Podcasts about tnfalpha

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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.12.536447v1?rss=1 Authors: Kaminska, P., Ovesen, P. L., Jakiel, M., Obrebski, T., Schmidt, V., Bieniek, M., Anink, J., Paterczyk, B., Draminski, M., Jensen, A. M. G., Piatek, S., Andersen, O. M., Aronica, E., Willnow, T. E., Kaminska, B., Dabrowski, M. J., Malik, A. R. Abstract: SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and in turn lose the ability to elicit anti-tumor responses. Instead, they acquire glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our analysis of scRNA-seq data from GBM patients revealed that the pro-tumorigenic and pro-inflammatory properties of GAMs are linked to high and low SORL1 expression, respectively. Using cell models, we confirm that SorLA levels are differentially regulated by the presence of glioma cells and by inflammatory cues. We further show that SorLA acts as a sorting receptor for the pro-inflammatory cytokine TNFalpha to restrain its secretion from microglia. As a consequence, loss of SorLA enhanced the pro-inflammatory potential of microglia, having a remarkable impact on glioma progression. In a murine model of glioma, SorLA-deficient mice develop smaller tumors and show hallmarks of anti-tumor response including altered microglia morphology, enhanced necroptosis, and massive neutrophil influx into the tumor parenchyma. Our findings indicate that SorLA is a key player in shaping the phenotype of GAMs, and its depletion can unlock an anti-tumor response. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Mast cells are important! Mast cells are implicated in autoimmune diseases and many other inflammatory processes - because mast cells RELEASE and TRIGGER inflammation. Like.... A LOT OF INFLAMMATION. We're talking vicious cycles of inflammation that can be hard to stop!Mast cells respond to stimuli in the environment like allergens, foods, viruses, bacteria, parasites, LPS, COVID-19, our "big 3" pathogens EBV, Lyme, mold/fungi/Candida, toxins like mercury, aluminum, glyphosate - but they also can be triggered by PSYCHOLOGICAL STRESS! That's pretty important. These mast cells are called "sentinel cells", because they sound the alarm when there is danger - think of someone with a dog allergy who walks into a friend's house with dogs and immediately their symptoms go off - runny nose, itchy eyes, sneezing. This allergic reaction happens SOMETIMES with mast cell-related problems, but not all the time. The sinuses are the most famous place we find mast cells (think: antihistamines), but they line all tissues that interface with the outside world like the skin, lungs, digestive tract, bladder, uterus/vagina, and highly vascularized tissues like the BRAIN.  They are 5-24x more highly expressed in the synovial tissues of patients with RA compared to normal people, they are implicated in Multiple Sclerosis, IBS/IBD, Endometriosis, Alzheimer's disease...the list goes on and on. Their activation is associated with a mixed bag of weird symptoms like anxiety, brain fog, fatigue, heart palpitations, rapid heart rate, vertigo, flushing, itching, heavy limbs, nausea, stomach pain, blood pressure changes, chemical sensitivities, food reactions, etc etc.....so often this person has maybe been to the the ER thinking they were having a heart attack, the cardiologist, the gastroenterologist, the neurologist, the ENT, the endocrinologist....and nothing has helped. These cells are super cool. They literally look like a sack filled with little "balls", or vesicles, and these vesicles are filled with different chemical mediators that have ALL SORTS of different effects - histamine is the most famous, TNFalpha is one of many highly inflammatory cytokines, Platelet Aggregating Factor can cause hypercoagulation....the list is several hundred long. Picture a big bag filled with a bunch of helium balloons. Sometimes the body releases all of the "balloons" at once very quickly, which is called degranulation, but sometimes the body only releases certain balloons - like red ones. Some triggers, like Lyme disease for example, mast cells only release inflammatory cytokines. This is tricky, because this means that sometimes mast cells can be implicated even with there is not a histamine response.SOMETIMES mast cells are activated by allergens. Most people know it when they have allergies. SOMETIMES mast cells are activated by other things - - STRESS, toxins, pathogens, dysbiosis of the gut.....but more often than not it's a combination of things - foods, stress, a toxic exposure, and the inflammation builds more gradually.  You can't always find the "one thing" that caused the response, and looking for that "one thing" is futile. Mast cell "activation" and associated inflammation can lead to a wide spectrum of symptom severity - you could have an autoimmune disease like RA or MS that has mast cells as a component but is much more complex, you could have full-blown MCAS (Mast Cell Activation Syndrome - which most people do not have!), you could have bloating, brain fog, and anxiety (COMMON!!) or you could occasionally suffer from minor seasonal allergies or joint pain, common mast cell-mediated inflammatory symptoms. But knowing how mast cells work and how to stabilize them is an important piece of many people's health puzzle!

A 35-year old woman, grew up in a rural Pennsylvania farming community. 4 neighborhoods in total and acres and acres of rural farmland. The water source is owned by a private company; the owner is a local farmer. Evidently, the water has been leaking up to 70%. Breast cancer, celiac, asthma are on the rise in the community. One girl died of an asthma attack.    Symptoms She feels misdiagnosed as a young girl. She feels they are POTS attacks, not anxiety attacks. She would often faint while working at McDonald's.  She also has Ellers Danslos Dx, chronic fatigue, and high levels of Epstein bar virus. She constantly has bruises on her legs, and trouble with tendons and ligaments, as well as being super bendy- she has tight muscles and loose joints. She is constantly in PT. Her sister has mast cell activation and asthma. Otherwise nothing else in her family history.  SNPs mentioned in this episode for the top objective of addiction Vitamins/Minerals/Omega 3s Category Vit D: GC, DHCR7, CYP2R1 Cognitive and Mental Health Category COMT met/met AA (Executive Function)  TPH2  (Serotonin Production) BDNF (Brain-Derived Neurotrophic Factor) Energy and Fitness Category COL1A1 (Tendon or Ligament Injury) COL5A1 (Tendon or Ligament Injury)   Detoxification Category SOD2  (Antioxidant Enzymes) GSTP1 (Environmental Toxins)   Immune Category TNF-alpha (TNFalpha activation) Resources Nutrigenomics Case Study Events 2021  GMOTG Events Line-up PureGenomics PureGenomics Trait Tutorials Schedule a complimentary 1:1 Welcome to PureGenomics coaching session Do you have a reputable water testing company? Let us know! Have questions about how cannabis fits into your toolbox? Email: kara@karawarecoaching.com

FDA 批准IL-23单克隆抗体用于治疗银屑病关节炎Rheumatology 幼年特发性关节炎患者的妊娠结局Ann Rheumat Dis间充质干细胞移植联合干扰素治疗RA古赛库单抗（Guselkumab）古赛库单抗（Guselkumab）是IL-23单克隆抗体，2017年被FDA批准用于治疗银屑病；2020年7月，FDA批准古赛库单抗用于治疗银屑病关节炎。《DISCOVER-1研究：古赛库单抗治疗肿瘤坏死因子α抑制剂效果不佳的、活动性银屑病关节炎的3期临床研究》Lancet，2020年4月 (1) 这项多中心、双盲、随机、安慰剂对照的3期试验中，纳入肿瘤坏死因子(TNF)α抑制剂的反应不佳的、活动性银屑病性关节炎的患者共381人，随机分入古赛库单抗q4w组、古赛库单抗q8w组或安慰剂组，共24周。古赛库单抗q4w组和q8w组的患者，相比安慰剂，24周时达到30%缓解的几率更高（59%、66% vs 22%，p均

FDA 批准IL-23单克隆抗体用于治疗银屑病关节炎Rheumatology 幼年特发性关节炎患者的妊娠结局Ann Rheumat Dis间充质干细胞移植联合干扰素治疗RA古赛库单抗（Guselkumab）古赛库单抗（Guselkumab）是IL-23单克隆抗体，2017年被FDA批准用于治疗银屑病；2020年7月，FDA批准古赛库单抗用于治疗银屑病关节炎。《DISCOVER-1研究：古赛库单抗治疗肿瘤坏死因子α抑制剂效果不佳的、活动性银屑病关节炎的3期临床研究》Lancet，2020年4月 (1) 这项多中心、双盲、随机、安慰剂对照的3期试验中，纳入肿瘤坏死因子(TNF)α抑制剂的反应不佳的、活动性银屑病性关节炎的患者共381人，随机分入古赛库单抗q4w组、古赛库单抗q8w组或安慰剂组，共24周。古赛库单抗q4w组和q8w组的患者，相比安慰剂，24周时达到30%缓解的几率更高（59%、66% vs 22%，p均

Managing a chronic condition like multiple sclerosis can be complicated. In the second part of Astrid’s story, we hear about her experiences with disease symptoms and complications, treatment, supportive therapies, lifestyle changes, and support networks, all of which play a part in helping her and others with MS live well. We’ll again hear from Dr. John Parratt about what it’s like managing the condition, including explanations of treatment types and strategies for getting the support you need as a person living with MS.  This episode is kindly supported by MS Australia and is sponsored by Roche Australia (Sydney). Material number EC-AU-9437, prepared Apr2020. Episode References: MS Australia. Symptoms. Available at: https://www.msaustralia.org.au/about-ms/symptoms. Accessed April 2020. MedicineNet. Medical Definition of Proprioception. Available at: https://www.medicinenet.com/script/main/art.asp?articlekey=6393. Accessed April 2020. International Association for the study of pain. IASP Terminology – Neuropathic pain. Available at: https://www.iasp-pain.org/terminology?navItemNumber=576#Neuropathicpain. Accessed April 2020. WebMD. What Are the Side Effects of Pain Medication? Available at: https://www.webmd.com/pain-management/pain-medication-side-effects#2. Accessed April 2020. MS Australia. Medications & Treatments. Available at: https://www.msaustralia.org.au/about-ms/medications-treatments. Accessed April 2020. MS Australia. Understanding Multiple Sclerosis – An Introductory Guide. Available at: https://www.msaustralia.org.au/publications/understanding-ms-introductory-guide. Accessed March 2020. MS Australia. Diet & Nutrition. Available at: https://www.msaustralia.org.au/wellbeing-ms/diet-nutrition. Accessed April 2020. Exercise is Medicine Australia Factsheet. Available at: http://exerciseismedicine.com.au/wp-content/uploads/2019/12/Factsheet-MS-BRIEF-VERSION-2014.pdf. Accessed April 2020. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psychiatr Clin North Am. 2007;30(4):803–817. MS Research Australia. MS Treatments. Available at: https://msra.org.au/treatments/. Accessed April 2020. Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, Hodgkinson S, Kermode AG, Lechner-Scott J, Macdonell RA, Marriott M, Mason DF, Parratt J, Reddel SW, Shaw CP, Slee M, Spies JM, Taylor BV, Carroll WM, Kilpatrick TJ, King J, McCombe PA, Pollard JD, Willoughby E. A new era in the treatment of multiple sclerosis. Medical Journal of Australia 2015; 203(3): 139-141. Clanet MC, Wolinsky JS, Ashton RJ, Hartung HP, Reingold SC. Risk evaluation and monitoring in multiple sclerosis therapeutics. Mult Scler 2014; 20(10): 1306-1311. Halabchi F, Alizadeh Z, Sahraian MA, Abolhasani M. Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations. BMC Neurol 2017; 17(1): 185. Klotz L, Havla J, Schwab N, Hohlfeld R, Barnett M, Reddel S, Wiendl H. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord 2019; 12: 1756286419836571. Mokhtarzade M, Ranjbar R, Majdinasab N, Patel D, Molanouri Shamsi M. Effect of aerobic interval training on serum IL-10, TNFalpha, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life. Endocrine 2017; 57(2): 262-271. Tintore M, Vidal-Jordana A, Sastre-Garriga J. Treatment of multiple sclerosis - success from bench to bedside. Nat Rev Neurol 2019; 15(1): 53-58. Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, Langdon D, Dalgas U, Kesselring J, Bansi J. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. Mult Scler 2018; 24(12): 1635-1644.

TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Progression of Disease Within 24 Months (POD24) in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune-Infiltration” by Dr. Tobin and colleagues. My name is Dr. Carla Casulo, and I am Associate Professor of Medicine, Hematology and Oncology at the Wilmot Cancer Institute of the University of Rochester in Rochester, NY, USA. My oncologic specialty is Lymphoma.   Follicular lymphoma is the most frequently occurring indolent non-Hodgkin lymphoma and has a long natural history, with median overall survival nearing two decades. Patients with follicular lymphoma may experience a variable clinical course, with periods of long remission punctuated by episodes of recurrent lymphoma requiring re-treatment. Among all patients, up to one third will have early disease recurrence, defined as occurring within 24 months of diagnosis. Please note that progression of disease within 24 months will be referred to as POD24 for the remainder of this podcast. These patients have inferior survival, ranging from 25-50% at 5 years. Consequently, POD24 has become a robust and well accepted indicator of identifying high-risk patients.   The implications of POD24 were first identified through our analysis of the National Lymphocare Study, which sought to test the hypothesis that time to disease progression had an impact on subsequent patient outcomes. 588 patients treated with RCHOP were included. Patients with POD24 were defined as early progressors, and those without relapse or death within 24 months were defined as the reference group. Patients with POD24 had OS of 50% at 5 years compared to 90% in the reference group. These findings have subsequently been independently validated by numerous investigators worldwide, corroborating the adverse prognostic impact of an early disease related event in follicular lymphoma. The largest of these validation studies pooled individual patient data from 5,453 patients on 13 Clinical Trials using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation.     In the FLASH analysis, we identified that male gender, poor performance status, high follicular lymphoma international Prognostic index (FLIPI) score, and elevated baseline beta 2 microglobulin B2M as predictors of early death and progression. Moreover, it confirmed POD24 as an early clinical endpoint of poor survival in follicular lymphoma that should be utilized to identify patients for prospective clinical trials.   The current status of biomarkers in follicular lymphoma has emerged from a wealth of clinical and laboratory-based factors to classify risk, towards a biologic based, molecular approach merging clinical factors with our current understanding of the follicular lymphoma genomic landscape.     There are numerous well-established and emerging clinical prognostic indices used at the time of diagnosis in follicular lymphoma that can help discriminate general outcome. These include the FLIPI and FLIPI -2. To an extent, these prognostic markers can identify subsets of patients with an expected POD24 with a sensitivity between 60-78%, and a specificity between 56-58%. However, in an attempt to use a precision approach, investigators from the German Low-Grade Lymphoma Study Group harmonized clinical and pathologic data to create a clinico-genetic risk model aimed at more accurate risk prognostication in patients receiving front line chemoimmunotherapy. They performed deep DNA sequencing from formalin fixed pre-treatment biopsies to analyze the mutational status of genes in 151 patients with follicular lymphoma tumor samples. The resulting prognostic tool, called the m7-FLIPI, distilled down 74 genes into 7 genes with non-silent mutations occurring at a variant allele frequency of 10% or greater, and combined these with high risk FLIPI status and ECOG performance status. These included genes that increased risk of progression, including EP300, FOX01, CREBBP, CARD11, and those that decreased risk of progression, including EZH2, ARID1A, and MEF2B. The cumulative risk score was calculated by combining relative weights of these genes in a multivariate analysis predicting failure-free survival. This m7-FLIPI score was tested to identify POD24 but only captured about 50% of patients as high risk. A later model included only 3 genes, including EP300, FOX01 and EZH2, performance status and FLIPI score. Defined as the POD24-PI, this was more sensitive at identifying POD24 patients but did not outperform other metrics due to lower specificity.   Biologic classification of POD24 patients remains an ongoing international research priority to seek actionable targets that might change the natural history of follicular lymphoma and improve survival of patients more likely to have morbidity and death from their disease. Several years ago, in the pre-rituximab era, the Leukemia and Lymphoma Molecular profiling project identified the importance of the follicular lymphoma tumor microenvironment in predicting favorable or poor outcome. The follicular lymphoma tumor microenvironment is composed of tumor infiltrating T cells, regulatory T cells, and lymphoma-associated macrophages. The immune survival score or ISS established that differential expression of gene expression signatures from intratumoral immune cells in the tumor microenvironment affected survival, and particular increased expression of macrophages was associated with poor prognosis.   The impact of the follicular lymphoma immune microenvironment on survival is changing in the current era of chemotherapy combined with antiCD20 immunotherapy, and particularly by available drugs that reverse tumoral immunosuppression by blocking programmed cell death. Studies from solid tumor literature demonstrate that low levels of tumor infiltration immune cells are associated with inferior survival. In follicular lymphoma, then, precise characterization of high or low immune infiltrating cells in the tumor microenvironment may have a critical effect on understanding the mechanisms of POD24. This particular relationship is what Tobin and colleagues investigated in the current study.   In this analysis, targeted gene sequencing using NanoString technology from paraffin-embedded tissue and multi-spectral immunofluorescence on a tissue microarray was applied to two groups: a discovery cohort of 132 patients from Princess Alexandria Hospital with early- and advanced-stage follicular lymphoma who received either chemotherapy or observation and two independent validation cohorts of 198 patients with advanced-stage disease treated with RCHOP and RCVP from the German Low grade lymphoma Study Group and the British Columbia Cancer Agency. They also performed T cell repertoire analysis, flow cytometry, immunofluorescence, and next-generation sequencing.   Here, they defined POD24 as primary refractory disease following treatment, transformation to a more aggressive histology, and relapse within 24 months of diagnosis, which is a more liberal definition from what was initially described in the national lymphocare study but does encompass patients at highest risk of lymphoma-related death.   Gene expression profiling revealed distinct clustering of follicular lymphoma samples based on high or low expression of immune infiltrating cells. Low expression of four immune markers, including PDL-2, TNFalpha, CD4, and CD68 were all associated with poor outcome, but the most specific marker with the highest specificity and sensitivity was PD-L2. They then dichotomized PD-L2 expression into “immune infiltration high” and “immune infiltration low” in subsequent analyses. PD-L2 is an immune checkpoint present broadly on both tumor cells and the tumor microenvironment. To localize its distribution, they performed flow cytometry in fresh FL samples and quantified PD-L2 expression by PCR. They identified that PD-L2 gene expression was distributed in both CD20+ tumor cells as well as non CD20+ cells in the tumor microenvironment. However, the proportion of PD-L2 was lower in the CD20+ cells. Overall, there was lower expression of all immune cells in the immune infiltration low phenotype compare to the immune infiltration high phenotype.   They tested the relevance of immune infiltration and POD24. Consistent with numerous other studies, POD24 events occurred in about 24% of patients. Patients with POD24 events in the Princess Alexandria discovery set were more enriched for the immune infiltration low phenotype. These findings were also validated in the British Columbia cancer agency and German lymphoma study group populations. Nearly 50% of patients with low PD-L2 had POD24 events, compared to 16% in those with high PD-L2, concluding that low PD-L2 identifies a subset of patients enriched for POD24. When evaluating the mutational profiles of those with immune infiltration high versus immune infiltration low based on the m7-FLIPI genes, mutations were detected equally among both populations, suggesting that this mutational profiling is not influenced by the immune infiltration phenotype.   The data presented by Tobin and colleagues makes an important contribution to our understanding of the biological and immune-based mechanism influencing early disease-related events in follicular lymphoma. They demonstrate that reduced immune infiltration is associated with greater chance of POD24. While the sensitivity of this was high, similar to other prognostic markers, it still did not capture the entire subset of future POD24 cases, underscoring the significant heterogeneity within this high-risk patient population. However, there remains opportunity to include PD-L2 as a surrogate for poor risk disease. If further applied to immunohistochemistry or other widespread diagnostic methods, it has the potential for more widespread application. Further validation is still required, particularly to patients treated with novel agents or other immunotherapies. However, the assessment of immune infiltration as described by these findings appears to be an encouraging step in determining risk of POD24. This concludes this JCO Podcast. Thank you for listening.

The TWiM team presents an extracellular bacterium associated with Paramecium, and induction of antiviral immunity by a bacteriophage that prevents bacterial clearance. Subscribe to TWiM (free) on iTunes, Google Podcasts, Stitcher, Android, RSS, or by email. You can also listen on your mobile device with the Microbeworld app. Become a Patron of TWiM! Bacteria on the outside of paramecia (ISME) Phage trigger antiviral immunity (Science) Image credit Letters read on TWiM 198 Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Send your microbiology questions and comments to twim@microbe.tv

Thu, 12 Jan 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/14225/ https://edoc.ub.uni-muenchen.de/14225/1/Schell_Christoph.pdf Schell, Christoph ddc:610, d

A growth factor that antagonizes signaling by tumor necrosis factor α relieves symptoms of inflammatory arthritis.

Cours d’immunologie de 4e année de pharmacie. Les cytokines : TNFalpha, IL1, chimiokines.

The study is subdivided into two different parts: the first part deals with the development of a method to gain uterus milk in vivo during the preimplantation periode in cattle for the investigation of regulatory factors. The second part investigates different proteases in bovine follicles 20 hours after GnRH (Gonadotropin releasing hormone) injection (shortly bevor ovulation) for comparable as well as in the corpus luteum (CL) during oestrous cycle and induced luteolysis. In addition apoptotic as well as anti-apoptotic factors were evaluated in the CL during oestrous cycle and induced luteolysis. For the development of a method for gaining uterus milk in vivo during the first 24 days of gravidity in cattle, nine heifers were cycle synchronised using the Ovsynch method and artificially inseminated. Before flushing an epiduralanaesthesia was given and both uterus horns were flushed with 13ml 0.9% NaCl using a balloon embryo transfer catheter at day 5, 7, 12, 17 and 24 of gravidity. The catheter was placed 1cm cranial to the bifurcatio uteri in both horns. It was possible to retrive between 3ml and 13ml of the used flushing fluid. The uterus milk from the ipsilateral horn was inspected for an embryo and an EDTA-stabilisator was given to the uterus milk of both horns. An infection of the uterus occured in three heifers after the second and in five heifers after the third flushing. In one heifer no infection was found. Between day 17 and day 24 all heifers showed clear signs of oestrus. It was possible to detect progesterone, oestradiol-17-beta, PGF2alpha and VEGF via enzyme immunoassay (EIA) and radio immunoassay (RIA), respectively. Because of the occurred infection no statistic analysis was made. But it could be seen that the level of progesterone ranged between

Im Angesicht der augenscheinlichen Insuffizienz vorhandener Optionen in der Behandlung des metastasierten Pankreaskarzinoms stellt die Immuntherapie mit dendritischen Zellen einen möglichen neuen Therapieansatz dar. Bei einer Vielzahl von Malignomen wird diese Art der Therapie experimentell bereits klinisch getestet, bisher jedoch nicht mit ausreichendem Erfolg. Ziel dieser Arbeit war es, zu eruieren, welchen Einfluss der Modus der Aktivierung dendritischer Zellen auf eine gegen Pankreaskarzinomzellen gerichtete Immunantwort besitzt. Dabei sollten Wege identifiziert werden, eine aus dendritischen Zellen bestehenden Vakzine durch eine effektive Stimulation der enthaltenen Zellen möglichst potent in der Induktion dieser Immunantwort zu machen. Zu diesem Zwecke wurden von Monozyten abgeleitete dendritische Zellen mit dem Überstand apoptotischer Tumorzellen eines duktalen Pankreaskarzinoms inkubiert und dann nach verschiedenen Schemata stimuliert. Die Potenz der dendritischen Zellen wurde eruiert über die Expression von Reifemarkern und kostimulatorischen Molekülen, die Zytokinproduktion und die Induktion von Aktivierungsmarkern auf T-Zellen sowie der CTL-getragenen spezifischen Immunantwort gegen Pankreaskarzinomzellen in einer halbautologen Kokultur von dendritischen Zellen und naiven T-Zellen. Zur Stimulation der dendritischen Zellen kamen ATP mit TNFalpha und die Kombination von IL-1beta, IL-6, TNFalpha und PGE2 mit und ohne die Zugabe von CD40-Ligand, einem zellgebundenen, DC-aktivierenden Oberflächenmolekül, zur Anwendung. Die kombinierte Anwendung von CD40L und proinflammatorischen Mediatoren (TNFalpha, IL-6, IL-1beta und PGE2 bzw. ATP plus TNFalpha) besaß, verglichen mit der getrennten Anwendung dieser Stimuli, einen synergischen Effekt bei der Aktivierung dendritischer Zellen. So stimulierte Zellen zeigten eine hohe Expression von Aktivierungsmarkern und des Zytokinrezeptors CCR7, induzierten effektiv ein Th1-gerichtetes Zytokinmillieu und eine CTL-vermittelte spezifische Immunantwort gegen Pankreaskarzinomzellen. Die Zugabe von CD40-Ligand 12 h nach der Stimulation der dendritischen Zellen mit ATP und TNFalpha bzw. der Kombination von IL-1beta, IL-6, TNFalpha und PGE2 erwies sich dabei als optimal. Die Ergebnisse dieser Arbeit legen nahe, dass die Art der Stimulation der dendritischen Zellen im Rahmen der Immuntherapie des duktalen Pankreaskarzinoms einen wesentlichen Einflussfaktor in Bezug auf die Potenz der verwendeten Vakzine darstellt. Geht man von einer Übertragbarkeit dieser in-vitro-Daten auf das menschliche Immunsystem aus, so kann mit Hilfe einer optimalen Aktivierung dendritischer Zellen die Effektivität einer Vakzine wesentlich gesteigert werden.

Im Rahmen der Arbeit wurde ein zelluläres System etabliert mit dem die transkriptionelle Aktivität des EpCAM-Promotors, ausgehend von der bisherig bekannten Promotorsequenz, beurteilbar ist. Experimentelle Basis war der Luziferase-Assay für den ein Luziferase-Reporterplasmid unter transkriptioneller Kontrolle der bisher bekannten EpCAM-Promotorsequenz generiert wurde. Es konnte mit Hilfe von FACS-Analysen und Immunoblots gezeigt werden, daß sich die gemessene transkriptionelle Aktivität in der tatsächlichen EpCAM-Expression widerspiegelt. Desweiteren konnte gezeigt werden, daß die kanzeromodulierenden Substanzen TNFalpha und TPA auf den EpCAM-Promotor reprimierend wirken. Im Falle von TNFalpha konnte experimentell belegt werden, daß die Repression über die spezifische Signaltransduktion über den NF-kappa-B-Signalweg zustande kommt, in dem letztlich NF-kappa-B über eine Kompetition um den wichtigen Transkriptionskoaktivator p300/CBP eine Repression des EpCAM-Promotors vermittelt.