saat arasında değişir.Ekstraselüler alanda, glukokortikoidlerin çoğunluğu kortikosteroid bağlayıcı globüline bağlı ve inaktif halde bulunur.Bağlı olmayan glukokortikoidler ise plazma membranından geçerek sitoplazmadaki glukokortikoid reseptörü ile bir araya gelir.Glukokortikoid ile bağlı olmadığı zamanlarda, glukokortikoid reseptörü sitoplazma içerisinde çeşitli şaperon moleküllerine (ısı şok proteinleri, immunofilinler) bağlı halde inaktif halde bulunur.Glukokortikoidlerin glukokortikoid reseptörleri ile bağlanması sonucu şaperon moleküller reseptörden ayrılır ve glukokortikoid-reseptör kompleksi çekirdek içerisine girerek belirli genleri aktive veye suprese eder. Glukokortikoidlerin dokulara geçişi çeşitli faktörlere bağlıdır. Örneğin, glukokortikoidlerin plazma proteinlerine bağlanması, beyin omurilik sıvısına geçişini etkiler. Prednizolonun proteine bağlanması konsantrasyon bağımlı olup %60-95 arasında değişmekteyken deksametazon daha sabit olarak %70 oranında proteine bağlanır. Buna göre, deksametazonun daha uzun yarı ömrüne ek olarak BOS geçişi daha iyidir. Glukokortikoid Kullanımın Genel Olarak Kabul Gördüğü Akut ve Kronik Hastalıklar : Bu hastalıklarda glukokortikoid kullanılmasında herkes hemfikir. Astım ve KOAH Alevlenmeleri Astım veya KOAH alevlenmesinde olan hastalar için glukokortikoidler hayat kurtarıcı olabilir.Ciddi astım tedavisinde 125 mg iv başlangıç dozunu takiben (GINA kılavuzuna göre 60-80 mg), hasta yanıtına göre her 6-12 saatte bir 60 mg oral metilprednizolon, toplam 5-10 gün süresince önerilir.KOAH alevlenmesinde, kısa süreli glukokortikoid kullanımının faydalı olduğu gösterilmiş.Glukokortikoid tedavisinin yardımlı ventilasyon ihtiyacı olmayan hastalarda havayolu obstrüksiyonu ve semptomlarda daha hızlı iyileşme, daha az tedavi başarısızlığı ve daha kısa hastane yatış süreleri ile ilişkili olduğu gösterilmiş. Bunun yanı sıra, glukokortikoidlerin oral veya iv yoldan verilmesinin tedavi başarısında, relaps veya mortalitede bir fark yaratmadığı da gösterilmiş​2​.KOAH alevlenmesi nedeniyle yoğun bakımda takip edilen 17.239 hastalık gözlemsel bir çalışmada, günlük 240 mg veya daha düşük dozda metilprednizolon verilmesinin, günlük 240 mg’dan daha yüksek dozda verilmesiyle mortaliteya katkısı açısından farkı olmadığı, bunun yanı sıra, düşük doz grubunun daha kıza yoğun bakım yatışı ve mekanik ventilasyon süresi ile ilişkili olduğu görülmüş​3​. Pnömosistoz Pneumocystis Jiroveci’nin neden olduğu, CD4+ T hücre sayısı< 200/mm3 olan veya intrinsik T hücre disfonksiyonu olan, sitotoksik kemoterapi veya uzamış yüksek doz glukokortikoid kullananlar gibi immunkompromize hastalarda meydana gelen bir enfeksiyondur.Tedavi seçenekleri arasında trimetoprim-sulfometaksazol, pentamidin, dapson+trimetoprim veya klindamisin+primakin bulunur.Pnömosistoz tedavisi alan HIV-pozitif hastalarda prednizon tedavisi eklenmesinin erken dönemde solunumsal kötüleşmeyi ve mortaliteyi azalttığı gösterilmiş. Bunun muhtemel sebebinin anti-pnömosistoz tedavisinin sonucunda ortaya çıkan inflamatuvar yanıt...

Immune reminisces about a year in COVID-19 immunology, Steph’s receiving the Pfizer vaccine, and answers to listener questions about a challenge study with common cold CoVs, T cell exhaustion, how CD4 T cells control infections, and more. Hosts: Vincent Racaniello, Stephanie Langel, Cynthia Leifer, and Brianne Barker Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode Immune response during common cold CoV infection (Epidem Infect) Summary of diagnostic tests (NAS) Letters read on Immune 40 Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

This week’s episode features author Karolina Szummer and Associate Editor Emmanouil Brilakis as they discuss the article "Comparison Between Ticagrelor and Clopidogrel in Elderly Patients with an Acute Coronary Syndrome: Insights from the SWEDEHEART Registry." TRANSCRIPT BELOW Dr Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, this week's feature article, we're going to investigate antiplatelet therapy use, but in older patients, as opposed to those that are middle-aged, and have sustained a prior acute myocardial infarction. But, before we get to that, how about we grab a cup of coffee and jump into the other papers in the issue? Dr Carolyn Lam: Absolutely, Greg. I've got my coffee right here, and I really want to start with a paper that adds to our understanding of, guess what, the sodium=glucose cotransporter 2 inhibitors, SGLT2 inhibitors, and their diuretic and natriuretic effects in combination with loop diuretics. Of course, a clinically really important question since now we know that SGLT2 inhibitors improve outcomes in patients with heart failure in whom they are likely to be co-prescribed with a loop diuretic. So, Professor Chim Lang from University of Dundee and his colleagues performed the RECEDE-CHF trial, which was a randomized double-blind placebo-controlled crossover trial of 23 patients with type 2 diabetes and HF REF taking regular loop diuretics who were randomized to the SGLT2 inhibitor empagliflozin 25 milligrams once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urine volume from baseline at week 6. Dr Greg Hundley: So, empa versus placebo. What did they find? Dr Carolyn Lam: In patients with heart failure and type 2 diabetes taking a regular loop diuretic, empagliflozin caused a significant increase in urine volume at both day 3 and week 6, compared to placebo, as well as empa also caused a significant increase in electrolyte-free water clearance. Though there was a small non-significant increase in natural uresis with empagliflozin at day 3, this was absent by week 6. These results suggest that empagliflozin may have an advantageous diabetic profile in patients with type 2 diabetes and heart failure in addition to loop diuretics, with only a short transient natriuresis. Dr Greg Hundley: Very nice, Carolyn. Great information. Diuretics, heart failure reduced ejection fraction, and empagliflozin. Well, my clinical paper comes from Dr Renato Lopes from Duke University Medical Center, and this is a sub study from the ISCHEMIA trial that evaluates whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in patients with a history of heart failure or left ventricular dysfunction when the EF is greater than 35%, but less than 45%. Dr Carolyn Lam: Aw, that mid-range ejection fraction. Favorite topic. So, Greg, what did they find? Dr Greg Hundley: Those with heart failure and left ventricular dysfunction randomized to the invasive versus the conservative strategy had a lower rate of the primary outcome, 17% versus 29%. Whereas those without heart failure and left ventricular dysfunction did not, 13% versus 14%. A similar differential effect was seen for the primary outcome, all-cause mortality and cardiovascular mortality, when invasive versus conservative strategy associated outcomes were analyzed with LVF as a continuous variable for those with and without prior heart failure. Dr Carolyn Lam: Wow, that is clinically important, Greg. So, can you summarize our take home message? Dr Greg Hundley: Well, Carolyn, ischemia trial participants with stable ischemic heart disease and at least moderate ischemia with a history of heart failure or LV dysfunction, were at increased risk for the primary outcome. And in this small high-risk subgroup with heart failure and an ETF between 35% and 45%, an initial invasive approach was associated with a better event free survival. This result should really be considered for hypothesis generation and future studies. Dr Carolyn Lam: Greg, for the next paper, do you remember hydrogen sulfide? The stuff we learned about in school. It's the gas with that characteristic foul odor of rotten eggs. Well, guess what? This whole paper is about hydrogen sulfide, and in the body, it actually has antihypertensive and anti-inflammatory effects, and its endogenous generation key enzyme is cystathionine gamma lyase, or CSE, and that's expressed in CD4+ T cells. So today's paper provides insights into how all of these players work together in the development of hypertension. To investigate the pathophysiological relevance of this CSE hydrogen sulfide system, co-corresponding authors, Doctors Geng and Cai from Fuwai hospital and Chinese Academy of Medical Sciences, Peking University Medical College, as well as Dr Xu from Peking University Health Science Center in Beijing. Well, they and their coauthors performed elegant experiments involving peripheral blood lymphocytes, isolated from hypertensive patients or spontaneously hypertensive rats. They also looked at mice with CSE-specific knockout in T cells, and CD4 null mice. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: Well, they found that endogenous cystathionine gamma lyase, or CSE, and hydrogen sulfide, but not cystathionine beta-synthase, in lymphocytes, responded to blood pressure changes. Deleting CSE in CD4+ T cells exacerbated angiotensin II-induced hypertension by reducing circulatory and renal T regulatory numbers. Hydrogen sulfide from CSE self-hydrates, liver kinase 1, thereby activating the AMP kinase energy pathway to promote TReg differentiation and proliferation, which then attenuates the vascular and renal immune inflammation, and thus, prevents hypertension. Dr Greg Hundley: Carolyn, this sounds like a very thorough study. What are the clinical implications? Dr Carolyn Lam: Endogenous CSE hydrogen sulfide in lymphocytes may be both a potential biomarker of hypertension, or its complications, or hydrogen sulfide donor may be a therapeutic approach to lower hypertension. Dr Greg Hundley: Great, Carolyn. Well, my next paper comes from Professor Goo Taeg Oh from Ewha Women's University, and it really involves the world of inflammation. So Carolyn, as you know, macrophages produce many inflammation-associated molecules released by matrix metalloproteinases, such as adhesion molecules, as well as cytokines, which play a crucial role in atherosclerosis. In this paper, the authors investigated the relationship between Ninjurin-1, or nerve injury-induced protein 1, a novel MMP9 substrate expression, and atherosclerosis progression. Dr Carolyn Lam: Ninjurin-1? Interesting. So, what were the results? Dr Greg Hundley: Well, Carolyn, Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from coronary artery disease patients and healthy controls, as well as athero-prone, apolipoprotein E-deficient, or APOE -/- wild type mice. Two important findings, Carolyn. First, the authors in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted pro-inflammatory gene expression by activating mitogene-activated protein kinase, or MAP kinase, and inhibiting the phosphoinositide 3-kinase signaling pathway. Whole-body and BM-specific Ninj1 deficiencies significantly increase monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Now, in addition and secondly, macrophage Ninj1 was directly cleaved by MMP9 to generate a soluble form that exhibited anti-atherosclerotic effects, as assessed both in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of the disorder in mice, regardless of the presence of Ninj1. So in summary, Carolyn, Ninj1 is a novel MMP9 substrate in macrophages, and sNinj1 is a secreted athero-protective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Dr Carolyn Lam: Wow, Greg, that was incredibly summarized. Thank you. Let's go through what else there is in today's issue. In cardiology news, Bridget Kuhn talks about how the pandemic intensifies the push for home-based cardiac rehabilitation options. There's a white paper by Dr Ho and colleagues, including me, describing the diagnostic dilemma of HFpEF. There's a Research Letter by Dr Gill talking about the cardiometabolic trait sepsis and severe COVID-19, a Mendelian randomization investigation. There's also a Research Letter by Dr Wu on the atlas of exosomes microRNAs secreted from human iPSC-derived cardiac cell type. Dr Greg Hundley: Carolyn, this issue is just packed with articles, because I've got five more to tell our listeners about. First, it's a research letter from Professor G. Hovingh, entitled, Inclisiran Durably Lowers LDLC and PCSK9 Expression in Homozygous Familial Hypercholesterolemia, The ORION-2 Pilot Study. Next, there's an ECG challenge from Dr Jason Gilge relating to AV conduction during atrial flutter. Next, Dr Keith Churchwell has a nice piece related to the importance of those involved in cardiovascular care and participating in their civic duties, including voting. Next, Professor Karthikeyan has nice On My Mind related to overestimation of stroke risk and rheumatic mitral stenosis and the implications for oral anticoagulation. And finally, Carolyn, another research letter, from Dr Pieter van Paassen, entitled, Neutrophils and Contact Activation of Coagulation as Potential Drivers of COVID-19. Well, Carolyn, how about we get on to our feature discussion and review in older patients, which antiplatelet therapy may be safest? Dr Carolyn Lam: Let's go! Dr Greg Hundley: Well, listeners, now we're turning to our feature discussion, and today we'll talk about antiplatelet therapy. And then we have with us, Dr Karolina Szummer from Karolinska Institutet, and our own Associate Editor, Dr Manos Brilakis from the Minneapolis Heart Institute. Welcome to you both, and Karolina, let's start with you. Could you describe for us your hypothesis and some of the background information that led you to perform this study? Dr Karolina Szummer: Thank you so much for having me here and for sharing the ideas behind our study. Current recommendations recommend that we use high-potent antiplatelet agents for treating myocardial infarctions, and in particular, elderly patients are not included. So we decided to do an observational study to look at patients in our Swedish registries treated for myocardial infarctions who were 80 years and older. Dr Greg Hundley: Very nice. Can you tell us a little bit more about your study design? And also the study population? Dr Karolina Szummer: The startup populations are all patients who were admitted to an acute coronary care unit for treatment of myocardial infarctions, and they were all 80 years and older, and they were included from 2010 to 2017. So this encompasses the period during which treatment with ticagrelor was introduced. So we are comparing to ticagrelor versus clopidogrel for the outcomes during the year, following the myocardial infarction. Dr Greg Hundley: And how many patients did you enroll in the study? And what were your study results? Dr Karolina Szummer: We enrolled, in total, 14,000 patients, and these consisted of non-STEMI and of STEMI patients. The majority, about two thirds, were non-STEMI patients. We show, in this study, elderly patients have a lower risk of readmission for myocardial infarction or stroke, but they have a higher risk of having readmission for bleeding and death. So the risk-benefit ratio seems to be skewed towards having, probably, more harm with ticagrelor being more risky than clopidogrel in this study population of elderly. Dr Greg Hundley: And was this true for both men and for women? Dr Karolina Szummer: Yes. So this was true for both men and women. And we did a sensitivity analysis. We looked closer at those who are younger than 80 years old, and in this patient population, the results selected in the same way as for our cohort of elderly, they actually did have the same benefit with a low risk of MI, stroke, and death, and high risk of bleeding. But in the elderly, we noticed a signal towards harm with an increased risk of death. Dr Greg Hundley: It sounds like with ticagrelor, did we have a lower risk of death and a slightly lower risk of myocardial infarction and stroke, but a higher risk of bleeding? Was that the findings? Dr Karolina Szummer: So for the elderly, there was a high-risk of death and bleeding with ticagrelor compared to clopidogrel, but a lower risk of ischemic component of MI and stroke. Dr Greg Hundley: And then with those under 80, those were the ones that had the lower risk of death, lower risk of MI and stroke, but the higher risk of bleeding? Dr Karolina Szummer: Yes, that's correct. So really the end point that differs most is that there is sustainment towards higher mortality in the elderly, because in both younger and elderly, the risk of readmission for bleeding was elevated in both. Dr Greg Hundley: Now, let's turn to our own Associate Editor, Manos Brilakis. Manos, can you help us put these results into perspective, relative to other studies that evaluate the efficacy of antiplatelet therapy, post myocardial infarction? Dr Emmanouil (Manos) Brilakis: I would like to start by congratulating Dr Szummer. It's a wonderful paper, and, I think, provide some new insights on how to use the medications in the ACS patients. And going on the background, if we look at the guidelines, both the European guidelines, as well as the American guidelines, what they say is that both ticagrelor, as well as prasugrel, are preferred and recommended for patients with ACS, both non-ST elevation ACS, as well as ST segment elevation myocardial infarction. And actually, European guidelines say that clopidogrel should only be used when prasugrel or ticagrelor are not available or are contraindicated. And this is based on two trials. One is the PLATO trial, and the other is the TRITON-TIMI 38, that both showed, actually, more benefit with the more intensive P2Y12 inhibitors. And this is what is extrapolated to all patient populations. But as you've heard before, there was only a minority of elderly patients that were included in those trials, about 13% to 15%, and that is why the present study is important, because it suggests that maybe we should look more carefully into the patient's age and potentially other characteristics like frailty or other comorbidities, that might actually alter the risk-benefit ratio. And maybe those medications should not be routinely given to all patients, but perhaps, elderly patients, or at least some of them, might not require, and actually be better off with clopidogrel. Dr Greg Hundley: Let's turn back to Karolina. Karolina, the study was observational. What do you see as, perhaps, a next study to follow up the results that you've brought to us with this study? Dr Karolina Szummer: So the next step would definitely be to do a randomized control trial in the elderly to explore this topic further, to really know for sure what the safety and efficacy is, and what's the best treatment would be for these patients. Dr Greg Hundley: Very good. And Manos, do you have anything to add? Dr Emmanouil (Manos) Brilakis: One more thing. So, there was actually a trial that compared ticagrelor as well as prasugrel with clopidogrel in elderly patients that was called the POPUlar AGE trial that was published last year. And actually this one, published earlier this year, and actually this trial randomized a thousand patients who were more than 70 years old, to either more-intensive or less-intensive. And the results were actually very similar to the findings from Dr Szummer's study from SWEDEHEART, showing that there was more bleeding without any ischemic benefit. And didn't show actually higher mortality but didn't show any significant benefit. So that actually adds to the data that maybe the elderly patients, the selection of antiplatelet agent should be taken into account. And I think for me, this also extrapolates the high bleed risk, higher risk of bleeding, based on criteria, which we currently use mainly for duration. We say, for example, if you're precise DAPT score, which is a score for determining risk of bleeding, is high, you should consider shorter duration of DAPT, but it doesn't say anything about the type of DAPT. And for me, this makes sense that the high bleeding risk, and age is one of the main risk factors for high bleeding risk, should be taken into account also for determining the type of P2Y12 inhibitor. Dr Greg Hundley: Well listeners, we've had a great discussion with Karolina Szummer from Karolinska Institutet, and our own Manos Brilakis from the Minneapolis Heart Institute, really reviewing the utility of ticagrelor versus clopidogrel in older individuals, above the age of 80, that have sustained myocardial infarction, and identifying that ticagrelor is associated with a higher risk of death and bleeding, as opposed to clopidogrel, opening the question up as to whether further studies in older individuals need to be performed to examine the efficacy of antiplatelet therapy. So, on behalf of Carolyn and myself, we wish you a great week and look forward to catching you On the Run next week. This program is copyright the American Heart Association, 2020.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.30.362715v1?rss=1 Authors: Andreoletti, G., Lanata, C. M., Paranjpe, I., Jain, T. S., Nititham, J., Taylor, K. E., Combes, A. J., Maliskova, L., Jimmie Ye, C., Katz, P., Dall Era, M., Yazdany, J., Criswell, L. A., Sirota, M. Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. The aim of this study is to leverage large-scale transcriptomic data from diverse populations to better sub-classify SLE patients into more clinically actionable groups. We leverage cell sorted RNA-seq data (CD14+ monocytes, B cells, CD4+T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four tier analytical approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on the individual cell type data resulted in three clusters for CD4 and CD14, and two clusters for B cells and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters of each immune cell and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across the four cell types were involved in SLE or other autoimmune related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into White-high, Asians-high (high disease activity defined by SLEDAI score >=6) and White-low, Asians-low (SLEDAI < 6). Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable precision medicine for SLE. Copy rights belong to original authors. Visit the link for more info

In this episode, Lucy Walker joins Monica Westley to discuss her research at the Walker Lab at the University College London. The group is exploring how CD4 T cell mediated immune responses are initiated and regulated. The principle research goal is to understand why immune regulation fails in certain individuals resulting in destructive autoimmune responses against self-tissues. To learn more about the Walker Lab, click on the link below!The Walker LabRecent Publication:Follicular helper Tcell profiles predict response to costimulation blockade in type 1 diabetes

Pillai explains IgG4-Related Disease (IgG4-RD), a chronic inflammatory condition characterized by elevated numbers of T cells and IgG4 secreting plasma cells in the affected tissue. Using tissue samples from patients with the disease, his laboratory isolated and characterized the CD4+ T cells associated with IgG4-RD. Furthermore, he explains how the crosstalk between these CD4+ T cells and B cells is important for IgG4-RD development, and showed that depletion of B cells improves the outcome of the disease.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.18.304071v1?rss=1 Authors: Narasimhan, R. L., Throm, A. A., Koshy, J. J., Saldanha, K. M. R., Chandranpillai, H., Lal, R. D., Kumravat, M., Kumar K M, A., Batra, A., Zhong, F., Liu, J. Abstract: Inflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohn's disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.298190v1?rss=1 Authors: Knoener, R., Evans, E., Becker, J. T., Scalf, M., Benner, B., Sherer, N. M., Smith, L. M. Abstract: HIV-1 generates unspliced (US), partially spliced (PS), and completely spliced (CS) RNAs; each playing distinct roles in viral replication. Elucidating their host protein "interactomes" is crucial to understanding virus-host interplay. Here, we present HyPR-MSSV for isolation of US, PS, and CS transcripts from a single population of infected CD4+ T-cells and mass spectrometric identification of their in vivo protein interactomes. Analysis revealed 212 proteins differentially associated with the unique RNA classes; including, preferential association of regulators of RNA stability with US- and PS-transcripts and, unexpectedly, mitochondria-linked proteins with US-transcripts. Remarkably, >80 of these factors screened by siRNA knock-down impacted HIV-1 gene expression. Fluorescence microscopy confirmed several to co-localize with HIV-1 US RNA and exhibit changes in abundance and/or localization over the course of infection. This study validates HyPR-MSSV for discovery of viral splice variant protein interactomes and provides an unprecedented resource of factors and pathways likely important to HIV-1 replication. Copy rights belong to original authors. Visit the link for more info

Immune explains a study demonstrating T cells that react with SARS-CoV-2 epitopes in individuals who have never been infected with the virus, implying cross-reactivity with common cold coronaviruses. Hosts: Vincent Racaniello and Cynthia Leifer Guest: Brianne Barker Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode Cross-reactive coronavirus CD4+ T cells (Science) Immune misfiring in severe COVID-19 (Nature) A COVID-19 riddle for the immune system (Nature) Letters read on Immune 34 Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

This is Special English. I'm Mark Griffiths in Beijing. Here is the news. To push for the nation's economic transition and industrial upgrading, Chinese leaders have pledged greater commitment to the research and application of science and technology. In a show of unprecedented importance, both President Xi Jinping and Premier Li Keqiang addressed an event combining three top-level science conferences attended by 4,000 scientists and science officials. Xi said the central government's commitment is aimed at making China a leading power in science and technology by the middle of the century, or around the 100th anniversary of the founding of the People's Republic of China. Xi stressed the role of science and technology as bedrock that "the country relies on for its power; enterprises rely on for victories; and people rely on for a better life." The president said that "Great scientific and technological capacity is a must for China to be strong and for people's lives to improve". He is calling for new ideas, designs and strategies in science and technology. Premier Li told the event that China's overall research and development input will keep rising to account for 2.5 percent of its GDP by 2020, from the current 2.1 percent. The conference is calling for more policy reforms to provide incentives for the talent needed in research and innovation. This is Special English. A UN report has lauded Beijing's efforts to battle air pollution but said it needs to do more to meet particulate matter standards. Published by the UN Environment Program, the report is entitled "A Review of Air Pollution Control in Beijing: 1998-2013". In the past 15 years, the number of registered vehicles increased by 300 percent in Beijing and energy consumption rose by 77 percent. The UN Environment Program executive director Achim Steiner remarked in the foreword to the report. He says concentrations of key pollutants decreased remarkably, and Beijing improved air quality even as it maintained fast paced growth. Steiner says Beijing's experience in controlling air pollution against a backdrop of rapid expansion is a story that should be shared with other emerging economies and burgeoning cities. An environment expert from Tsinghua University says the report recognized Beijing's continual efforts to improve air quality; and Beijing's solution was a combination of energy structure optimization, coal-fired emission control and enhanced air quality monitoring. The report also offered some suggestions, including improving city planning and optimizing the layout of city functions. You are listening to Special English. I'm Mark Griffiths in Beijing. Australian experts say Australia will have a very meaningful role to play in the healthcare sector in China. HSBC Australia head of commercial banking James Hogan has said there were three key markets Australian businesses were set to benefit from in China, namely food, energy and healthcare. The research at HSBC found that 70 percent of Chinese mainland citizens say that health is their number one biggest concern. Hogan said China's demand for healthcare will certainly increase rapidly over the coming year, as healthcare reform becomes a priority for the Chinese government. He said there were opportunities across the healthcare space in China awaiting Australian investment. Macquarie University health economy center director Dr. Henry Cutler believes any investment within China would have to be long term. Cutler says that obviously, developing relationships with those in China to make sure that services delivered are culturally appropriate is important. He added that dumping in a model from Australia would not work. HSBC noted the recent China-Australia Free Trade Agreement provides Australian medical services and healthcare providers with favorable access to expand into or do business with China. This is Special English. Sixty-six kinds of Chinese medicinal herbs have been added to the European Pharmacopoeia, an authoritative reference work for quality control of medication. Professor Dr. Gerhard Franz is Chairman of the Traditional Chinese Medicine Working Party of the European Pharmacopoeia. He says the event means there are clear quality standards for Chinese herbs exported to Europe, which help the drugs gain wider acceptance in foreign markets. Franz made the remarks at an international conference on the future of Traditional Chinese Medicine. The conference, entitled TCM's future, was held in Hangzhou, the capital of east China's Zhejiang Province. The professor said the herbs have undergone strict examination and discussion, and been approved by all 37 signatory countries. The listed Chinese herbs, including ginseng, account for almost a third of all herbs in the pharmacopoeia. The professor said their goal is to include at least 300 commonly used Chinese herbs. Exports of traditional Chinese drugs have been impeded by misuse and substitutions for similar plants, as well as contamination by heavy metals and microbial insecticides. An official from Zhejiang's health and family planning commission said that due to lack of quality standards, China's traditional medicine industry lags far behind its counterparts in Japan and South Korea in foreign markets. He added that modern technology and concepts must be applied in developing Traditional Chinese Medicine. You are listening to Special English. I'm Mark Griffiths in Beijing. A farmer in central China's Henan Province is seeking 2 million yuan, roughly 300,000 U.S. dollars, in compensation after he was wrongly diagnosed with HIV and AIDS. Fifty-three-year-old Yang Shou-fa was diagnosed with HIV and AIDS during a provincial-wide check in 2004, during which more than 280,000 people were tested. It was not until 2012 that he found out that the result was false. The local disease control center still has samples from 2004, and a retest of Yang's sample came up positive, again. The center says the test equipment did not fail, so someone must have mixed up Yang's blood with an HIV patient. Yang had taken HIV medication from his diagnosis until 2012. He had to attend annual health checks, which only tested the amount of CD4+T cells in his blood. In people with HIV, this is the strongest indicator of HIV progression and the most important indicator of how the immune system is working. Yang's CD4+T cell count was higher than other AIDS patients, but concerns were never raised, as no one doubted the diagnosis. Before Yang was incorrectly diagnosed in 2004, his health had been failing. He had donated blood once and then suffered from repeated fever. When he was told he had AIDS, he was convinced. The local health department is considering compensation for him. You're listening to Special English. I'm Mark Griffiths in Beijing. You can access the program by logging on to newsplusradio.cn. You can also find us on our Apple Podcast. If you have any comments or suggestions, please let us know by e-mailing us at mansuyingyu@cri.com.cn. That's mansuyingyu@cri.com.cn. Now the news continues. Chinese playwright, author and translator Yang Jiang has died at the age of 105. Born in Beijing, Yang studied in Soochow University and then Tsinghua University in the 1930s. She was married to Qian Zhongshu, a household name in China. Qian is best known for his sarcastic novel "Fortress Besieged" that depicted the lives of Chinese intellectuals in the 1930s. He died in 1997. After studying in Britain and France together with Qian, Yang returned and became a foreign language professor at Tsinghua University. She was a literature researcher with Peking University in the 1950s. Fluent in English, French and Spanish, her translations of such classics as Don Quixote and French picaresque novel Gil Blas remain the definitive versions for Chinese readers. Yang also penned numerous plays, novels and essays and is known for her plain but resonant style. Her most popular works include "We Three", a 2003 essay collection recalling her husband and daughter, who died of cancer. The book became an instant hit both in China and overseas. In 2001, Yang and her husband donated all their royalties to Tsinghua University and established a scholarship that has benefited more than 1,000 students. This is Special English. Researchers have confirmed that snow leopards live in areas south and north of Qinghai Lake in Northwest China's Qinghai province. The animals' presence had been rumored but was never proved, as experts have tried to understand the distribution range and habitat selection patterns of the rare big cat. The new finding was released by the Wildlife Conservation Society of China, which did not reveal specific locations, in a bid to protect the snow leopards. It referred to the two locations only as areas A and B. The Wildlife Conservation Society of China says researchers spotted snow leopards in Area A and found evidence of them, which were hours-old footprints, in Area B. Previously, there were reports from herdsmen and other witnesses, but they were unconfirmed. There were no scientific reports supporting the claims. The new findings will offer basic information for people studying snow leopards and attempting to protect them. The International Union for the Conservation of Nature has placed the snow leopard on its Red List of Threatened Species as globally endangered. The Wildlife Conservation Society says that so far, China still has the largest population of the animal, known as the "ghost of the mountains". You're listening to Special English. I'm Mark Griffiths in Beijing. The authorities in northwest China's Xinjiang Uygur Autonomous Region plan to recruit more than 11,000 teachers from around the country to ease its teacher shortage. The teachers will be recruited for primary and middle schools, high schools, kindergartens and special education schools this year. Of those, 60 percent will work in four prefectures in the southern part of Xinjiang, where a dearth of bilingual teachers poses a challenge for education. The recruits in these areas should be able to speak mandarin and a language of the local minorities. Xinjiang has hired more than 72,000 teachers in the past five years, with around 62,000 of them bilingual. This is Special English. Lhasa, the capital of southwest China's Tibet Autonomous Region, has passed a law to protect its ancient villages. The law came into effect on June 1. It stipulates principles on ancient village protection and restoration, funds, responsibilities and building a long-term protection mechanism. It also demands a "supervisor mechanism" and encourages volunteer groups to help with protection efforts. Lhasa has around 1,000 villages, which feature unique landscapes and traditions. As the local economy speeds up, many ancient villages have yet to be restored, and the law was enacted to address the issue. The local government says the law will enhance protection efforts for precious cultural resources in Lhasa. This is Special English. （全文见周日微信。）

Dr. Anne O'Garra talks about the 1997 work of Zheng and Flavell on the role of GATA-3 in Th2 cytokine gene expression in CD4 T cells.