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Why do some people sleep just 4 hours and feel great?

BUFFALO, NY — May 6, 2025 — A new #research paper was #published in Aging (Aging-US) Volume 17, Issue 4, on April 2, 2025, titled “Fisetin ameliorates vascular smooth muscle cell calcification via DUSP1-dependent p38 MAPK inhibition.” In this study, researchers at Johannes Kepler University Linz found that fisetin, a natural substance found in fruits and vegetables, helps protect blood vessels from hardening, which is a common problem in older adults and people with kidney disease. This discovery highlights fisetin's potential to prevent vascular calcification and reduce cardiovascular damage caused by aging and chronic kidney disease. The research, led by first author Mehdi Razazian and corresponding author Ioana Alesutan, focused on vascular calcification—a condition in which blood vessels stiffen due to calcium deposits. This process is common in aging and chronic kidney disease and increases the risk of heart attacks and strokes. Using human and mouse study models, the researchers tested fisetin's ability to prevent this calcification in vascular smooth muscle cells (VSMC), which play a key role in maintaining vessel health. Fisetin, known for its anti-inflammatory and antioxidant properties, significantly reduced calcium buildup and calcification markers under stress conditions that mimic disease. The team also discovered that fisetin suppresses activity in a signaling pathway called p38 MAPK, which is known to promote calcification. This effect depends on a protein called DUSP1. When DUSP1 was blocked, fisetin could no longer protect the cells, showing that this protein is essential for its anti-calcification activity. The researchers confirmed fisetin's protective effects in isolated mouse arteries and in living mice treated with high doses of vitamin D, which typically increases arterial calcification. “Mechanistically, fisetin requires the phosphatase DUSP1 to inhibit p38 MAPK in order to mediate its protective effect on VSMC calcification.” Importantly, the researchers tested fisetin under conditions similar to human disease. When VSMCs were exposed to blood serum from kidney dialysis patients—a condition known to trigger vascular calcification—fisetin again reduced calcium buildup and protected the cells. These findings suggest fisetin could be useful in countering the harmful vascular effects seen in chronic kidney disease. This study adds to growing evidence that fisetin may protect blood vessels from aging-related damage. While more research is needed before it can be used in clinical treatments, the study highlights fisetin as a promising candidate for slowing or preventing vascular calcification. The findings could have broad implications for aging populations and individuals with kidney disease, who are at greater risk for heart problems due to vascular stiffening. Read the full paper: DOI: https://doi.org/10.18632/aging.206233 Corresponding author: Ioana Alesutan – ioana.alesutan@jku.at Keywords: aging, vascular calcification, vascular smooth muscle cells, fisetin, dual-specificity phosphatase 1, p38 MAPK ______ To learn more about the journal, please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Bluesky - https://bsky.app/profile/aging-us.bsky.social Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Le syndrome de canitie subite, ou syndrome de Marie-Antoinette, désigne une situation où les cheveux d'une personne deviennent gris ou blancs en très peu de temps, parfois du jour au lendemain. Bien que ce phénomène ait souvent été considéré comme une légende ou une exagération, des cas historiques et des études récentes suggèrent qu'il pourrait être lié au stress extrême.Les chercheurs ont longtemps débattu des mécanismes sous-jacents. La canitie subite n'est pas une perte de pigments préexistants, mais plutôt une explication plausible liée à la chute massive des cheveux pigmentés en raison d'un stress important, laissant place aux cheveux gris ou blancs déjà présents.Le stress et les cheveux gris : des preuves scientifiques inéditesUne étude récente publiée dans Nature (2020) a apporté des preuves concrètes liant le stress au grisonnement des cheveux. Des chercheurs de l'Université de Harvard ont démontré que le stress active le système nerveux sympathique, libérant une hormone appelée noradrénaline. Celle-ci affecte les cellules souches mélanocytaires, responsables de la production de mélanine, le pigment qui colore les cheveux. Sous l'effet du stress, ces cellules souches s'épuisent prématurément, entraînant une repousse de cheveux gris ou blancs.Identification des protéines responsablesUne étude complémentaire publiée en 2021, relayée par Science Post, a identifié les protéines jouant un rôle clé dans ce processus. Les chercheurs ont constaté que le stress modifie l'expression de protéines spécifiques dans les follicules pileux, altérant ainsi la production de mélanine. Parmi ces protéines, celles impliquées dans la régulation des cellules souches et des réponses au stress, comme la protéine p38 MAPK, semblent particulièrement importantes.La possibilité d'une inversionUne découverte révolutionnaire de cette même étude est que, dans certains cas, la réduction du stress pourrait inverser le grisonnement des cheveux. Des tests ont montré que lorsque les niveaux de stress diminuaient, certains cheveux retrouvaient leur pigmentation d'origine. Ce phénomène est encore mal compris et dépend de la préservation des cellules souches dans le follicule.En conclusionLe syndrome de canitie subite est une manifestation extrême du lien entre stress et cheveux gris, désormais étayée par des preuves scientifiques. Ces recherches ouvrent la voie à de nouvelles approches pour prévenir ou même inverser ce phénomène, notamment par la gestion du stress ou des thérapies ciblant les mécanismes cellulaires impliqués. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.

BUFFALO, NY- August 12, 2024 – A new research perspective was published in Oncotarget's Volume 15 on July 16, 2024, entitled, “Targeting the multifaceted BRAF in cancer: New directions.” In cancer patients, BRAF-targeting precision therapeutics are effective against Class I BRAF alterations (p.V600 hotspot mutations) in tumors such as melanoma, thyroid cancer, and colorectal cancer. However, numerous non-Class I BRAF inhibitors are also in development and have been explored in various cancers. Researchers Eamon Toye, Alexander Chehrazi-Raffle, Justin Hwang, and Emmanuel S. Antonarakis from the Masonic Cancer Center, University of Minnesota-Twin Cities, Department of Medicine, University of Minnesota-Twin Cities, Perelman School of Medicine, University of Pennsylvania, and the City of Hope Comprehensive Cancer Center in Duarte, California, discuss the diverse forms of BRAF alterations found in human cancers and the strategies used to inhibit them in patients with cancers of various origins. As part of their conclusion, the researchers highlighted that Class I BRAF inhibitors represent a landmark achievement in precision oncology, as demonstrated by the recent tissue-agnostic FDA approval of dabrafenib/trametinib for patients with metastatic BRAF p.V600E-mutant solid tumors. Additionally, the accelerated approval of tovorafenib for patients with relapsed/refractory BRAF-altered pediatric low-grade glioma underscores the therapeutic potential of this and other next-generation strategies targeting aberrant MAPK signaling. DOI - https://doi.org/10.18632/oncotarget.28612 Correspondence to - Emmanuel S. Antonarakis - anton401@umn.edu, and Justin Hwang - jhwang@umn.edu Video short - https://www.youtube.com/watch?v=3dRWRvOnssc Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28612 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, BRAF, MAPK, pan-cancer, precision oncology, genomics About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. Michael Jurgelewicz is the Director of Product Development, Research, and Clinical Support for Designs for Health, Inc., and has been studying nutrition and wellness for the past 17 years. He is a licensed Doctor of Chiropractic in Pennsylvania and Connecticut and is an adjunct professor for the Master of Science in Human Nutrition program at the University of Bridgeport as well as Sonoran University of Health Sciences. He is board-certified in Nutrition by the American Clinical Board of Nutrition, a Diplomate of the Chiropractic Board of Clinical Nutrition, and Certified Nutrition Specialist, and a Doctor of Chiropractic. He is also a member of the American Clinical Board of Nutrition's Item Writer's Committee and a contributor to various professional publications. In addition, Dr. Jurgelewicz specializes in functional medicine in the management of a variety of chronic health conditions.   Together Dr. Jurgelewicz and I discuss autoimmune disease treatments, the third most common cause of chronic illness in women, with functional medicine. He highlights the most common autoimmune diseases, the health stage at which many patients come to work with him, and what he expects from patients from their very first interactions to optimize success. He shares probable outcomes with optimized vitamin levels and dosing preferences for his patients, his autoimmunity supplements preferences, and the rate at which he treats patients with gut-healing herbs and nutrients. As a key player in the development team at Designs for Health, he offers an overview of each phase of his treatment strategy, shares exciting developments in the field of autoimmune research, and underscores some of his all-time favorite product and technology developments in the world of autoimmune research and development. I'm your host, Evelyne Lambrecht, thank you for designing a well world with us. Episode Resources:   Dr. Michael Jurgelewicz    Clinical Trial: Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial   Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1   Review: An Update on the Effects of Vitamin D on the Immune System and Autoimmune Diseases   Clinical Trial: Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial The influence of omega-3 supplementation on vitamin D levels in humans: a systematic review and dose-response meta-analysis of randomized controlled trials   Design for Health Resources: Designs for Health Science Update: Recent Trial Investigates Potential Link Between Vitamin D, PUFAs, and Autoimmunity Science Update: Pilot Study Explores Immunomodulatory Actions of Selenium and Vitamin D for Thyroid Health Science Update: New study demonstrates selenium reduces antibody levels in Hashimoto's patients Science Update: New review demonstrates the role of dietary supplements in thyroid conditions Nutrition Blog: Micronutrients to Support the Autoimmune Response Research Blog: The Immune Supportive Properties of Mushrooms Nutrition Blog: The Versatility of Nigella (Black Cumin) Seeds Nutrition Blog: The Immune Support of Andrographis Research Blog: Serum-derived Bovine Immunoglobulins and Gut Barrier Function Educational Webinar - The Thyroid Reboot with Justin Marchegiani Visit the Designs for Health Research and Education Library which houses medical journals, protocols, webinars, and our blog. Chapters: 00:00 Intro 02:30 Michael shares his journey into nutrition and the need for his work with autoimmune disease. 04:53 The most common autoimmune diseases and the health stage at which many patients come to work with Dr. Jurgelewicz. 09:14 Standard procedures and lab tests for patients with positive ANA antibodies. 14:29 Dr. Jurgelewicz shares ideal Omega 3 index and Vitamin D levels and probable outcomes with optimized levels. 20:35 Dosing preferences for patients with low Vitamin D levels and supplement recommendations for stimulators versus modulators. 28:48 Ideal levels for thyroid antibody recommendations and testing guidelines. 32:57 Dr. Jurgelewicz shares his preferences for autoimmunity supplements including medicinal mushrooms, black cumin seed oil, and Andrographis. 37:49 The rate at which Dr. Jurgelewicz is treating patients with gut-healing herbs and nutrients. 40:02 A closer look at the role of immunoglobulins in optimal gut health from a treatment perspective. 42:31 An overview of each phase of Dr. Jurgelewicz's treatment strategy and the supplements and dietary restrictions he recommends at each stage. 50:20 Exciting developments in the field of autoimmune research including targeted therapies and antibody testing. 53:26 Dr. Jurgelewicz shares his top supplements, favorite health practices, and the testing approach that he has changed his mind about in recent years. 59:28 A bonus question - Dr. Jurgelewicz reveals his favorite product and technology developments at Designs for Health.

Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer-related deaths worldwide. It often starts in the colon or rectum with small, noncancerous clumps of cells called polyps, which can develop into cancer over time. Risk factors for colorectal cancer include age, family history, inflammatory bowel diseases, diet, smoking, and physical activity. The development and progression of colorectal cancer are driven by the aberrant activation of multiple signaling pathways, such as EGFR (epidermal growth factor receptor), RAS-RAF, and PTEN-PI3K. Among these pathways, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathways are particularly important, as they are frequently mutated in colorectal cancer. Therapeutic targeting of these pathways has shown promise in suppressing tumor growth. However, cancer cells often develop resistance to targeted therapies, leading to treatment failure and disease progression. In a new study, researchers Astha Lamichhane, Gary D. Luker, Seema Agarwal, and Hossein Tavana from The University of Akron, University of Michigan and Georgetown University aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies. Their research paper was published in Oncotarget on October 4, 2023, entitled, “Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.” Full blog - https://www.oncotarget.org/2023/12/14/triple-combination-treatment-overcomes-colorectal-cancer-resistance/ Paper DOI - https://doi.org/10.18632/oncotarget.28517 Correspondence to - Hossein Tavana - tavana@uakron.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28517 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, drug resistance, cancer stem cells, patient-derived tumor model, colorectal cancer, combination treatment About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this rebroadcasted episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Drs. Rachel Grisham, David Gershenson, and Brian Slomovitz to discuss "Low Grade Ovarian Cancer: The Expert Consensus".    Highlights:   A panel of experts convened in October 2022 to discuss recent scientific and clinical progress, resulting in a consensus document that provides recommendations for diagnosis, treatment, and ongoing research to improve patient care of low-grade serous ovarian cancer.  Alterations affecting the MAPK pathway are frequent in low-grade serous ovarian cancer and provide prognostic information  Recent advances in the use of targeted therapy (in particular with novel MEK inhibitor and endocrine therapy regimens) have led to unprecedented response rates in patients with recurrent low-grade serous ovarian cancer 

En parallèle de son activité de coach de santé, Camille anime une vaste communauté autour des huiles essentielles doTerra. Dans cet épisode, elle revient sur les raisons de son engagement avec DoTerra, puis elle va dans le détail de certaines huiles essentielles qui peuvent être bénéfiques pour le système nerveux et des alliées précieuses sur le chemin de guérison. DANS CET ÉPISODE, TU VAS APPRENDRE :  Pourquoi il est primordial d'utiliser des huiles de grade thérapeutique Le lien entre trauma, système nerveux et inflammation chronique Les bienfaits de certaines huiles essentielles, comme l'Encens et le Copaiba Comment utiliser les huiles  ***** VIENS AUX PROCHAINES MASTERCLASS: https://www.eventbrite.fr/o/camille-tomat-26376074075 COMMENT TE LANCER AVEC DŌTERRA:  KIT PAS DE SOUCIS INTÉGRAL (15ml d'Encens offert en décembre - valeur: 81€): https://doterra.me/93U6tm  KIT PAS DE SOUCIS TOUCH (formats roll-on, déjà dilués dans de l'huile de coco fractionnée, applicable directement sur la peau): https://doterra.me/HRRs1_  KIT SYSTÈME NERVEUX: https://doterra.me/UxLXCMKIT INFLAMMATION CHRONIQUE: https://doterra.me/H0Q_VW  Si tu es dans un autre pays que la France ou que tu veux te lancer avec une commande personnalisée, clique ici: https://360essentielles.com/camille-tomat  Si tu souhaites des conseils personnalisés sur les huiles qui pourraient te correspondre, viens à ma prochaine intro aux huiles ou envoie directement un email à contact@camilletomat.com  LES KITS: https://media.doterra.com/fr/fr/flyers/kits-enrolment.pdf  LES PRIX: https://media.doterra.com/fr/fr/forms/price-list.pdf  ***** RESSOURCES:  Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study, American Journal of Preventive Medicine, 1998 Adverse Childhood Experiences and the Risk of Premature Mortality, American Journal of Preventive Medicine, 2009 Therapeutic Potential of α- and β-Pinene: A Miracle Gift of Nature,  Distribution of the anti-inflammatory and anti-depressant compounds: Incensole and incensole acetate in genus Boswellia, Phytochemistry, 2019 The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress, Dialogues in Clinical Neuroscience, 2006 Effects of Inhaled (S)-Linalool on Hypothalamic Gene Expression in Rats under Restraint Stress, Bioscience, Biotechnology, and Biochemistry, 2013 Antidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression, Behavioural Brain Research, 2020 Bornyl acetate: A promising agent in phytomedicine for inflammation and immune modulation, Phytomedicine, 2023 The additive properties of Oxygen Radical Absorbance Capacity (ORAC) assay: the case of essential oils, Food Chemistry, 2014 Inhibitory Activities of Essential Oil Obtained from Turmeric and Its Constituents against β-Secretase, Sage journals, 2016 Frankincense and myrrh suppress inflammation via regulation of the metabolic profiling and the MAPK signaling pathway, Scientific Reports, 2015 Dr Josh Axe: https://www.youtube.com/@drjoshaxe Le site source to you: https://sourcetoyou.com/fr/  Roue de la chimie: https://media.doterra.com/us/en/flyers/doterra-oil-chemistry-wheel-2018.pdf  ***** NOUVEAU/NOUVELLE ICI ? Coucou ! Je suis Camille, coach, praticienne en Somatic Experiencing et podcasteuse. Je suis entrepreneure, pas seulement du bien-être, mais d'une vraie santé optimale à travers mon travail avec le système nerveux. J'aide les personnes à se libérer de l'anxiété et de leurs maux chroniques. Si tu veux en savoir plus, clique sur les liens en dessous: TU VEUX COMPRENDRE LES CAUSES DE TON ANXIÉTÉ ? Fais le test gratuit: https://bit.ly/test-anxiete PRÊT/E À COMMENCER ? Si tu es prête à te libérer de l'anxiété avec ma méthode, tu trouveras toutes les informations sur mon programme ARISE sur mon site: https://arise.camilletomat.com

Explore the incredible benefits of algae with Catharine Arnston. First, you need to know that it's not a supplement, but a true superfood. This episode focuses on two remarkable algae varieties: spirulina, a vibrant blue-green algae packed with collagen, B vitamins, and essential amino acids, and chlorella, another green gem with unique properties. Discover the differences between these algae powerhouses, when and how to incorporate them into your daily routine, and the science behind their health-boosting effects.Prepare to also dive into the intricate world of enzymes, including superoxide dismutase and ficocyanin, as we explore their role in reducing angiogenesis in cancer cells and enhancing immunity against viral infections, including a certain well-known virus we've all heard about in recent years.Our discussion doesn't stop there. Dr. Stephanie and Catharine explore the myriad applications of algae, from helping children with autism to supporting the demanding lifestyles of athletes and individuals like Dr. Stephanie, a 45-year-old woman dedicated to weight training and cardio.This episode offers a deep, scientifically rich conversation that promises to captivate your inner nerd.Bio:Catharine started ENERGYbits after her sister was diagnosed with breast cancer and advised by her oncologist that an alkaline diet would help her heal. Catharine immediately sprung into action to help her sister research alkaline foods and in the process she discovered algae. When Catharine learned that algae was the most alkaline, plant-based, nutrient-dense food in the world and had been used for fifty years in Asia to improve health and longevity, she knew she had discovered something big (and yes, her sister fully recovered - thanks for asking).As Catharine dug into the science of algae, she learned it had 64% protein, and 40 vitamins/minerals and was endorsed by the United Nations and NASA as the most nutrient-dense food in the world. She also discovered there were 100,000 studies documenting its long list of benefits and it was the world's most sustainable, eco-friendly food crop. And yet algae remained virtually unknown outside of Asia. How could this be possible? Catharine knew algae could be a game changer for our health, our children and our world if she could only convince people it wasn't weird. And so ENERGYbits was born.Links for this episode:EnergyBits.com/better and use code BETTER for 20% off anything on the websiteSpirulina in Clinical Practice: Evidence-Based Human Applications - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136577/A deep dive into Zero Hunger: the seaweed revolution - https://news.un.org/en/story/2020/11/1077212Phycocyanin: A Potential Drug for Cancer Treatment - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687155/C-Phycocyanin exerts anti-cancer effects via the MAPK signaling pathway in MDA-MB-231 cells - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785878/NAC, Spirulina, Other Nutraceuticals May Play Role On Coronavirus Treatment - https://scienceblog.com/514404/nac-spirulina-other-nutraceuticals-may-play-role-on-coronavirus-treatment/Anti-Inflammatory and Anti-Aging Evaluation of Pigment-Protein Complex Extracted from Chlorella Pyrenoidosa - https://pubmed.ncbi.nlm.nih.gov/31623220/Studies on the biosorption of heavy metals onto Chlorella vulgaris - https://www.tandfonline.com/doi/abs/10.1080/10934529409376043Chlorella vulgaris functional alcoholic beverage: Effect on propagation of cortical spreading depression and functional properties - https://pubmed.ncbi.nlm.nih.gov/34370788/Algae Protects Mitochondria Health With Superoxide Dismutase (SOD)Algae Tablets for Brain HealthBrain Health with AlgaeCancer Free with AlgaeEpisode Overview:0:04:50 Understanding Algae: Macroalgae vs. Microalgae0:09:10 Introduction to Spirulina and Chlorella0:11:35 The Power of Vegetables and Proper Supplementation0:21:06 Mechanism of Action: Phycocyanin and Cancer Cell Destruction0:30:51 Spirulina: The Ultimate Calorie-Conscious Superfood0:41:15 Collagen and its Role in Muscle Growth0:50:41 Spirulina and Chlorella for Detox and Wellness Benefits0:53:37 Spirulina and Chlorella for Improving Brain Function in Autistic Children0:57:09 Spirulina and Chlorella as Food for Athletes, Providing Focus and Energy1:00:06 Try Taking 30 EnergyBits Before Your Next WorkoutWe'd like to thank our sponsors:LEVELSLevels helps you see how food affects your health by giving you real-time feedback on your diet using a continuous glucose monitor. Right now Levels is offering you an additional two free months off of the levels annual membership when you use the link levels.link/better.

When it comes to glycogen, does "train low" actually work? Rory joints to co-host as we examine and dissect the existing literature, and explore the limits of knowledge on p38 MAPK signaling as it relates to aerobic performance. We go through Kolie's coaching experience with these protocols, compare to existing recommendations, discuss why you should always check someone's references, and answer your listener questions.

BUFFALO, NY- October 11, 2023 – A new research paper was published in Oncotarget's Volume 14 on October 4, 2023, entitled, “Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.” Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. In their new study, researchers Astha Lamichhane, Gary D. Luker, Seema Agarwal, and Hossein Tavana from The University of Akron, University of Michigan and Georgetown University aimed to elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies. “[...] we developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis.” They found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. The team examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer. “Our approach to identify mechanisms of drug resistance of patient-derived cancer cells to targeted therapies and develop effective treatments is promising toward cancer precision medicine.” DOI - https://doi.org/10.18632/oncotarget.28517 Correspondence to - Hossein Tavana - tavana@uakron.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28517 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, drug resistance, cancer stem cells, patient-derived tumor model, colorectal cancer, combination treatment About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Drs. Rachel Grisham, David Gershenson, and Brian Slomovitz to discuss "Low Grade Ovarian Cancer: The Expert Consensus".   Highlights:   A panel of experts convened in October 2022 to discuss recent scientific and clinical progress, resulting in a consensus document that provides recommendations for diagnosis, treatment, and ongoing research to improve patient care of low-grade serous ovarian cancer.  Alterations affecting the MAPK pathway are frequent in low-grade serous ovarian cancer and provide prognostic information.  Recent advances in the use of targeted therapy (in particular with novel MEK inhibitor and endocrine therapy regimens) have led to unprecedented response rates in patients with recurrent low-grade serous ovarian cancer.

A new research paper was published on the cover of Aging (Aging-US) Volume 15, Issue 15, entitled, “Natural aging and ovariectomy induces parallel phosphoproteomic alterations in skeletal muscle of female mice.” The loss of skeletal muscle strength mid-life in females is associated with the decline of estrogen. In this new study, researchers Mina P. Peyton, Tzu-Yi Yang, LeeAnn Higgins, Todd W. Markowski, Kevin Murray, Cha Vue, Laurie L. Parker, and Dawn A. Lowe from the University of Minnesota questioned how estrogen deficiency might impact the overall skeletal muscle phosphoproteome after contraction, as force production induces phosphorylation of several muscle proteins. “Importantly, identification of these altered phosphosites and candidate kinases and phosphatases sensitive to the presence of estrogen will help advance our understanding of the contributions of estrogen deficiency to muscle strength loss in aging females.” Phosphoproteomic analyses of the tibialis anterior muscle after contraction in two mouse models of estrogen deficiency, ovariectomy (Ovariectomized (Ovx) vs. Sham) and natural aging-induced ovarian senescence (Older Adult (OA) vs. Young Adult (YA)), identified a total of 2,593 and 3,507 phosphopeptides in Ovx/Sham and OA/YA datasets, respectively. Further analysis of estrogen deficiency-associated proteins and phosphosites identified 66 proteins and 21 phosphosites from both datasets. Of these, 4 estrogen deficiency-associated proteins and 4 estrogen deficiency-associated phosphosites were significant and differentially phosphorylated or regulated, respectively. Comparative analyses between Ovx/Sham and OA/YA using Ingenuity Pathway Analysis (IPA) found parallel patterns of inhibition and activation across IPA-defined canonical signaling pathways and physiological functional analysis, which were similarly observed in downstream GO, KEGG, and Reactome pathway overrepresentation analysis pertaining to muscle structural integrity and contraction, including AMPK and calcium signaling. IPA Upstream regulator analysis identified MAPK1 and PRKACA as candidate kinases and calcineurin as a candidate phosphatase sensitive to estrogen. “In summary, our results from contracted skeletal muscle highlight CAST Ser-82 as a candidate phosphosite, and MAPK1/ERK2, PRKACA, and calcineurin as candidate upstream regulators sensitive to estrogen deficiency that may contribute to changes in the force-generating capacity of skeletal muscle.” DOI - https://doi.org/10.18632/aging.204959 Corresponding author - Dawn A. Lowe - lowex017@umn.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204959 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, estrogen deficiency, CAST, MAPK, PKA, calcineurin About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.01.551503v1?rss=1 Authors: Swanson, K. A., Nguyen, K. L., Gupta, S., Ricard, J., Bethea, J. R. Abstract: Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) (Clark et al., 2013; Empl et al., 2001; Ji et al., 2018; Lindenlaub and Sommer, 2003). To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex+ neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that following chronic constriction injury (CCI), pain resolves in males; however, female acute pain transitions to chronic. Subsequently, we investigated two downstream pathways, p38MAPK and NF-{kappa}B, important in TNFR1 signaling and injury response. We detected p38MAPK and NF- {kappa}B activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed similar behavioral results following CCI in NexCreERT2::p38MAPKf/f mice. Previously, we established estrogen's ability to modulate sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP (Bouhassira et al., 2008; Claiborne et al., 2006; de Mos et al., 2007; Del Rivero et al., 2019; Li et al., 2009). To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor {beta} (ER {beta}) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lend "male-like" therapeutic relief to females following CCI. These data suggest that TNFR1/p38MAPK signaling in Nex+ neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER {beta} interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes. 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/2023.07.23.550205v1?rss=1 Authors: He, L., Ioannidis, A., Arambula, E., Hoffman, C. J., Joshi, P., Kathiravan, A., Whitelegge, J. P., Liau, L. M., Kornblum, H. I., Pajonk, F. Abstract: Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level. Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells. 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/2023.07.17.549377v1?rss=1 Authors: Broce, I., Sirkis, D., Nillo, R. M., Bonham, L. W., Lee, S. E., Miller, B. L., Sturm, V., Sugrue, L. S., Desikan, R., Yokoyama, J. S. Abstract: Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. Conclusions: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD. 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/2023.07.12.548684v1?rss=1 Authors: Pranty, A. I., Wruck, W., Adjaye, J. Abstract: Bilirubin induced neurological damage (BIND), which is also known as Kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus resulting in unconjugated bilirubin (UCB) to cross the blood brain barrier (BBB) and accumulation. Severe hyperbilirubinemia can be caused by a mutation within the UGT1A1 encoding gene. This mutation has a direct contribution towards bilirubin conjugation leading to Kernicterus as a symptom of Crigler Najjar Syndromes (CNS1, CNS2) and Gilbert syndrome, which results in permanent neurological sequelae. In this comparative study, we used human induced pluripotent stem cells (hiPSCs) derived 3D-brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of UCB in the developing human brain. hiPSC derived from healthy and CNS patients were differentiated into day 20 brain organoids, these were then stimulated with 200nM UCB. Analyses at 24 and 72 hrs post-treatment point at UCB induced neuro-inflammation in both cell lines. Transcriptome and associated KEGG and Gene Ontology analyses unveiled activation of distinct inflammatory pathways such as cytokine cytokine receptor interaction, MAPK signaling, calcium signaling, NFkB activation. Furthermore, both mRNA expression and secretome analysis confirmed an upregulation of proinflammatory cytokines such as IL6 and IL8 upon UCB stimulation. In summary, this novel study has provided insights into how a human iPSC derived 3D-brain organoid model can serve as a prospective platform for studying the etiology of BIND Kernicterus. 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/2023.07.05.547546v1?rss=1 Authors: Breitwieser, G., Cippitelli, A., Wang, Y., Pelletier, O., Dershem, R., Wei, J., Toll, L., Fakhoury, B., Brunori, G., Metpally, R., Genetics Center, R., Carey, D. J., Robishaw, J. D. Abstract: GPR37L1 is an orphan receptor that couples through heterotrimeric G-proteins to regulate physiological functions. Since its role in humans is not fully defined, we used an unbiased computational approach to assess the clinical significance of rare GPR37L1 genetic variants found among 51,289 whole-exome sequences from the DiscovEHR cohort. Briefly, rare GPR37L1 coding variants were binned according to predicted pathogenicity, and then analyzed by Sequence Kernel Association testing to reveal significant associations with disease diagnostic codes for generalized epilepsy and migraine, among others. Since associations do not prove causality, rare GPR37L1 variants were then functionally analyzed in SK-N-MC cells to evaluate potential signaling differences and pathogenicity. Notably, receptor variants exhibited varying abilities to reduce cAMP levels, activate MAPK signaling, and/or upregulate receptor expression in response to the agonist prosaptide (TX14(A)), as compared to wild-type receptor. In addition to signaling changes, knockout of GPR37L1 or expression of certain rare variants altered cellular cholesterol levels, which were also acutely regulated by administration of the agonist TX14(A) via activation of the MAPK pathway. Finally, to simulate the impact of rare nonsense variants found in the large patient cohort, a knockout (KO) mouse line lacking Gpr37L1 was generated, revealing loss of this receptor produced sex-specific changes implicated in migraine-related disorders. Collectively, these observations define the existence of rare GPR37L1 variants in the human population that are associated with neuropsychiatric conditions and identify the underlying signaling changes that are implicated in the in vivo actions of this receptor in pathological processes leading to anxiety and migraine. 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/2023.07.02.547408v1?rss=1 Authors: Nguyen, V., Gao, C., Hochman, M., Kravitz, J., Chen, E., Friedman, H., Wenceslau, C., Chen, D., Wang, Y., Nelson, J. S., Jegga, A. G., Tan, W. Abstract: Background: Port Wine Birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models is an unmet need for PWB studies. Objective: This study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and those-iPSC-derived ECs that preserve disease-related phenotypes. Method: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and were differentiated into ECs. Bulk RNA-seq and ATAC-seq were performed to identify enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized using capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo. Result: Human PWB and normal iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) into them; The iPSCs were differentiated into ECs. These iPSCs and their-derived ECs were validated by expression of series of stem cell and EC biomarkers, respectively. PWB EC showed impaired CLS in vitro with larger perimeters and thicker branches comparing with control iPSC-derived ECs. In plug-in assay, perfused human vasculature formed by PWB iPSC-derived ECs showed bigger perimeters and greater densities than those formed by control iPSC-derived ECs in SCID mice. The transcriptome analysis showed that the impaired pathways of stem cell differentiation, Hippo, Wnt, and focal adhersion persisted through PWB iPSCs to ECs during differentiation. Interactive networks showed that the Hippo and Wnt pathway-related differentially expressed genes (DEGs) significantly function in vasculature development, tube morphology, endothelium development, and EC differentiation. Members of zinc-finger (ZNF) gene family were among the top changed DEGs in both PWB iPSCs and ECs. The ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinol acid pathway. In addition, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were upregulated in PWB ECs as readouts of impaired differentiation. Conclusion: PWB iPSC-derived ECs can be served as novel and clinically relevant disease models by retaining pathological phenotypes. Our data suggests the impaired Hippo and Wnt pathways underlie the development of differentiation-defective ECs in PWB lesions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on May 26, 2023, entitled, “Deconstructing the role of MALAT1 in MAPK-signaling in melanoma: insights from antisense oligonucleotide treatment.” The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK, and ERK in melanoma is largely unknown. In this study, researchers Valentin Feichtenschlager, Yixuan James Zheng, Wilson Ho, Linan Chen, Ciara Callanan, Christopher Chen, Albert Lee, Jose Ortiz, Klemens Rappersberger, and Susana Ortiz-Urda from the University of California San Francisco and Medical University Vienna demonstrated the impacts of antisense oligonucleotide (ASO)-based MALAT1-inhibition on MAPK-pathway gene regulation in melanoma. “Our results showed that MALAT1-ASO treatment decreased BRAF RNA expression and protein levels, and MALAT1 had increased correlation with MAPK-pathway associated genes in melanoma patient samples compared to healthy skin.” Additionally, drug-induced MAPK inhibition upregulated MALAT1-expression, a finding that resonates with a paradigm of MALAT1-expression presented in this work: MALAT1 is downregulated in melanoma and other cancer types in which MALAT1 seems to be associated with MAPK-signaling, while MALAT1-ASO treatment strongly reduced the growth of melanoma cell lines, even in cases of resistance to MEK inhibition. MALAT1-ASO treatment significantly inhibited colony formation in vitro and reduced tumor growth in an NRAS-mutant melanoma xenograft mouse model in vivo, while showing no aberrant toxic side effects. “Our findings demonstrate new insights into MALAT1-mediated MAPK-pathway gene regulation and a paradigm of MALAT1 expression in MAPK-signaling-dependent cancer types. MALAT1 maintains essential oncogenic functions, despite being downregulated.” DOI - https://doi.org/10.18632/oncotarget.28447 Correspondence to - Valentin Feichtenschlager - valentin.feichtenschlager@ucsf.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28447 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - MALAT1, MAPK-pathway, BRAF, melanoma, antisense oligonucleotides About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there's been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we're now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, 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 podcast. Thank you for your attention. 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.   Follow today's speakers: Dr. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538102v1?rss=1 Authors: Guan, Y., Fang, Z., Hu, A., Roberts, S., Johansson, P. K., Heilshorn, S. C., Enejder, A., Peltz, G. Abstract: Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. To overcome this barrier, we engineered a live cell imaging system that identifies collagen producing cells in a human multi-lineage hepatic organoid. This system was adapted for use as a microwell-based platform (i.e., microHOs) where exposure to PDGF or TGFb1 induced the formation of thick collagen fibers. Transcriptomic analysis revealed that TGFb1 exposure converted mesenchymal cells into myofibroblast-like cells with a significantly altered pattern of production of proteases and anti-proteases, which contribute to the development of liver fibrosis. When pro-fibrotic intracellular signaling pathways were examined using pharmacological probes, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates that their antifibrotic efficacy would be limited to fibrotic diseases that were solely mediated by that growth factor. In contrast, GSK3b or p38 MAPK inhibitors could prevent TGFb1- or PDGF-induced fibrosis in microHOs because they block intracellular signaling pathways that are commonly utilized by the TGFb1 and PDGF receptors. Hence, these studies identified GSK3b and p38 MAPK inhibitors as potential new broad-spectrum therapies for liver fibrosis, and it is likely that other new therapies could subsequently be identified using this microHO system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on April 10, 2023, entitled, “A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.” Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. In a new phase I trial, researchers Kristen R. Spencer, Daniella E. Portal, Joseph Aisner, Mark N. Stein, Jyoti Malhotra, Weichung Shih, Nancy Chan, Ann W. Silk, Shridar Ganesan, Susan Goodin, Murugesan Gounder, Hongxia Lin, Jiadong Li, Robert Cerchio, Christina Marinaro, Suzie Chen, and Janice M. Mehnert from Rutgers University, Dana-Farber Cancer Institute, and the Perlmutter Cancer Center of NYU Langone Health identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. “Riluzole functions as an inhibitor of GRM1 signaling through antagonism of glutamate release, and sorafenib is a multi-kinase inhibitor targeting both the MAPK and PI3K/AKT pathways through the inhibition of RAF1, ARAF and, to a lesser extent BRAF, as well as a set of tyrosine kinases including VEGFR. Our phase I study determined the tolerable dose of this combination and investigated its biologic effects.” Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. In total, 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. “Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.” DOI: https://doi.org/10.18632/oncotarget.28403 Correspondence to: Janice M. Mehnert - Janice.Mehnert@nyulangone.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28403 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - GRM1, riluzole, sorafenib, phase I, clinical trial About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.25.534211v1?rss=1 Authors: Mariano, N. C., Rusin, S. F., Nasa, I., Kettenbach, A. N. Abstract: Protein phosphorylation is an essential regulatory mechanism that controls most cellular processes, including cell cycle progression, cell division, and response to extracellular stimuli, among many others, and is deregulated in many diseases. Protein phosphorylation is coordinated by the opposing activities of protein kinases and protein phosphatases. In eukaryotic cells, most serine/threonine phosphorylation sites are dephosphorylated by members of the Phosphoprotein Phosphatase (PPP) family. However, we only know for a few phosphorylation sites which specific PPP dephosphorylates them. Although natural compounds such as calyculin A and okadaic acid inhibit PPPs at low nanomolar concentrations, no selective chemical PPP inhibitors exist. Here, we demonstrate the utility of endogenous tagging of genomic loci with an auxin-inducible degron (AID) as a strategy to investigate specific PPP signaling. Using Protein Phosphatase 6 (PP6) as an example, we demonstrate how rapidly inducible protein degradation can be employed to identify dephosphorylation SITES and elucidate PP6 biology. Using genome editing, we introduce AID-tags into each allele of the PP6 catalytic subunit (PP6c) in DLD-1 cells expressing the auxin receptor Tir1. Upon rapid auxin-induced degradation of PP6c, we perform quantitative mass spectrometry-based proteomics and phosphoproteomics to identify PP6 substrates in mitosis. PP6 is an essential enzyme with conserved roles in mitosis and growth signaling. Consistently, we identify candidate PP6c-dependent phosphorylation sites on proteins implicated in coordinating the mitotic cell cycle, cytoskeleton, gene expression, and mitogen-activated protein kinase (MAPK) and Hippo signaling. Finally, we demonstrate that PP6c opposes the activation of large tumor suppressor 1 (LATS1) by dephosphorylating Threonine 35 (T35) on Mps One Binder (MOB1), thereby blocking the interaction of MOB1 and LATS1. Our analyses highlight the utility of combining genome engineering, inducible degradation, and multiplexed phosphoproteomics to investigate signaling by individual PPPs on a global level, which is currently limited by the lack of tools for specific interrogation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on March 21, 2023, entitled, “Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior.” Glypicans (GPC1-6) are associated with tumorigenic processes and their involvement in neoplastic behavior has been discussed in different cancer types. In this recent cancer-wide GPC expression study, researchers Fang Cheng, Victor Chérouvrier Hansson, Grigorios Georgolopoulos, and Katrin Mani from Lund University and Genevia Technologies used clinical cancer patient data in The Cancer Genome Atlas to reveal net upregulation of GPC1 and GPC2 in primary solid tumors. On the other hand, GPC3, GPC5 and GPC6 displayed lowered expression patterns compared to normal tissues. “[...] we identify and propose a mechanism where GPC1 interacts with extracellular matrix mediating signal transduction by mitogenic molecules involving TGF-β and p38 MAPK.” Focusing on GPC1, the researchers conducted survival analyses of the clinical cancer patient data that revealed a statistically significant correlation between high expression of GPC1 and poor prognosis in 10 particular cancer types: bladder urothelial carcinoma, brain lower grade glioma, liver hepatocellular carcinoma, colon adenocarcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, mesothelioma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma, and uveal melanoma. In vitro studies targeting GPC1 expression by CRISPR/Cas9 or siRNA or treatment with an anti-GPC1 antibody resulted in attenuation of proliferation of cancer cells from bladder carcinoma, glioma and hepatocellular carcinoma patients (T24, U87 and HepG2 cells). Further, GPC1 overexpression exhibited a significant and negative correlation between GPC1 expression and proliferation of T24 cells. Their attempt to reveal the mechanism through which downregulation of GPC1 leads to attenuation of tumor growth using systematic Ingenuity Pathway Analysis indicated that suppression of GPC1 results in ECM-mediated inhibition of specific pro-cancer signaling pathways involving TGF-β and p38 MAPK. The team also identified differential expression and pleiotropic effects of GPCs in specific cancer types. This emphasizes their potential as novel diagnostic tools and prognostic factors, and open doors for future GPC targeted therapy. “It is plausible to measure circulating GPCs in serum, plasma or urine using a variety of methods including ELISA, urine cell sediments or exosome isolation [13, 24]. Further, detection and quantification of GPC1 by histopathological and immunohistochemical methods in tumor biopsies could be a new way to predict the biological outcome. The results of this investigation would also emphasize the potential of GPCs as novel tumor antigens, and open for GPC targeted immunotherapy. GPC targeted immunotherapy would be of high value, especially as we move into an era of precision and personalized cancer therapy.” DOI: https://doi.org/10.18632/oncotarget.28388 Correspondence to: Katrin Mani - katrin.mani@med.lu.se Keywords: Glypican-1, TCGA, bladder carcinoma, hepatocellular carcinoma, glioma About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533566v1?rss=1 Authors: Sun, W., Liu, Z., Jiang, X., Chen, M. B., Dong, H., Liu, J., Sudhof, T. C., Quake, S. R. Abstract: Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala (BLA) is a center of salience networks that underlie emotional experience and thus plays a key role in long-term fear memory formation. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide signaling, mitogen-activated protein kinase (MAPK), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), ubiquitination pathways, and synaptic connectivity in long-term memory. We also discovered that a neuronal sub-population, defined by increased Penk expression and decreased Tac expression, constitutes the most prominent component of the BLA's memory engram. These transcriptional changes were observed both with single-cell RNAseq and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to show that this neuronal subpopulation further interacts with spatially related astrocytes that are essential for memory consolidation, indicating that neurons require interactions with astrocytes to encode long term memory. 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/2023.03.13.532495v1?rss=1 Authors: Wible, D. J., Parikh, Z., Cho, E. J., Chen, M.-D., Mukhopadhyay, S., Dalby, K. N., Varadarajan, S., Bratton, S. B. Abstract: p38 mitogen-activated protein kinases (MAPKs) regulate early endocytic trafficking, but their effects on late endocytic trafficking remain unclear. Herein, we report that the pyridinyl imidazole p38 MAPK inhibitors, SB203580 and SB202190, induce a rapid but reversible Rab7-dependent accumulation of large cytoplasmic vacuoles. While SB203580 did not induce canonical autophagy, phosphatidylinositol 3-phosphate [PI(3)P] accumulated on vacuole membranes, and inhibition of the class III PI3-kinase (PIK3C3/VPS34) suppressed vacuolation. Ultimately, vacuolation resulted from the fusion of ER/Golgi-derived membrane vesicles with late endosomes and lysosomes (LELs), combined with an osmotic imbalance in LELs that led to severe swelling and a decrease in LEL fission. Since PIKfyve inhibitors induce a similar phenotype by preventing the conversion of PI(3)P to PI(3,5)P2, we performed in vitro kinase assays and found that PIKfyve activity was unexpectedly inhibited by SB203580 and SB202190, corresponding to losses in endogenous PI(3,5)P2 levels in treated cells. However, vacuolation was not entirely due to off-target inhibition of PIKfyve by SB203580, as a drug-resistant p38 mutant suppressed vacuolation. Moreover, genetic deletion of both p38 and p38{beta} rendered cells dramatically more sensitive to PIKfyve inhibitors, including YM201636 and apilimod. In subsequent washout experiments, the rate of vacuole dissolution upon the removal of apilimod was also significantly reduced in cells treated with BIRB-796, a structurally unrelated p38 MAPK inhibitor. Thus, p38 MAPKs act epistatically to PIKfyve to promote LEL fission; and pyridinyl imidazole p38 MAPK inhibitors induce cytoplasmic vacuolation through the combined inhibition of both PIKfyve and p38 MAPKs. 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/2023.03.13.532403v1?rss=1 Authors: Tomasin, R., Rodrigues, A. M., Manucci, A. C., Bruni-Cardoso, A. Abstract: Cell context is key for cell phenotype. Using physiologically relevant models of laminin-rich ECM (lrECM) induction of mammary epithelial cell quiescence and differentiation, we have provided a landscape of the status of key molecular players involved in the proliferation/quiescence decision. Repression of some positive regulators of the cell cycle, such as cyclins and CDKs, occurred already at the mRNA level, whereas negative regulators of the cell cycle, such as Pten and p27, were upregulated only at the protein level. Interestingly, cell cycle arrest occurred despite the active status of Fak, Src and PI3k, because their downstream proliferative signalling pathways were repressed, suggesting the existence of a disconnecting node between upstream and downstream proliferative signalling in quiescent cells. Pten fulfils this role. Inhibition of Pten increased proliferation and restored Akt/mTORC1/2 and Mapk signalling in cells exposed to lrECM. In mice, Pten levels were positively correlated to the basement membrane thickness in the developing mammary epithelia, and Pten localized to the apicolateral membrane of luminal cells both in in ducts and near the nascent lumen in terminal end bud, characteristics consistent with a role for Pten in inducing and sustaining quiescence and tissue architecture. Accordingly, in 3D acininogenesis models, Pten was required for the onset and maintenance of quiescence, cell polarity and lumen assembly. The notion that lrECM-triggered differentiation involves a signalling circuitry with many layers of regulation provides an explanation for the resilience of quiescence within a growth-suppressive microenvironment, and that perturbations in master regulators, such as Pten, could disrupt the quiescent phenotype. 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/2023.02.27.530371v1?rss=1 Authors: Candray, K., Nakagama, Y., Masamichi, I., Nakagama, S., Tshibangu-Kabamba, E., Takeda, N., Sugiura, Y., Nitahara, Y., Michimuko-Nagahara, Y., Kaku, N., Onizuka, Y., Arias, C.-E., Mejia, M., Alas, K., Pena, S., Maejima, Y., Komuro, I., Nakajima-Shimada, J., Kido, Y. Abstract: Chagas disease can lead to life-threatening cardiac manifestations that occur more frequently in geographic areas more prevalent with the TcI/II circulating genetic strains. To elucidate the differential transcriptomic signatures of the cardiomyocyte resulting from infection with TcI/II or TcVI T. cruzi strains and explore their relationships with pathogenesis, HL-1 rodent cardiomyocytes were infected with TcI/II or TcVI T. cruzi trypomastigotes. RNA was isolated serially post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change greater than or equal to 2 or less than or equal to 0.5) highlighted the over-represented biological pathways. We found that Oxidative stress-related GO terms, 'Hypertrophy model', 'Apoptosis', and 'MAPK signaling' pathways (all with p less than 0.01) were upregulated. 'Glutathione and one-carbon metabolism' pathway, and 'Cellular nitrogen compound metabolic process' GO term (all with p less than 0.001) were upregulated exclusively in the cardiomyocytes infected with the TcI/II strains. Upregulation in the oxidative stress-related and hypertrophic responses are shared hallmarks with viral myocarditis, another inflammatory cardiac pathology. Nitrogen metabolism upregulation and Glutathione metabolism imbalance may implicate the relation of nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of chagasic cardiomyopathy development. 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/2023.03.03.530727v1?rss=1 Authors: Chauhan, C., Kraemer, A., Knapp, S., Windheim, M., Kotlyarov, A., Menon, M. B., Gaestel, M. Abstract: Receptor-interacting protein kinases (RIPK) -1 and -3 are master regulators of cell fate decisions in response to diverse stimuli and are subjected to multiple checkpoint controls. Earlier studies have established the presence of distinct IKK1/2 and p38/MK2-dependent checkpoints which suppress RIPK1 activation by directly phosphorylating it at different residues. In the present study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and show that MK2-deficiency or inactivation predominantly results in necroptotic cell death, even in the absence of caspase inhibition. While MK2-deficient cells can be rescued from necroptosis by RIPK1 inhibitors, RIPK3 inhibition seems to revert the process to apoptosis. To understand the mechanism of this necroptosis switch, we screened a 149-compound kinase inhibitor library for compounds which preferentially sensitize MK2-deficient MEFs to TNF-induced cell death. The most potent inhibitor identified was 5-Iodotubericidin, an adenosine analogue acting as adenosine kinase and protein kinase inhibitor. 5-ITu also potentiated LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-Iodotubericidin induces RIPK1-dependent necroptosis in the absence of MK2 activity by suppressing IKK signaling. The identification of this role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis will have potential implications in RIPK1-targeted therapies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on February 11, 2023, entitled, “Oncogenic driver FGFR3-TACC3 requires five coiled-coil heptads for activation and disulfide bond formation for stability.” FGFR3-TACC3 represents an oncogenic fusion protein frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Various exon breakpoints of FGFR3-TACC3 have been identified in cancers. In this recent study, researchers Clark G. Wang, Malalage N. Peiris, April N. Meyer, Katelyn N. Nelson, and Daniel J. Donoghue from University of California San Diego analyzed these FGFR3-TACC3 exon breakpoints to determine the minimum contribution of TACC3 for activation of the FGFR3-TACC3 fusion protein. “In this work, we characterize the signaling, transforming abilities, and post-translational modifications of FGFR3-TACC3 fusion proteins arising from different exonic breakpoints to determine the requirements for dimerization and constitutive activation of the fusion protein.” While TACC3 exons 11 and 12 are dispensable for activity, the researchers' results show that FGFR3-TACC3 requires exons 13-16 for biological activity. A detailed analysis of exon 13, which consists of 8 heptads forming a coiled coil, further defined the minimal region for biological activity as consisting of 5 heptads from exon 13, in addition to exons 14-16. These conclusions were supported by transformation assays of biological activity, examination of MAPK pathway activation, analysis of disulfide-bonded FGFR3-TACC3, and by examination of the Endoglycosidase H-resistant portion of FGFR3-TACC3. These results demonstrate that clinically identified FGFR3-TACC3 fusion proteins differ in their biological activity, depending upon the specific breakpoint. This study further suggests the TACC3 dimerization domain of FGFR3-TACC3 as a novel target in treating FGFR translocation driven cancers. “Taken together, these results provide a better understanding of the mechanism for activation of FGFR3-TACC3 and narrow the scope of targeting TACC3 to create effective dimerization disruption-based therapies for treating patients with FGFR3-TACC3 driven tumors.” DOI: https://doi.org/10.18632/oncotarget.28359 Correspondence to: Daniel J. Donoghue - ddonoghue@ucsd.edu Keywords: oncogenic fusion protein, chromosomal translocation, glioblastoma, FGFR3-TACC3, coiled-coil About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529379v1?rss=1 Authors: Li, Y., Ding, J., Araki, D., Zou, J., Larochelle, A. Abstract: Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecule regulators CHIR99021, SB431542 and LY294002, respectively, and measured the impact on hematoendothelial formation in culture. Manipulation of these pathways provided a synergy sufficient to enhance formation of arterial hemogenic endothelium (HE) relative to control culture conditions. Importantly, this approach significantly increased production of human HSPCs with self-renewal and multilineage differentiation properties, as well as phenotypic and molecular evidence of progressive maturation in culture. Together, these findings provide a stepwise improvement in human iPSC differentiation protocols and offer a framework for manipulating intrinsic cellular cues to enable de novo generation of human HSPCs with functionality in vivo. 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/2023.02.17.529005v1?rss=1 Authors: He, H., Yang, J., He, Y., Li, Z., Fu, C., Zhang, D., Li, M., Lu, A., Dong, J., Liu, J., Gu, H., Shen, S. Abstract: Ulva prolifera is the dominant species of "green tide", and has higher tolerance to environmental stresses such as temperature. However, the molecular mechanisms are still unclear. Here, transcriptome analysis, Western blot and RT-qPCR analysis of U. prolifera suggested that, under temperature stresses (4{degrees}C, 36{degrees}C), the expression of PCNA and CyclinA was promoted, and the MAPK signaling was activated. Besides, the results showed that PCNA interacted with CyclinA. Interestingly, the expression of miR-2916, which was predicted to bind PCNA at -552~-772, was negatively correlated with the expression of PCNA under temperature stresses (4{degrees}C, 36{degrees}C). In addition, the results showed that low temperature (4{degrees}C) had no obvious effect on the survival, the formation of cell walls, and the division of protoplasts. However, high temperature (36{degrees}C) had obvious effect on them. PCNA inhibitors increased the sensitivity of the protoplasts under temperature stresses. Together, our results suggested PCNA regulating the proliferation in response to the temperature stress of U. prolifera was associated with miR-2916/PCNA/CyclinA/MAPK pathway. In conclusion, the study preliminarily illuminates the molecular mechanism in response to temperature stress of U. prolifera, and may provide a new insight for prevention of green tide. 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/2023.02.17.528950v1?rss=1 Authors: Gayen, N., Mitra, S., Roy, S., Mandal, A. K. Abstract: The stability and activity of CRAF kinase are stringently regulated by heat shock protein 90 (Hsp90). Hsp90-mediated client folding and maturation is governed by its co-chaperones, but their functionality in chaperoning CRAF/Raf1 kinase to accomplish signaling under physiological conditions remains poorly understood. Here, we show that Hsp70/Hsp90 organizing protein (HOP) associates with CRAF kinase for maintaining its kinase activity and facilitates the activation of the MAPK pathway. Such activation is mediated by TPR2A-2B-DP2 domain of HOP and requires efficient binding to Hsp90. Being a recruiter of Hsp90, Cdc37 is unable to supplement the function of HOP/Sti1. Downregulation of HOP/Sti1 in yeast and in vitro cell culture significantly reduces the CRAF signaling. Our data suggest that Hsp90 is recruited to CRAF in two steps, separately initiated by co-chaperones HOP and Cdc37 respectively during CRAF folding/maturation, and again upon CRAF activation mediated by HOP during MAPK signaling. Therefore, HOP is a regulator of CRAF kinase during activation of MAPK pathway and serves as a sensor of growth signaling beyond its client folding and maturation function. 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/2023.02.01.526449v1?rss=1 Authors: Ettelt, R., Didusch, S., Vucak, G., Riemelmoser, B., Ehrenreiter, K., Hartl, M., Huber, L., Baccarini, M. Abstract: Lysosomes are highly dynamic organelles regulating numerous metabolic signaling pathways by recruiting cytosolic proteins to their membrane-bound protein platforms. To identify new proteins recruited to the lysosomal membrane, we performed a proximity-dependent labelling (PDL) screen using as bait a component of the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR) complex, which regulates lysosome positioning as well as mTORC1, AMPK and MEK/ERK signaling. The screen identified a network of proteins involved in actin remodelling, the most prominent of which was Pleckstrin homology domain-containing family G member 3 (PLEKHG3), a Rho guanine nucleotide exchange factors (GEF) that binds to actin filaments and is enriched in the protrusions formed by migrating cells. We show that GFP-PLEKHG3 accumulates in focal adhesion sites (FAs), where it colocalizes with peripheral lysosomes independently of LAMTOR3 (L3). By altering the intracellular position of lysosomes, we demonstrate that the accumulation of lysosomes in the periphery concentrates PLEKHG3 below the plasma membrane (PM) while inhibiting the formation of protrusions and also limiting cell motility. Overall, this study reveals that the subcellular positioning of lysosomes plays a role in the intracellular distribution of PLEKHG3 and in the cell's protrusion activity, shape, and motility. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Videos: Brought to you by… Pfizer! FORMER PFIZER VP, DR. MIKE YEADON – EVERYTHING WE HAVE BEEN TOLD ABOUT COVID-19 WAS A LIE Fauci didn't want autopsies done on Covid victims. I wonder why? Dr. Peter McCullough SLAMS Pfizer board member over censorship and propaganda | Redacted News Study explores effects of dietary choline deficiency on neurologic and system-wide health Arizona State University, January 16, 2023 Choline, an essential nutrient produced in small amounts in the liver and found in foods including eggs, broccoli, beans, meat and poultry, is a vital ingredient for human health. A new study explores how a deficiency of dietary choline adversely affects the body and may be a missing piece in the puzzle of Alzheimer's disease. It's estimated that more than 90% of Americans are not meeting the recommended daily intake of choline. The current research, conducted in mice, suggests that dietary choline deficiency can have profound negative effects on the heart, liver and other organs. Lack of adequate choline is also linked with profound changes in the brain associated with Alzheimer's disease. These include pathologies implicated in the development of two classic hallmarks of the illness: amyloid plaques, which aggregate in the intercellular spaces between neurons; and tau tangles, which condense within the bodies of neurons. The new research, led by scientists at Arizona State University and published in Aging Cell, describes pathologies in normal mice deprived of dietary choline and in choline-deficient transgenic mice, the latter of which already exhibit symptoms associated with the disease. In both cases, dietary choline deficiency results in liver damage, enlargement of the heart and neurologic alterations in the AD mice, typically accompanying Alzheimer's disease and including increased levels of plaque-forming amyloid-beta protein and disease-linked alterations in tau protein. Further, the study illustrates that choline deficiency in mice causes significant weight gain, alterations in glucose metabolism (which are tied to conditions such as diabetes), and deficits in motor skills. In the case of humans, “it's a twofold problem,” according to Ramon Velazquez, senior author of the study and assistant professor with the ASU-Banner Neurodegenerative Disease Research Center. “First, people don't reach the adequate daily intake of choline established by the Institute of Medicine in 1998. And secondly, there is vast literature showing that the recommended daily intake amounts are not optimal for brain-related functions.” The research highlights a constellation of physical and neurological changes linked to choline deficiency. Sufficient choline in the diet reduces levels of the amino acid homocysteine, which has been recognized as a neurotoxin contributing to neurodegeneration, and is important for mediating functions such as learning and memory through the production of acetylcholine. The growing awareness of choline's importance should encourage all adults to ensure proper choline intake. This is particularly true for those on plant-based diets, which may be low in naturally occurring choline, given that many foods high in choline are eggs, meats, and poultry. Plant-based, choline-rich foods, including soybeans, Brussels sprouts and certain nuts can help boost choline in these cases. Moreover, inexpensive, over-the-counter choline supplements are encouraged to promote overall health and guard the brain from the effects of neurodegeneration. The new study examines mice at 3-12 months, or early to late adulthood (roughly equivalent to 20-60 years of age for humans). In the case of both normal and transgenic mice displaying symptoms of Alzheimer's, those exposed to a choline-deficient diet exhibited weight gain and adverse effects to their metabolism. Damage to the liver was observed through tissue analysis, as was enlargement of the heart. Elevated soluble, oligomeric and insoluble amyloid-beta protein were detected, as well as modifications to tau protein characteristic of those leading to neurofibrillary tangles in the brain. Further, choline-deficient mice performed poorly in a test of motor skills, when compared with mice receiving adequate choline in their diet. These adverse effects were heightened in the transgenic mice. Translating these findings to humans, this implies that people who are predisposed to Alzheimer's disease or in the throes of the illness should ensure they are getting enough choline.”Our work provides further support that dietary choline should be consumed on a daily basis given the need throughout the body,” Velazquez says. (NEXT) Melanoma: Vitamin D supplements linked to reduced skin cancer risk University of Eastern Finland & Kuopio University, January 15, 2023 A new study finds that the regular use of vitamin D is associated with lower rates of melanoma skin cancer. The cross-sectional study was a collaboration between the University of Eastern Finland and Kuopio University Hospital. The research involved 498 Finnish adults determined by dermatologists to be at high risk of skin cancer, such as melanoma, as well as squamous cell carcinoma and basal cell carcinoma. According to researchers, people who took vitamin D regularly were less likely to have had melanoma in the past or currently and were deemed by dermatologists to be less likely to develop melanoma in the future. Study participants ranged in age from 21 to 79 years old, including 253 males and 245 females. Participants were divided into three groups based on their intake of vitamin D supplements: non-use, occasional use, or regular use. The researchers were also interested in finding out whether regular use of vitamin D supplements corresponded to higher blood levels of vitamin D, known as serum calcidiol or 25-hydroxy-vitamin D3. This is the “storage form” of vitamin D in the body. Some research has linked low serum calcidiol with increased cancer risk, while other research has suggested otherwise. Nonetheless, it is a measure often used to determine a person's vitamin D levels. After testing serum calcidiol levels in 260 participants, researchers found that regular vitamin D supplementation corresponded with the highest levels of serum calcidiol and non-supplementation with the lowest levels. “Human skin itself expresses [the enzyme] CYP27A1 that produces calcidiol from vitamin D, and CYP27B1 that produces biologically very active calcitriol from calcidiol,” Dr. Harvima explained, noting that enzyme expression determines the level of vitamin D and its metabolites in the body. (NEXT) New research furthers case for exercise promoting youthfulness University of Arkansas, January 17, 2023 A recent paper published in the Journal of Physiology deepened the case for the youthfulness-promoting effects of exercise on aging organisms, building on previous work done with lab mice nearing the end of their natural lifespan that had access to a weighted exercise wheel. For this paper, the researchers compared aging mice that had access to a weighted exercise wheel with mice that had undergone epigenetic reprogramming via the expression of Yamanaka factors. The Yamanaka factors are four protein transcription factors (identified as Oct3/4, Sox2, Klf4 and c-Myc, often abbreviated to OKSM) that can revert highly specified cells (such as a skin cell) back to a stem cell, which is a younger and more adaptable state. The Nobel Prize in Physiology or Medicine was awarded to Dr. Shinya Yamanaka for this discovery in 2012. In the correct dosages, inducing the Yamanaka factors throughout the body in rodents can ameliorate the hallmarks of aging by mimicking the adaptability that is common to more youthful cells. Of the four factors, Myc is induced by exercising skeletal muscle. Myc may serve as a naturally induced reprogramming stimulus in muscle, making it a useful point of comparison between cells that have been reprogrammed via over expression of the Yamanaka factors and cells that have been reprogrammed through exercise—”reprogramming” in the latter case reflecting how an environmental stimulus can alter the accessibility and expression of genes. Ultimately, the team determined that exercise promotes a molecular profile consistent with epigenetic partial programming. That is to say, exercise can mimic aspects of the molecular profile of muscles that have been exposed to Yamanaka factors (thus displaying molecular characteristics of more youthful cells). This beneficial effect of exercise may in part be attributed to the specific actions of Myc in muscle. Murach sees their research as further validation of exercise as a polypill. “Exercise is the most powerful drug we have,” he says, and should be considered a health-enhancing—and potentially life-extending—treatment along with medications and a healthy diet. (NEXT) Exploiting the synergy of nutraceuticals for cancer prevention and treatment Research suggests that free radicals (ROS) generated upon mixing two nutraceuticals—resveratrol and copper—can help ameliorate various diseases by inactivating cell-free chromatin particles Tata Memorial Centre (India), January 16, 2023 Chromatin comprises a complex mixture of DNA and proteins that forms the structural basis of chromosomes in the cellular nuclei. When cells die, they release cell-free chromatin particles or “cfChPs” into the circulatory system. In 1996, evidence for tumour-derived DNA circulating in the blood of cancer patients was first reported. This evidence caught the interest Dr. Indraneel Mittra, who is now Professor Emeritus and the Dr. Ernest Borges Chair in Translational Research at Tata Memorial Centre in Mumbai, India. His tryst with research on genetic material in cancer metastases began, and after 15 years of research he has presented various papers, developing a body of evidence that indicates the critical role of cfChPs in orchestrating development of not only cancer, but various other diseases. Emerging evidence indicates that cfChPs play an essential role in ageing, sepsis, cancer development, and chemotherapy-related toxicity. With respect to the latter, Prof. Mittra explains, “Chemo-toxicity is not primarily caused by chemotherapeutic drugs, but rather by cfChPs that are released from the first cells that die after chemotherapy. The released cfChPs set in motion a cascading effect, increasingly damaging the DNA of healthy host cells, and triggering inflammatory processes in a vicious cycle that perpetuates and prolongs the toxicity of chemotherapy.” Recently, a team from Tata Memorial Centre have demonstrated the therapeutic benefits of a pro-oxidant mixture of resveratrol and copper, R-Cu, in patients undergoing chemotherapy for advanced gastric cancer. Combining R with Cu (R-Cu) leads to the generation of free oxygen radicals which can inactivate the offending cfChPs. In this context, the research team launched a single-arm phase II clinical trial to study the synergistic effects of R-Cu administration on cfChPs inactivation in patients with advanced gastric cancer. The primary objective was to determine whether R-Cu, via cfChPs' inactivation, was successful in reducing the grade ≥ 3 toxicity seen with docetaxel-based chemotherapies. To this end, the researchers monitored the likely changes in the toxicities of chemotherapeutic treatments using a grading system that provides a framework for the assessment of unwanted physiological effects. The results were promising—although R-Cu did not reduce haematological toxicities, it significantly reduced the incidence of non-haematological toxicities comprising hand-foot syndrome, diarrhoea, and vomiting. Moreover, R-Cu reduced docetaxel exposure compared to the control arm without affecting efficacy in terms of overall survival. (NEXT) Deep meditation may alter gut microbes for better health Shanghai Jiao Tong University School of Medicine (China), January 16, 2023 Regular deep meditation, practiced for several years, may help to regulate the gut microbiome and potentially lower the risks of physical and mental ill health, finds a small comparative study published in the open access journal General Psychiatry. The gut microbes found in a group of Tibetan Buddhist monks differed substantially from those of their secular neighbors, and have been linked to a lower risk of anxiety, depression, and cardiovascular disease. Research shows that the gut microbiome can affect mood and behavior through the gut–brain axis. This includes the body's immune response, hormonal signaling, stress response and the vagus nerve—the main component of the parasympathetic nervous system, which oversees an array of crucial bodily functions. The significance of the group and specimen design is that these deep-thinking Tibetan monks can serve as representatives of some deeper meditations. Although the number of samples is small, they are rare because of their geographical location. The researchers analyzed the stool and blood samples of 37 Tibetan Buddhist monks from three temples and 19 secular residents in the neighboring areas. None of the participants had used agents that can alter the volume and diversity of gut microbes: antibiotics; probiotics; prebiotics; or antifungal drugs in the preceding 3 months. Sample analysis revealed significant differences in the diversity and volume of microbes between the monks and their neighbors.”Collectively, several bacteria enriched in the meditation group [have been] associated with the alleviation of mental illness, suggesting that meditation can influence certain bacteria that may have a role in mental health,” write the researchers. These include Prevotella, Bacteroidetes, Megamonas and Faecalibacterium species, the previously published research suggests. Finally, blood sample analysis showed that levels of agents associated with a heightened risk of cardiovascular disease, including total cholesterol and apolipoprotein B, were significantly lower in the monks than in their secular neighbors by their functional analysis with the gut microbes. (NEXT) Curcumin/Boswellia shows promise in chronic kidney disease Baylor University, January 14, 2023. The Journal of Complementary and Integrative Medicine reports the finding of researchers at Baylor University of a reduction in a marker of inflammation among chronic kidney disease patients given a combination of Curcuma longa (curcumin) and Boswellia serrata. The study included sixteen individuals receiving standard care for chronic kidney disease who were not undergoing dialysis. Participants were randomized to receive capsules containing curcumin from turmeric extract plus Boswellia serrata, or a placebo for eight weeks. Blood samples collected before and after treatment were analyzed for plasma interleukin-6 (IL-6), tumor necrosis factor alpha (markers of inflammation), and the endogenous antioxidant enzyme glutathione peroxidase, as well as serum C-reactive protein (CRP, another marker of inflammation.) Blood test results from the beginning of the study revealed increased inflammation and reduced glutathione peroxide levels. At the study's conclusion, participants who received curcumin and Boswellia serrata experienced a reduction in interleukin-6 in comparison with pretreatment values, indicating decreased inflammation, while IL-6 values rose among those who received a placebo. In their discussion of the findings, the authors remark that curcumin and Boswellia serrata have been separately shown to lower interleukin-6 via inhibition of the nuclear factor kappa beta and mitogen activated protein kinase (MAPK) signaling pathways.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.04.522734v1?rss=1 Authors: Marziali, L. N., Hwang, Y., Palmisano, M., Cuenda, A., Sim, F., Volsko, C., Dutta, R., Trapp, B., Wrabetz, L., Feltri, M. Abstract: Multiple Sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with aging, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKg from oligodendrocyte precursors. We found that p38{gamma}MAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38{gamma}MAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38{gamma}MAPK was enriched in samples of leukocortical multiple sclerosis lesions from patients, which represent areas of failed remyelination. Our data suggest that p38{gamma} could be targeted to improve myelin repair in multiple sclerosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 13 on December 17, 2022, entitled, “The role of pyrethroid derivatives in autophagy and apoptosis crosstalk signaling and potential risk for malignancies.” Pyrethroids are extensively used insecticides by virtue of insecticidal activity potential in Asia, especially India, and in different nations worldwide to counter mosquitoes and insects for household or agricultural needs. The continuous widespread and uncontrolled use of pyrethroids and its derivatives have influenced multiple deleterious effects resulting in a potential risk factor causing damage to organ systems. Allethrin and prallethrin are extensively used, yet their influences on human primary cells are very limited or under-reported. The potential mechanisms by which allethrin and prallethrin modulates human primary cells, especially the molecular mechanisms or interconnectivity of autophagy-apoptosis, their clinical relevance in human subjects or patients are not well defined. In the current study, researchers Jyothi Puvula, Narendra Maddu, Nagajothi Gutam, Asha Parimal, and Raghavendra B. Pongali from Sri Krishnadevaraya University, Queen Mary's College, Manipal University, and National Institute of Biomedical Genomics furnished the evidence that both allethrin and prallethrin user samples significantly induced Ccl2 mRNA expression, increased amount of reactive oxygen intermediate, inhibited membrane bound enzymes and altered membrane fluidity. Pyrethroid derivative users had induced levels of lipid peroxidation and induced binding activities of transcription factors(tfs) like CEBP-β and NF-AT. Pyrethroid derivatives induced autophagy, elicited intracellular Ca2+ concentration, calcineurin and regulated proapoptotic genes, DAPK1, Bim. “Our current study presumably comprises the initial investigation of a very new mechanism of pyrethroid derivatives-moderated programmed cell death in various cell sets or types, like human primary cells where-in this is a late event, is documented.” Hence, the current research study might be significant in the various pyrethroid derivatives-allied hematological-related cancers and immunosuppressant or auto-immune disorders. In the foremost instance, the researchers present data stating that pyrethroid derivatives induces multiple cell signaling cascades, like CEBP-β, NF-AT, ERK and MAPK having a role in autophagy thereby; synchronously effectively impact on the apoptosis, therefore causing hematological tumors and toxic or immune related disorders. “Overall this current study might facilitate to formulate therapeutics or intervention targets that might serve to decrease the effect or impact of pyrethroids derivatives by targeting the signaling cascade that serves to minimize the modulation of autophagy mediated apoptosis.” DOI: https://doi.org/10.18632/oncotarget.28328 Correspondence to: Raghavendra B. Pongali - raghavbiot@gmail.com Keywords: allethrin, prallethrin, autophagy, apoptosis, Ccl2 About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter - https://twitter.com/Oncotarget Facebook - https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram - https://www.instagram.com/oncotargetjrnl/ LinkedIn - https://www.linkedin.com/company/oncotarget/ Pinterest - https://www.pinterest.com/oncotarget/ LabTube - https://www.labtube.tv/channel/MTY5OA SoundCloud - https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.15.520572v1?rss=1 Authors: Wang, Z., Zhou, L., Lee, C., Shi, J., Liu, L., Yang, X., Deng, Y., Liu, J., Wang, J., Zhu, W., Sun, Y. E., Lin, Q. Abstract: Perturbations during critical time windows in the normal series of development can lead to adverse functional consequences that manifest later in life. Here, we report that prenatal stress (PNS) during the last week of gestation (E14-delivery) dramatically increased the number of proliferating neural stem/progenitor cells (NSC/NPCs) in the ependymal-subventricular zone (E-SVZ) of male mouse offspring. PNS did not cause significant cell death or a deficit in neuroblast migration to the olfactory bulb (OB). Olfactory behavioral tests showed that while prenatally stressed male mice displayed normal olfactory function in differentiating nonsocial odors, these mice showed impairment in discriminating different social smells. Bulk and single nucleus transcriptomic analyses combined with rescue assays using mitogen-activated protein kinases (MAPK) phosphorylation inhibitors revealed that PNS exposure during the critical period of neurogenesis promoted NSC/NPC proliferation in adult male offspring by sustaining MAPK3/1 activity. Compared to prenatally stressed males, their female littermates showed less change in the number of proliferating cells in the E-SVZ. 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/2022.12.02.518869v1?rss=1 Authors: Baur, K., Carrillo Garcia, C., San, S., von Hahn, M., Strelau, J., Hölzl-Wenig, G., Mandl, C., Ciccolini, F. Abstract: Late in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE). However, the function of GDF15 in this region is unknown. We here show that ablation of GDF15 leads to an increase in proliferation of apically and subapically dividing progenitors in the GE. This is associated with faster cell cycle progression in both progenitor groups, and an increase in the total number of cycling progenitors. Enhanced proliferation of apically dividing progenitors leads to a permanent significant increase in the number of ependymal and apical neural stem cells (NSCs). Our data also indicate that the extra proliferation of subapically dividing progenitors causes a transient increase in the number of neuronal progenitors, which is compensated by increased apoptosis. Independent of the genotype, activity of endogenous epidermal growth factor (EGFR) signalling is essential for the proliferation of apically and subapically dividing progenitors. However, lack of GDF15 leads to a reduced cell surface expression of EGFR and altered dynamics of MAPK activation in response to EGF stimulation. Application of exogenous GDF15 rescued the effect of the genotype on the expression of EGFR and decreased proliferation in the mutant GE. Taken together, our results indicate that GDF15 modulates proliferation and growth factor responsiveness of apical progenitors in the developing GE, thereby regulating the number of total ependymal and NSCs. 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/2022.11.24.516014v1?rss=1 Authors: Duangjan, C., Arpawong, T. E., Spatola, B. N., Curran, S. P. Abstract: The clearance of insulin from circulation is critical for metabolic homeostasis. Insulin is depleted in the liver by the insulin degrading enzyme (IDE). WDR23 is a substrate receptor of the Cul4-ubiquitin ligase complex and acts as a sophisticated regulator of protein activation and turnover. Here we establish hepatic WDR23 in the regulation of insulin metabolism by regulating IDE. An unbiased proteomic analysis of liver tissue of mice lacking Wdr23 revealed a significant increase in the steady state levels of IDE which accompanied reduced circulating insulin and diminished sensitivity to insulin stimulation. A comparative assessment of the transcriptomic changes in livers from animals with and without WDR23 reveals significant changes in the targets responding to insulin and glucose receptor signaling. Furthermore, phosphorylation of the insulin signaling cascade proteins, IRS-1, AKT, MAPK and mTOR were dysregulated in Wdr23KO mice. These findings are recapitulated in cultured human cell models with genetic ablation of Wdr23 revealing a conserved role for WDR23 from mice to humans. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults that supports the use of WDR23 as new molecular determinant of metabolic health in humans. 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/2022.11.04.515245v1?rss=1 Authors: Hu, J., Zuo, L., Qu, W., He, H., Bao, J., Zhang, W., Zhang, Y., Zhu, M., Li, T. Abstract: Objective: Based on network pharmacology, the response of Qing-tong-hua-yu Decoction (QTHY) to the regulation of EGFR/MAPK signaling cascade in cerebral ischemia-reperfusion injury was discussed and the possible mechanism of the protective effect of QTHY on the cerebral ischemia-reperfusion injury was studied. Methods: A compound-target disease-function-pathway network was established and analyzed based on the network pharmacology approach used in Chinese medicine. The correlation, which is between effect of the components of QTHY Decoction against CI/RI with EGFR/MAPK signalling cascade response, was observed. And then the degree of neurological deficits in each group was assessed after cerebral ischemia for 2 hours and reperfusion for 3 hours, 24 hours, 3 days and 7 days. Expression levels of EGFR and p44/42MAPK in ischemic brain tissue at different time points in various groups of rats were tested by Western bolt (WB), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). Results: Network pharmacology analysis revealed that QTHY-mediated treatment involved 439 key targets, in which the effect of QTHY groups against CI/RI was associated with EGFR/MAPK signaling cascade. QTHY treatment reduced neurological deficit scores and improved ischemic changes in rats. In addition, QTHY promoted EGFR and p44/42MAPK expression in the SVZ through the EGFR/MAPK signaling cascade, with varying degrees of improvement at different time points. Conclusion: QTHY can better improve cerebral ischemia injury in CI / RI rats and exert the neuroprotective effect of cerebral ischemia-reperfusion injury. This may be related to the potential of QTHY to activate the EGFR / MAPK signaling cascade, which is consistent with the results of network pharmacology analysis. 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/2022.11.02.514841v1?rss=1 Authors: Kajitani, N., Okada-Tsucioka, M., Inoue, A., Miyano, K., Masuda, T., Boku, S., Iwamoto, K., Ohtsuki, S., Uezono, Y., Aoki, J., Takebayashi, M. Abstract: Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), in treating severe depression. However, the molecular mechanisms underlying the high efficacy of TCAs have not been completely understood. Herein, we found that lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, mediates the antidepressant effects of amitriptyline, a typical TCA. Amitriptyline directly bound to LPAR1 and activated downstream G protein signaling without affecting {beta}-arrestin signaling, which implied that amitriptyline could act as a G protein-biased agonist of LPAR1. This biased agonism is unique to TCAs and has not been observed in other antidepressants, such as SSRIs. Long-term infusion of mouse hippocampus with 1-oleoyl-2-O-methyl-glycerophosphothionate (OMPT), a potent G protein-biased LPAR1 agonist, induced behavior similar to that induced by antidepressants. In contrast, LPA, a non-biased agonist of LPAR1, induced anxious behavior, indicating that LPAR1 may regulate conflicting emotional behaviors because of the downstream signaling bias. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in hippocampus. Ingenuity pathway analysis indicated that chronic intrahippocampal administration of OMPT could activate LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. The results reveal the unique antidepressant effects of TCAs and indicate the potential of G protein-biased agonists of LPAR1 as targets for novel antidepressants. 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/2022.10.12.511969v1?rss=1 Authors: Bogucka-Janczi, K., Harms, G., May-Coissieux, M., Bentires-Alj, M., Thiede, B., Rajalingam, K. Abstract: The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding proteins and nucleation-promoting factors to perform fundamental cellular functions. Here, we show that ERK3, an atypical MAPK, directly acts as a guanine nucleotide exchange factor for Cdc42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent Rac1 and Cdc42 activation, maintenance of F-actin content, filopodia formation and epithelial cell migration. Further, ERK3 protein binds directly to the purified ARP2/3 complex and augments polymerization of actin in vitro. ERK3 kinase activity is required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Videos : New Rule: Let the Population Collapse | Real Time with Bill Maher (HBO) – 8:29 The De-Population Bomb – hoover institution (0:43 – 8:15) THE GREAT AWAKENING: PLANDEMIC 3 PRELAUNCH PARTY – (21:00 – 30:20) Gary Null Speaking Out at the NYS Assembly Hearing  (25:00)   Meta-analysis finds less fatigue with CoQ10 supplementation National Yang Ming Chiao Tung University (Taiwan), September 16 2022. The results of a systematic review and meta-analysis of clinical trials, published in Frontiers in Pharmacology, support an anti-fatigue effect among individuals who supplemented with coenzyme Q10. “Coenzyme Q10 (CoQ10) is a popular nutritional supplement and a lipid-soluble antioxidant that is endogenously produced by the human body,” authors I-Chen Tsai of National Yang Ming Chiao Tung University and associates observed. “CoQ10 supplementation has been successfully applied for reducing fatigue in patients with various conditions, including chronic fatigue and fibromyalgia, as well as in healthy subjects.” For their analysis, Tsai colleagues identified 13 randomized, controlled trials that compared fatigue scores of participants who received CoQ10 or a placebo. The trials included a total of 1,126 participants. Analysis of the 13 trials showed a consistent significant effect for CoQ10 in reducing fatigue. When trials that included healthy participants were analyzed separately from trials that included patients with fatigue-associated diseases, both supplemented populations showed decreases in fatigue, however the effects were significant among the unhealthy participants, who may have more severe CoQ10 depletion. Higher CoQ10 doses and longer duration of supplementation were correlated with increased fatigue reduction. The anti-fatigue effect of CoQ10 is unsurprising, given its role in energy production. Chronic fatigue syndrome patients have lower plasma levels of CoQ10 in comparison with healthy subjects. While the body makes some CoQ10, the authors remarked that studies have provided evidence that supplementing with CoQ10 does not affect the body's synthesis of the coenzyme. Researchers identify a potential new approach with a dietary supplement to treat HER2 positive breast cancer Mayo Clinic, September 9, 2022 Researchers at Mayo Clinic have identified an important new pathway by which HER2 positive breast cancers grow and have discovered that a dietary supplement called cyclocreatine may block the growth of HER2 positive breast cancer. Their findings were published in Cell Metabolism. “The HER2 receptor tyrosine kinase, which functions as an ‘on' or ‘off' switch in cellular functions, is a key driver of breast cancer, and is overexpressed in about a quarter of all breast cancers,” says Taro Hitosugi, Ph.D., a pharmacologist at Mayo Clinic and corresponding author of the paper. Dr. Hitosugi and his colleagues decided to explore ways to resolve an unmet clinical need. Their strategy was to develop a treatment to target tumor mitochondrial energy metabolism, which is the process cancer cells use to manipulate energy during cell metabolism in order to grow. Dr. Hitosugi and his colleagues discovered that cyclocreatine, a dietary supplement used in sports drinks, effectively targets mitochondrial creatine kinase 1 enzyme and reduces cancer growth without toxicity. This finding was confirmed in mice models where a patient-derived, trastuzumab-resistant HER2 positive tumors were administered to the mice. “Mitochondrial creatine kinase 1 may be a new drug target for the treatment of HER2 positive breast cancer,” says Matthew Goetz, M.D., director of the Mayo Clinic Breast Cancer research program. “Future clinical trials will be necessary to determine the effectiveness of this drug for HER2 positive breast cancer resistant to standard therapies.” Excessive smartphone screen time linked to earlier puberty onset Gazi University (Turkey), September 16, 2022 Exposure to blue light, via regular use of tablets and smartphones, may alter hormone levels and increase the risk of earlier puberty, according to data from a rat study presented at the Annual European Society for Paediatric Endocrinology Meeting. Longer duration of blue light exposure was associated with earlier puberty onset in the female rats, which also showed reduced levels of melatonin, increased levels of some reproductive hormones and physical changes in their ovaries. Use of blue light-emitting mobile devices has previously been linked to disrupted sleeping patterns in children but these findings suggest there could be additional risks for childhood development and future fertility. The escalating use of blue light-emitting devices, such as tablets and smartphones, has previously been implicated in reducing sleep quality in both children and adults. This is thought to be through disruption of our body clock as blue light inhibits the evening rise in levels of the hormone, melatonin, which prepares our bodies for rest and sleep. Melatonin levels are overall higher during pre-puberty than in puberty, which is believed to play a role in delaying the start of puberty. Puberty is a complex process that involves co-ordination of several body systems and hormones. In recent years, several studies have reported increases in early puberty onset for girls, particularly during the COVID-19 pandemic. The link between blue light exposure and reduced melatonin levels suggests that increased screen time, such as during the pandemic restrictions, may be playing a role in this reported increase. However, it is very difficult to assess this in children. In this study, Dr. Aylin Kilinç Uğurlu and colleagues in Ankara, Turkey, used a rat model to investigate the effects of blue light exposure on reproductive hormone levels and the time of puberty onset. Female rats were divided into three groups of six and exposed to either a normal light cycle, 6 hours or 12 hours of blue light. The first signs of puberty occurred significantly earlier in both groups exposed to blue light, and the longer the duration of exposure, the earlier the onset of puberty. Rats exposed to blue light also had reduced melatonin levels and elevated levels of specific reproductive hormones (estradiol and luteinizing hormone), as well as physical changes in their ovarian tissue, all consistent with puberty onset. At the 12-hour exposure, rats also showed some signs of cell damage and inflammation in their ovaries. Dr. Aylin Kilinç Uğurlu comments, “We have found that blue light exposure, sufficient to alter melatonin levels, is also able to alter reproductive hormone levels and cause earlier puberty onset in our rat model. In addition, the longer the exposure, the earlier the onset.” Fitness trackers reveal links among exercise, memory, and mental health Dartmouth College, September 15, 2022 Exercise can improve your cognitive and mental health—but not all forms and intensities of exercise affect the brain equally. The effects of exercise are much more nuanced, as specific intensities of exercise over a long period of time are associated with different aspects of memory and mental health, according to a new Dartmouth study. The findings are published in Scientific Reports and provide insight into how exercise could be optimized. “Mental health and memory are central to nearly everything we do in our everyday lives,” says lead author Jeremy Manning, an assistant professor of psychological and brain sciences at Dartmouth. “Our study is trying to build a foundation for understanding how different intensities of physical exercise affect different aspects of mental and cognitive health.” The researchers asked 113 Fitbit users to perform a series of memory tests, answer some questions about their mental health, and share their fitness data from the previous year. They expected that more active individuals would have better memory performance and mental health, but the results were more nuanced. People who tended to exercise at low intensities performed better at some memory tasks while those who exercised at a high intensities did better on other memory tasks. Participants who were more intensely active also reported higher stress levels, whereas people who regularly exercised at lower intensities showed lower rates of anxiety and depression. Participants who had been more active over the prior year tended to show better memory performance overall, but the specific areas of improvement depended on which types of activity people did. The researchers found that participants who often exercised at moderate intensities tended to perform better on the episodic memory tasks while participants who often exercised at high intensities did better on the spatial memory tasks. Sedentary participants who seldom exercised tended to perform worse on the spatial memory tasks. The researchers also identified connections between participants' mental health and their memory performance. Participants with self-reported anxiety or depression tended to perform better on the spatial and associative memory tasks, while those with self-reported bipolar disorder tended to perform better on the episodic memorytasks. Participants who reported higher levels of stress tended to perform worse on the associative memory tasks. Positive psychological well-being can improve overall heart health Northwestern University, September 10, 2022 Maintaining positive thoughts and feelings through intervention programs can help patients achieve better overall outcomes when it comes to their cardiovascular health, according to a review paper published in the Journal of the American College of Cardiology. “We addressed how social environment, psychological well-being and the effectiveness of intervention strategies can help strengthen a patient's outlook,” said Darwin R. Labarthe, MD, MPH, Ph.D., professor of Preventive Medicine at Northwestern University Feinberg School of Medicine and the review's lead author. “We focused on whether psychological well-being can be consistently related with a reduced risk of heart disease.” In this review, the authors looked at a growing body of research to examine whether psychological well-being might lead to reduced risk of heart disease. Prospective studies have shown a positive relationship between optimism (one facet of psychological well-being) and heart disease, including a study showing older women in the highest quartile of optimism had a 38 percent reduced risk of heart disease mortality. Additional studies since 2012 have associated a perceived higher purpose in life with lower odds of having a stroke. Optimistic patients sustained healthier diets by consuming more fruits and vegetables, and less processed meats and sweets, leading patients to maintain a healthy BMI. The review authors found that psychological well-being influenced heart health through biological processes, health behaviors and psychosocial resources. Having a strong network of social support also gives patients confidence about their future health and helps them act readily on medical advice, engage in problem solving and take active preventive measures. A likely link is that favorable social environment, known to influence heart disease risk, has also been shown to predict psychological well-being. Milk thistle protects against COPD caused by secondhand smoke Sichuan University, (China), September 11, 2022 According to the U.S. Centers for Disease Control and Prevention (CDC), 15.7 million people suffer from chronic obstructive pulmonary disease (COPD) – a serious respiratory condition which can cause scarring of the lungs, narrowing of the airway and extreme difficulty breathing. Taking enough milk thistle – on a regular basis – can help protect you from harm. Exposure to tobacco smoke – whether through actively smoking or simply inhaling the smoke from another's cigarette – is the primary cause of COPD. Although Western medicine currently offers no cure for COPD, recent studies generate a ray of hope. Groundbreaking new research suggests that milk thistle extracts may not only prevent COPD but, help to treat it. In a study published in the journal Inflammation, researchers exposed mice to the equivalent of 1.5 packs of cigarettes a day for four weeks, creating drastic increases in peribronchial inflammation, thickening of airway walls and airway obstruction. The team found that pretreating the mice with silymarin – the active component of milk thistle – an hour before exposure dramatically decreased inflammatory changes, and cut production of pro-inflammatory chemicals such as TNF-alpha and interleukin. Encouragingly, silymarin also helped safeguard levels of superoxide dismutase, an important disease-fighting antioxidant produced in the body. A year later, the same team of researchers took another, closer look at the workings of milk thistle. And what they found was encouraging. In a study of human bronchial cells published in Scientific Report, the team explored the molecular and cellular mechanisms of silymarin – and found once again that the flavonoid attenuated cigarette smoke-induced upregulation of pro-inflammatory chemicals. And, researchers discovered for the first time that silymarin modulated a certain pathway – known as MAPK – that governs inflammation. The takeaway? The team concluded that silymarin might be “an ideal agent for treating inflammatory pulmonary diseases.” In a third study, recently published in Food and Chemical Toxicology, researchers treated mice with silibinin (a constituent of silymarin) one hour before exposure to cigarette smoke. The team found that the silibinin caused the mice to not only experience the sharp reductions in inflammatory changes seen in earlier studies – but discovered that it also suppressed the scarring and fibrosis that are typical of COPD in humans. This means that silibinin may not only help prevent COPD – but, reverse it! Intriguingly, the silibinin directly affected the expression of a certain pro-inflammatory protein – transforming growth factor beta-1 – that is activated and spurred on by exposure to smoke, making it appear that this compound is custom-designed to protect against secondhand smoke. Milk thistle extracts are available in the form of pills, powders, extracts, liposomes and teas. Look for a high-quality preparation that is standardized to contain 70 to 80 percent silymarin.

Aging (Aging-US) Volume 14, Issue 15: https://www.aging-us.com/issue/v14i15 Research Paper (Cover): “Profiles of behavioral, social and psychological well-being in old age and their association with mobility-limitation-free survival” https://doi.org/10.18632/aging.204182 Editorial: “Sex difference in epigenomic instability during human aging” https://doi.org/10.18632/aging.204199 Editorial: “NAD+ to assess health in aging humans” https://doi.org/10.18632/aging.204220 Editorial: “T cell senescence by N-glycan branching” https://doi.org/10.18632/aging.204239 Research Paper: “mtDNA variability determines spontaneous joint aging damage in a conplastic mouse model” https://doi.org/10.18632/aging.204153 Research Paper: “Senolytic drugs relieve pain by reducing peripheral nociceptive signaling without modifying joint tissue damage in spontaneous osteoarthritis” ​​https://doi.org/10.18632/aging.204204 Research Paper: “Ascorbic acid induces salivary gland function through TET2/acetylcholine receptor signaling in aging SAMP1/Klotho (-/-) mice” https://doi.org/10.18632/aging.204213 Research Paper: “Regulation of microglial activation in stroke in aged mice: a translational study” https://doi.org/10.18632/aging.204216 Research Paper: “PDCD10 promotes the aggressive behaviors of pituitary adenomas by up-regulating CXCR2 and activating downstream AKT/ERK signaling” https://doi.org/10.18632/aging.204206 Research Paper: “Influence of cardiovascular risk burden on pulmonary function trajectory: role of physical and social activities” https://doi.org/10.18632/aging.204201 Research Paper: “miRNA-338-3p inhibits the migration, invasion and proliferation of human lung adenocarcinoma cells by targeting MAP3K2” https://doi.org/10.18632/aging.204198 Research Paper: “Serial neurocognitive changes following transcatheter aortic valve replacement: comparison between low and intermediate-high risk groups” https://doi.org/10.18632/aging.204202 Research Paper: “MAB21L1 promotes survival of lens epithelial cells through control of αB-crystallin and ATR/CHK1/p53 pathway” https://doi.org/10.18632/aging.204203 Research Paper: “Interleukin-17D promotes lung cancer progression by inducing tumor-associated macrophage infiltration via the p38 MAPK signaling pathway” ​​https://doi.org/10.18632/aging.204208 Research Paper: “A signature constructed with mitophagy-related genes to predict the prognosis and therapy response for breast cancer” https://doi.org/10.18632/aging.204209 Research Paper: “Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells” https://doi.org/10.18632/aging.204210 Research Paper: “SIAH1-mediated RPS3 ubiquitination contributes to chemosensitivity in epithelial ovarian cancer” https://doi.org/10.18632/aging.204211 Research Paper: “CBXs-related prognostic gene signature correlates with immune microenvironment in gastric cancer” https://doi.org/10.18632/aging.204214 Research Paper: “Targeting circRNA-MAP4K2 for the treatment of diabetes-induced retinal vascular dysfunction” https://doi.org/10.18632/aging.204215 Research Paper: “The comprehensive expression and functional analysis of m6A modification “readers” in hepatocellular carcinoma” https://doi.org/10.18632/aging.204217 Research Paper: “Establishing and validating an ADCP-related prognostic signature in pancreatic ductal adenocarcinoma” https://doi.org/10.18632/aging.204221 Research Paper: “SAAL1, a novel oncogene, is associated with prognosis and immunotherapy in multiple types of cancer” https://doi.org/10.18632/aging.204224 Research Paper: “Comprehensive pan-cancer analysis reveals the prognostic value and immunological role of SPIB” https://doi.org/10.18632/aging.204225 Research Paper: “Clinical outcomes and potential therapies prediction of subgroups based on a ferroptosis-related long non-coding RNA signature for gastric cancer” https://doi.org/10.18632/aging.204227 Visit our website at https://www.Aging-US.com​​.

Article: How the organized Left got Covid wrong, learned to love lockdowns and lost its mind: an autopsy https://thegrayzone.com/2022/03/31/left-covid-lockdowns-mind-autopsy/   EU Renews Digital COVID Pass Despite 99% Negative Public Feedback https://www.zerohedge.com/geopolitical/eu-renews-digital-covid-pass-despite-99-negative-public-feedback   Videos: 1. Psywars Documentary. – The Obama Clip (0:23) 2. Clare Daly her best speech so far . Ukraine (1:22) 3. Vitamin Authentication. Electronic pill that stays in your body & will become a 18bit Battery operated chip (1:00) 4. Is Klaus Schwab the Most Dangerous Man in the World? (15:07)  5. Kim Iversen: Inside The SECRET Bilderberg Meetings Between Spies, War Hawks And World Leaders (9:28) 6.  The great recycling LIE (what really happens to plastic) (10:44) 7.  New Rule: How the Left Was Lost | Real Time (HBO)  (8:30) HEALTH NEWS Grape consumption may offer benefits for symptomatic knee osteoarthritis Bad habits that lead to cancer, chronic disease corrected by simple lifestyle intervention The blueberry component pterostilbene has potent anti-myeloma activity Exercise makes the blood of obese people healthier People who go to bed late have less control over OCD symptoms Green tea-capsaicin-ginger combo linked to weight and metabolic improvements Grape consumption may offer benefits for symptomatic knee osteoarthritis Texas Woman's University, June 20, 2022 New research suggests that regular grape consumption may help alleviate pain associated with symptomatic osteoarthritis of the knee, and improve joint flexibility and overall mobility. Researchers attribute these potential benefits to the polyphenols found in grapes. The sixteen week clinical study, undertaken by Texas Woman's University, was designed to investigate the benefits of grape consumption on inflammation and osteoarthritis outcomes. 72 men and women with knee osteoarthritis (OA) were assigned to either consume grapes in the form of a whole grape freeze-dried powder, or a placebo powder. The study results showed that both men and women consuming a grape-enriched diet had a significant decrease in self-reported pain related to activity and an overall decrease in total knee symptoms. This beneficial effect was more pronounced in females. Additionally, age-related differences were observed: there was a 70% increase in very hard activity for those under 64 years of age consuming the grape powder, while those receiving the placebo reported a significant decrease in very hard activity. Participants over 65 years, whether consuming grapes or the placebo, reported a decline in moderate to hard activities. Evidence of increased cartilage metabolism was observed in men consuming the grape-enriched diet; they had higher levels of an important cartilage growth factor (IGF-1) than those on placebo. This protective effect was not observed in the females. T Bad habits that lead to cancer, chronic disease corrected by simple lifestyle intervention Northwestern University, June 19, 20122 Does this sound like someone you know? He or she spends too much time in front of screens, gets little exercise and eats a diet high in fat and low in fruits and vegetables. It likely sounds familiar because it describes a significant portion of the U.S. population. A new Northwestern Medicine study found that a lifestyle intervention could fully normalize these four unhealthy behaviors, which put people at risk of developing heart disease and common cancers, including breast, colon and prostate. “Our findings suggest that prevention of chronic disease through behavior change is feasible. They contradict the pessimistic assumption that it's not possible to motivate relatively healthy people to make large, long-lasting healthy lifestyle changes,” said lead author Bonnie Spring at Northwestern University Feinberg School of Medicine. With the help of a smartphone app, a wearable activity tracker, some social support from a coach and a small financial incentive, study participants made large improvements in their eating and activity habits. From a starting point of less than two servings of fruits and vegetables per day, they increased their intake by 6.5 servings per day. They decreased saturated fat intake by 3.6 percent to consume less than 8 percent of their calories from saturated fat. From a baseline of 4.5 hours per day of leisure screen time, they decreased screen time by almost three hours and increased their moderate to vigorous exercise by 25 minutes per day over a nine-month trial. Previous research has found that healthy behavior change usually reverts once financial incentives cease. But this study stopped offering the financial incentive after only 12 weeks, and participants still achieved positive results throughout the nine-month trial. The blueberry component pterostilbene has potent anti-myeloma activity  Tongji University (China), June 23, 2022 Investigators at Tongji University School of Medicine Zero  stated, “Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes.” The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways. DNA damage and S-phase arrest might be involved in Pter-related toxicity in H929R cells.  The research concluded: “These data supported that Pter might be a promising natural compound for relapsed/refractory myeloma therapy, especially against myeloma resistant to bortezomib chemotherapy.” Exercise makes the blood of obese people healthier Exercise can reduce inflammation in obese people by changing the characteristics of their blood, according to new research published in The Journal of Physiology. University of Illinois, June 20, 2022 Many of the health problems linked to obesity are a result of chronic inflammation. Inflammation is a natural process in the body in response to harm, but in obese people it can become long term and this can lead to damage of healthy tissue. Certain blood cells are more likely to cause inflammation, and if these cells are made in the body in greater numbers than normal they can spread to organs in the body and cause them to malfunction. The blood cells responsible for causing inflammation are formed from stem cells within the body.  This new research is the first to show that exercise alters the characteristics of these blood forming stem cells and therefore reduces the number of blood cells likely to cause inflammation. These findings provide a new explanation of how exercise may improve health in adults with obesity. Young, lean adults and young, obese adults (who were otherwise healthy) were recruited for this study.  The exercise program consisted of three bicycling or treadmill running sessions per week with each session lasting approximately one hour. Blood was collected before and after the exercise training intervention to quantify blood-forming stem cells. The results of the study demonstrated that exercise reduced the number of blood-forming stem cells associated with the production of the type of blood cells responsible for inflammation. People who go to bed late have less control over OCD symptoms Binghamton University, June 24, 2022 A late bedtime is associated with lower perceived control of obsessive thoughts, according to new research from Binghamton University, State University of New York. Binghamton University Professor Meredith E. Coles monitored twenty individuals diagnosed with OCD and ten individuals endorsing subthreshold OCD symptoms during one week of sleep. Participants completed sleep diaries and daily ratings of perceived degree of control over obsessive thoughts and ritualized behaviors. The researchers found that previous night's bedtime significantly predicted participants' perceived ability to control their obsessive thoughts and compulsive behavior on the subsequent day. “We're really interested in how this kind of unusual timing of sleep might affect cognitive functioning,” said Schubert. “It might be that something about shifting the timing of your sleep might reduce your ability to control your thoughts and your behaviors, so it might make it more likely that you're going to have a hard time dismissing intrusive thoughts characteristic of obsessions, and it might make it more difficult for you to refrain from compulsive behaviors that are designed to reduce the anxiety caused by obsessive thoughts.” On average participants in the study went to bed around 12:30 at night. Patients who met criteria for delayed sleep phase disorder, about 40% of the sample, went to bed around 3 a.m. Green tea-capsaicin-ginger combo linked to weight and metabolic improvements Kashan University of Medical Sciences (Iran), June 24, 2022 Dietary supplements containing green tea, capsaicin and ginger extracts may lead to weight loss and improvements in BMI, says a new study. Data from the randomized double-blind placebo-controlled clinical trial involving 50 overweight women also produced beneficial changes in insulin levels, and measure of insulin resistance. “Our study indicated that taking green tea, capsaicin and ginger co-supplements for 8 weeks among overweight women had beneficial effects on weight, BMI, markers of insulin metabolism and plasma [glutathione] levels,” wrote the scientists.  Women were assigned to consume daily supplements containing 500 mg green tea, 100 mg capsaicin, and 200 mg ginger extracts, while another 25 women were assigned to consume placebo. After eight weeks, the results showed that, in addition to the improvements in body weight and BMI, women receiving the extracts showed significant decreases in serum insulin concentrations (-2.6 µIU/mL) compared to the placebo (-0.6 µIU/mL). Insulin resistance, as measured by HOMA-IR, also improved compared to placebo, while levels of the antioxidant enzyme glutathione also improved in the women consuming the green tea, capsaicin and ginger supplements (+73.8 µmol/L), while levels decreased in the women receiving placebo (-28.3 µmol/L).

Video: 1. A Rockefeller Document: Resetting The US Food System – Control The Food – Control The People 2. Neil Oliver – ‘we're definitely moving towards a one world government' (3:45) 3.  Exclusive Klaus Schwab Tell All interview! – JP  (11:30) 4. A Rockefeller Document: Resetting The US Food System – Control The Food – Control The People (start @ 0:26 ) 5. New Rule: How the Left Was Lost | Real Time (HBO) HEALTH NEWS Grape consumption may offer benefits for symptomatic knee osteoarthritis Bad habits that lead to cancer, chronic disease corrected by simple lifestyle intervention The blueberry component pterostilbene has potent anti-myeloma activity Exercise makes the blood of obese people healthier People who go to bed late have less control over OCD symptoms Green tea-capsaicin-ginger combo linked to weight and metabolic improvements Grape consumption may offer benefits for symptomatic knee osteoarthritis Texas Woman's University, June 20, 2022 New research suggests that regular grape consumption may help alleviate pain associated with symptomatic osteoarthritis of the knee, and improve joint flexibility and overall mobility. Researchers attribute these potential benefits to the polyphenols found in grapes. The sixteen week clinical study, undertaken by Texas Woman's University, was designed to investigate the benefits of grape consumption on inflammation and osteoarthritis outcomes. 72 men and women with knee osteoarthritis (OA) were assigned to either consume grapes in the form of a whole grape freeze-dried powder, or a placebo powder. The study results showed that both men and women consuming a grape-enriched diet had a significant decrease in self-reported pain related to activity and an overall decrease in total knee symptoms. This beneficial effect was more pronounced in females. Additionally, age-related differences were observed: there was a 70% increase in very hard activity for those under 64 years of age consuming the grape powder, while those receiving the placebo reported a significant decrease in very hard activity. Participants over 65 years, whether consuming grapes or the placebo, reported a decline in moderate to hard activities. Evidence of increased cartilage metabolism was observed in men consuming the grape-enriched diet; they had higher levels of an important cartilage growth factor (IGF-1) than those on placebo. This protective effect was not observed in the females. T Bad habits that lead to cancer, chronic disease corrected by simple lifestyle intervention Northwestern University, June 19, 20122 Does this sound like someone you know? He or she spends too much time in front of screens, gets little exercise and eats a diet high in fat and low in fruits and vegetables. It likely sounds familiar because it describes a significant portion of the U.S. population. A new Northwestern Medicine study found that a lifestyle intervention could fully normalize these four unhealthy behaviors, which put people at risk of developing heart disease and common cancers, including breast, colon and prostate. “Our findings suggest that prevention of chronic disease through behavior change is feasible. They contradict the pessimistic assumption that it's not possible to motivate relatively healthy people to make large, long-lasting healthy lifestyle changes,” said lead author Bonnie Spring at Northwestern University Feinberg School of Medicine. With the help of a smartphone app, a wearable activity tracker, some social support from a coach and a small financial incentive, study participants made large improvements in their eating and activity habits. From a starting point of less than two servings of fruits and vegetables per day, they increased their intake by 6.5 servings per day. They decreased saturated fat intake by 3.6 percent to consume less than 8 percent of their calories from saturated fat. From a baseline of 4.5 hours per day of leisure screen time, they decreased screen time by almost three hours and increased their moderate to vigorous exercise by 25 minutes per day over a nine-month trial. Previous research has found that healthy behavior change usually reverts once financial incentives cease. But this study stopped offering the financial incentive after only 12 weeks, and participants still achieved positive results throughout the nine-month trial. The blueberry component pterostilbene has potent anti-myeloma activity  Tongji University (China), June 23, 2022 Investigators at Tongji University School of Medicine Zero  stated, “Multiple myeloma (MM) is an incurable hematologic malignancy because of its drug resistance. Pterostilbene (Pter) is found mainly in blueberries and grapes.” The effects of Pter and its exact pharmacologic mechanisms on chemoresistant myeloma are not known. Herein, we investigated the anti-myeloma activity of Pter in bortezomib-resistant cell line H929R and explored the related mechanism of action for the first time. We found that Pter inhibited proliferation of H929R cells and promoted apoptosis of the cells through a caspase-dependent pathway, loss of mitochondrial membrane potential, and activation of Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways. DNA damage and S-phase arrest might be involved in Pter-related toxicity in H929R cells.  The research concluded: “These data supported that Pter might be a promising natural compound for relapsed/refractory myeloma therapy, especially against myeloma resistant to bortezomib chemotherapy.” Exercise makes the blood of obese people healthier Exercise can reduce inflammation in obese people by changing the characteristics of their blood, according to new research published in The Journal of Physiology. University of Illinois, June 20, 2022 Many of the health problems linked to obesity are a result of chronic inflammation. Inflammation is a natural process in the body in response to harm, but in obese people it can become long term and this can lead to damage of healthy tissue. Certain blood cells are more likely to cause inflammation, and if these cells are made in the body in greater numbers than normal they can spread to organs in the body and cause them to malfunction. The blood cells responsible for causing inflammation are formed from stem cells within the body.  This new research is the first to show that exercise alters the characteristics of these blood forming stem cells and therefore reduces the number of blood cells likely to cause inflammation. These findings provide a new explanation of how exercise may improve health in adults with obesity. Young, lean adults and young, obese adults (who were otherwise healthy) were recruited for this study.  The exercise program consisted of three bicycling or treadmill running sessions per week with each session lasting approximately one hour. Blood was collected before and after the exercise training intervention to quantify blood-forming stem cells. The results of the study demonstrated that exercise reduced the number of blood-forming stem cells associated with the production of the type of blood cells responsible for inflammation. People who go to bed late have less control over OCD symptoms Binghamton University, June 24, 2022 A late bedtime is associated with lower perceived control of obsessive thoughts, according to new research from Binghamton University, State University of New York. Binghamton University Professor Meredith E. Coles monitored twenty individuals diagnosed with OCD and ten individuals endorsing subthreshold OCD symptoms during one week of sleep. Participants completed sleep diaries and daily ratings of perceived degree of control over obsessive thoughts and ritualized behaviors. The researchers found that previous night's bedtime significantly predicted participants' perceived ability to control their obsessive thoughts and compulsive behavior on the subsequent day. “We're really interested in how this kind of unusual timing of sleep might affect cognitive functioning,” said Schubert. “It might be that something about shifting the timing of your sleep might reduce your ability to control your thoughts and your behaviors, so it might make it more likely that you're going to have a hard time dismissing intrusive thoughts characteristic of obsessions, and it might make it more difficult for you to refrain from compulsive behaviors that are designed to reduce the anxiety caused by obsessive thoughts.” On average participants in the study went to bed around 12:30 at night. Patients who met criteria for delayed sleep phase disorder, about 40% of the sample, went to bed around 3 a.m. Green tea-capsaicin-ginger combo linked to weight and metabolic improvements Kashan University of Medical Sciences (Iran), June 24, 2022 Dietary supplements containing green tea, capsaicin and ginger extracts may lead to weight loss and improvements in BMI, says a new study. Data from the randomized double-blind placebo-controlled clinical trial involving 50 overweight women also produced beneficial changes in insulin levels, and measure of insulin resistance. “Our study indicated that taking green tea, capsaicin and ginger co-supplements for 8 weeks among overweight women had beneficial effects on weight, BMI, markers of insulin metabolism and plasma [glutathione] levels,” wrote the scientists.  Women were assigned to consume daily supplements containing 500 mg green tea, 100 mg capsaicin, and 200 mg ginger extracts, while another 25 women were assigned to consume placebo. After eight weeks, the results showed that, in addition to the improvements in body weight and BMI, women receiving the extracts showed significant decreases in serum insulin concentrations (-2.6 µIU/mL) compared to the placebo (-0.6 µIU/mL). Insulin resistance, as measured by HOMA-IR, also improved compared to placebo, while levels of the antioxidant enzyme glutathione also improved in the women consuming the green tea, capsaicin and ginger supplements (+73.8 µmol/L), while levels decreased in the women receiving placebo (-28.3 µmol/L).

In this episode of the IJGC podcast, Editor-in-Chief Dr. Pedro Ramirez is joined by Dr. David M. Gershenson to discuss the use of trametinib in low-grade serous cancer. Dr. Gershenson is Professor and former Chair of the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. His major focus is on the clinical and translational research of rare ovarian cancers. Highlights: Trametinib represents a new standard for the treatment of recurrent low-grade serous carcinoma of the ovary/peritoneum. The findings of GOG 281 suggest that women whose tumor harbors a MAPK mutation (KRAS, NRAS, BRAF) may have a greater probability of response to trametinib, but the results are hypothesis-generating, and further studies are needed. Importantly, trametinib should not be withheld from a woman whose tumor lacks MAPK mutations. Based on the findings of GOG 281 and preclinical studies, future trials will include combinations of a MEK inhibitor plus endocrine therapy and novel agents targeting the MAPK signaling pathway or, more specifically, RAS.

FDA 批准MAPK激酶抑制剂治疗手术无法切除的1型神经纤维瘤BMJ 哮喘发作与空气污染和母亲孕期吸烟有关Nature Metabolism 母亲运动带来的后代的健康获益是通过母乳中的3′-唾液酸乳糖介导的司美替尼（selumetinib）神经纤维瘤是常染色体显性遗传病，分1、2和3型。1型神经纤维瘤最常见，标志性特征是多发的牛奶咖啡斑和相关皮肤神经纤维瘤。没有针对性的总体的治疗，只能对症治疗。50%的1型神经纤维瘤患者合并丛状神经纤维瘤，丛状神经纤维瘤是一种组织学上良性的周围神经鞘肿瘤，常累及多个神经束，造成毁容、运动功能障碍、疼痛、甚至脊髓受压。司美替尼是一种MAPK激酶的抑制剂，在2020年4月，FDA批准了司美替尼用于治疗1型神经纤维瘤。《司美替尼治疗不能手术的丛状神经纤维瘤患儿》New England Journal of Medicine，2020年4月 (1)这项开放标签的2期试验，旨在确定丛状神经纤维瘤患儿服用司美替尼后的临床益处和安全性。50名、平均年龄10.2岁的、不能手术的丛状神经纤维瘤的1型神经纤维瘤病患儿入组，随机接受了司美替尼和安慰剂治疗。最常见的神经纤维瘤相关症状包括毁容（44人）、运动功能障碍（33人）和疼痛（26人）。治疗后70%达到了部分缓解，56%≥1年的持久缓解。1年后，肿瘤疼痛评分平均降低了2分，疼痛对日常功能、总体健康相关生活质量、力量和关节活动范围等多项功能结局也观察到了有临床意义的改善。其中5人因副作用停药；6人疾病发展。最常见的毒性作用为恶心、呕吐或腹泻、无症状的肌酸磷酸激酶水平升高、痤疮样皮疹及甲沟炎。结论：对于手术无法切除的丛状神经纤维瘤患儿，司美替尼产生了持久的缩小肿瘤作用。儿童哮喘哮喘（asthma）是一种异质性疾病，特点是慢性气道炎症。12岁以下儿童哮喘是最常见的儿童期慢性疾病，约80%的患儿在5岁以前出现症状，咳嗽、哮鸣、呼吸急促、胸闷胸痛是常见的症状。最常见的诱发因素包括病毒性上呼吸道感染（合胞病毒、流感病毒、鼻病毒）、运动、天气、二手烟和变应原（如尘螨、宠物毛发、花粉、霉菌）。《病例队列研究：空气污染和家庭相关因素与儿童哮喘发作和持续性喘息的关系》BMJ，2020年8月(2)研究目的探讨儿童哮喘和持续性喘息发病的危险因素（空气污染和家庭相关因素）。这项全国病例对照研究中随访了1-15岁儿童儿童哮喘发病率升高，与父母患有哮喘（风险比 2.29）、母亲在怀孕期间吸烟（风险比 1.20）相关。儿童哮喘发病率低，与父母受教育程度高（风险比0.72）和父母收入高（风险比 0.85）相关。空气污染物PM2.5和PM10与哮喘的风险增加和持续喘息相关。结论：暴露于空气污染中的儿童更容易患哮喘和持续性喘息，哮喘与父母哮喘病史、父母教育程度和母亲在怀孕期间吸烟有关。《观察性研究：母亲在怀孕期间吸烟影响子女成年后哮喘发作》European Respiratory Journal 2020年7月 (3)研究的目的是确定产前哮喘和成人哮喘发病之间的关系。研究纳入5200名、1966年芬兰北部出生的、31岁前未诊断为哮喘的人群。研究发现孕妇妊娠最后3个月吸烟，其后代31岁至46岁之间哮喘累积发病率（男性为5.1%，女性为8.8%），尤其是与无哮喘病史（风险比9.63）或咳嗽喘息病史（风险比3.21）的后代中有显著相关性。同时在妊娠期吸烟与31岁时子代的用力呼气量（FEV1）/用力肺活量（FVC）比率之间有发现了显著的相关性，在在RUNX1单倍型rs11702779-AA的后代中成年期患哮喘的风险比为5.53。结论：怀孕期间吸烟与后代成年后哮喘累积发病率有关。《观察性研究：空气污染和从出生到成年的哮喘发展》European Respiratory Journal 2020年7月 (4)空气污染对青春期至成年期哮喘发展的影响尚不清楚，研究纳入了3687个参与者，评估空气污染和哮喘发生的年龄的相关关系。研究20岁之前哮喘的发病率，与出生地空气污染物的比例增加相关（接触PM10的风险比为1.09，接触NO2的风险比为1.20）。对近期家庭居住地的空气污染进行分析后，得到了类似的结果。结论：早年暴露在空气污染中，特别是来自机动交通的污染，与儿童、青春期到成年早期罹患哮喘的风险增加有关。《哮喘患儿卧室颗粒物过滤与气道病理生理变化的关系》JAMA Pediatrics，2020年8月 (5)细颗粒物PM2.5是一种普遍存在的空气污染物，可沉积在小气道中，对哮喘起着至关重要的作用。来自杜克大学与北京上海的研究人员合作，研究PM2.5过滤装置的使用是否能改善哮喘患儿的小气道生理学和呼吸系统炎症。研究人员在患儿的卧室里随机安装了真实的过滤设备和假的过滤设备，试验前有2周的洗脱期，研究是在臭氧含量低的季节在中国上海的郊区进行的。研究纳入轻中度哮喘的、共43个、5-13岁的儿童参加了研究。室外PM2.5浓度中度升高（28.6-69.8μg/m3)；经过滤的卧室PM2.5浓度比不经过滤降低63.4%。过滤的卧室空气能显著改善气道力学，总气道阻力下降24.4%，减少小气道阻力43.5%，呼气流量峰值也显著改善。这些改善与卧室PM2.5的减少显著相关。总体的小气道功能改善均没有统计学意义，但在不伴有嗜酸性气道炎症的参与者中改善显著（13.2%）。结论：室内PM2.5过滤可以通过改善气道力学和功能，减少炎症，改善哮喘患者肺部的气体流动。《VDKA研究：补充维生素D3对低维生素D和哮喘患儿哮喘加重的影响》JAMA，2020年8月 (6)研究的目的探讨维生素D3的补充是否能改善儿童哮喘和低维生素D水平严重恶化的时间。这项随机、双盲、安慰剂对照临床试验，纳入6-16岁的、哮喘严重发作高危儿童共192人，平均年龄9.8岁，女孩40%维生素D3组的37.5%和安慰剂组的34.4%出现≥1次严重恶化。补充维生素D3并没有显著改善哮喘严重恶化的时间，没有显著改善病毒诱导哮喘严重加重的时间，没有显著改善糖皮质激素剂量减量的患者比例，也没有显著减少糖皮质激素的累积剂量。两组严重不良事件相似。结论：该研究不支持在持续性哮喘和低维生素D水平的儿童维生素D3来预防哮喘加重。《前瞻性队列研究：抗生素的使用减少，影响肠道菌群和儿童哮喘发病率》Lancet Respiratory Medicine，2020年7月 (7)在欧洲和北美的一些地区，儿童哮喘的发病率正在下降；有研究提示婴儿期使用抗生素与哮喘风险增加有关。该研究的目的是验证哮喘发病率的降低是否与抗生素处方减少有关，并验证这种变化是由肠道菌群变化介导的。本研究包括基于人群和前瞻性队列分析，使用加拿大不列颠哥伦比亚省（人口400万·700万）每年抗生素处方率和哮喘诊断率的管理数据进行人群分析。2000 - 2014年，1-4岁儿童的哮喘发病率从27·3‰ 下降到20·2‰，降幅26·0%。发病率的降低与