Podcasts about jak1

A phase 3 study showed that combining pelabresib with ruxolitinib significantly improved spleen volume reduction and symptom relief in myelofibrosis patients compared to ruxolitinib alone, offering a promising new treatment option. Long-term use of gantenerumab may delay Alzheimer's dementia onset in individuals with inherited Alzheimer's, supporting the amyloid hypothesis and paving the way for future prevention strategies. Phase 3 trials demonstrated that povorcitinib, an oral JAK1 inhibitor, significantly improved clinical outcomes in adults with moderate to severe hidradenitis suppurativa, potentially offering a new treatment option. Research linked red meat allergy to bites from additional tick species, expanding the geographic risk area and highlighting the need for clinicians to consider this diagnosis in patients with unexplained allergic symptoms following tick bites.

Welcome to the Evidence-Based Hair Podcast, hosted by dermatologist and hair loss specialist Dr. Jeff Donovan. In this episode, Dr. Donovan explores a groundbreaking study published in the journal Curious, highlighting the effectiveness of the JAK1 inhibitor, upadacitinib, in treating recalcitrant dissecting cellulitis of the scalp. Dissecting cellulitis, a challenging form of scarring alopecia, often affects males and presents with debilitating symptoms. While traditional treatments like isotretinoin and antibiotics offer relief for some, they aren't always effective. The study discusses a case where upadacitinib brought significant improvement after conventional options were exhausted. Dr. Donovan provides a comprehensive overview of the study, emphasizing the potential of JAK inhibitors as third-line treatments in managing persistent dissecting cellulitis. He also shares insights on the broader implications for future research and treatment strategies. Join Dr. Donovan next week for an analysis of a study on alopecia areata and cardiovascular comorbidities, and don't miss the annual "Top 20 of 2024" event on December 30th. For more information about the Donovan Hair Academy's programs, visit their website.     STUDY REFERENCED IN THIS EPISODE Zahidul Islam, Michelle Toker, Isha M Gandhi, Ariel Sher, Kristina Campto. Improvement of Recalcitrant Dissecting Cellulitis of the Scalp After a Trial of Upadacitinib. Cureus . 2024 Jan 16;16(1):e52377. doi: 10.7759/cureus.52377. eCollection 2024 Jan.  

13.19.24 J. Martens Predigtreihe Weisheit 1: Was ist Weisheit? Bücher der Weisheit in der Bibel: Sprüche, Hiob, Prediger Weisheit beginnt mit Gottes Erkenntnis.   Sprüche 9, 10 Die Ehrfurcht vor dem HERRN ist der Anfang der Weisheit. Gott, den Heiligen, zu erkennen führt zur Einsicht.  Ein Gedicht über die Weisheit: bibleserver.com/NLB/Sprüche8,22-36 : die Weisheit hat ihren Ursprung bei Gott, sie ist in. Der Schöpfung zu finden  Weisheit ist der Schlüssel für ein gelingendes Leben  bibleserver.com/NLB/Sprüche3,14-18: "... Die Weisheit ist ein Baum des Lebens für alle, die sie ergreifen; wer an ihr festhält, ist ein glücklicher Mensch" Wie kann das gelingen? Beispiel Salomon in 1.Könige3, 9-10:"Schenk deinem Diener ein gehorsames Herz, damit ich dein Volk gut regiere und den Unterschied zwischen Gut und Böse erkenne. Denn wer könnte dieses große Volk, das dir gehört, regieren?« Dem HERRN gefiel Salomos Antwort, und er freute sich, dass er ihn um Weisheit gebeten hatte." Jak1,5 :"Wenn jemand unter euch Weisheit braucht, weil er wissen will, wie er nach Gottes Willen handeln soll, dann kann er Gott einfach darum bitten. Und Gott, der gerne hilft, wird ihm bestimmt antworten, ohne ihm Vorwürfe zu machen" Weisheit ist angewandtes Wissen → Salomo  Weisheit ist die Fähigkeit, Gottes Prinzipien in deinem Leben Realität werden zu lassen. Gottes Prinzipien  -  Weisheit     -   Unsere konkrete Situation

Send us a textBen Zimmer is CEO of Priovant Therapeutics ( https://www.priovanttx.com/ ), a clinical-stage biotechnology company focused on delivering novel therapies for autoimmune diseases associated with the greatest morbidity and mortality. Priovant is developing oral brepocitinib, a potential first-in-class dual inhibitor of TYK2 and JAK1, across multiple severe autoimmune indications, unlocking new treatment options for patients who are underserved by existing therapies.Ben joined Priovant from Roivant, where he was a member of the founding team in early 2015 and held multiple leadership roles across the organization, including President, Roivant Health, Chief Operating Officer, and Head, Public Affairs. As President, Roivant Health, Ben led and oversaw the launch of Roivant's Chinese biopharmaceutical subsidiaries, healthcare technology companies (including Datavant), and computationally powered drug discovery platform (including VantAI). Earlier in his career, Ben was a consultant at McKinsey & Co and co-founded and led a public policy non-profit. He holds a BA magna cum laude from Harvard College and a JD from Yale Law School.#BenZimmer #PriovantTherapeutics #AutoimmuneDiseases #Brepocitinib #TYK2 #JAK1 #Dermatomyositis #NonInfectiousUveitis #Pfizer #Roivant #VivekRamaswamy #ProgressPotentialAndPossibilities #IraPastor #Podcast #Podcaster #STEM #Innovation #Technology #Science #ResearchSupport the show

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

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

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

Too busy to read the Lens? Listen to our weekly summary here! In this week's episode we discuss… Recurrent acute anterior uveitis is associated with Māori ethnicity and HLA-B27 disease, and moderate vision loss is associated with shorter time to first recurrence JAK1 inhibitors may reduce the rate of treatment failure in inflammatory uveitis when compared to patients receiving placebo Asymptomatic vitreoretinal lymphoma (VRL) associated with primary CNS lymphoma exhibits lower rates of anterior segment involvement, vitritis, and subretinal infiltrates when compared to primary vitreoretinal lymphoma and symptomatic vitreoretinal lymphoma associated with primary CNS disease A study identifies patient factors that influence the presence of non-retinal hemorrhage ocular abnormalities in infants

US-based biotech company Priovant Therapeutics is dedicated to developing novel therapies for autoimmune diseases with high morbidity and few available treatment options. The company's lead asset, brepocitinib, is a dual selective inhibitor of TYK2 and JAK1. Through dual TYK2/JAK1 inhibition, brepocitinib suppresses key cytokines linked to autoimmunity—including type I IFN, type II IFN, IL6, IL12, and IL23—with a single, targeted therapy. Brepocitinib has generated positive data in seven phase 2 studies with oral once-daily administration. It is currently being evaluated in a phase 3 program for dermatomyositis and is entering a phase 3 program for non-infectious uveitis.This week on the podcast we have a conversation with Priovant's CEO Benjamin Zimmer about dermatomyositis, non-infectious uveitis, current treatments, potential options, and how brepocitinib is making a difference. 00:55-02:34: About Priovant02:34-06:38: What are dermatomyositis and non-infectious uveitis?06:38-08:35: What are the current treatments?08:35-12:32: What is brepocitinib?12:32-15:36: Are there other treatments in development? 15:36-17:50: What is your relationship with Pfizer?17:50-20:48: Brepocitinib clinical trials20:48-24:06: Future plans and timeline24:06-27:59: Finding patients for clinical trials27:59-29:19: Future opportunities Interested in being a sponsor of an episode of our podcast? Discover how you can get involved here! Stay updated by subscribing to our newsletter

BUFFALO, NY- February 7, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma.” In this new paper, researchers Ashley Del Dosso, Elizabeth Tadevosyan, and James R. Berenson from ONCOtherapeutics, Berenson Cancer Center, and Institute for Myeloma and Bone Cancer Research discussed multiple myeloma (MM) — the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM. “The following sections of this article will be focused on studies of RUX [Ruxolitinib] in the preclinical [21–24] and clinical settings [18–20] focused on the treatment of relapsed/refractory (RR) MM.” DOI - https://doi.org/10.18632/oncotarget.28547 Correspondence to - James R. Berenson - jberenson@berensoncancercenter.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28547 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, multiple myeloma, ruxolitinib, JAK/STAT, cytokine, clinical trial About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

BUFFALO, NY- January 29, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.” In this new paper, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss thyroid cancer. A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short-lived due to multiple compensatory resistance mechanisms. “One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation.” DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. “Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.” DOI - https://doi.org/10.18632/oncotarget.28544 Correspondence to - Luc GT Morris - morrisl@mskcc.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28544 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, thyroid cancer, drug resistance, anaplastic transformation, BRAF inhibitors, PIK3CA About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

Go online to PeerView.com/XMX860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Psoriasis, a chronic inflammatory disease that affects up to 1 in 20 people worldwide, can drastically impact a patient's quality of life and health. The number of therapies for patients with moderate-to-severe psoriasis has grown steadily over the past 2 decades. Biologic immunotherapies have been the primary agents to gain approval, while small-molecule therapies have lagged in development. Deucravacitinib is a newly approved oral small molecule that inhibits the activity of TYK2, a member of the JAK family. Deucravacitinib allosterically inhibits TYK2 activity by binding to the regulatory domain rather than the catalytic domain. Binding in this way gives deucravacitinib greater specificity for TYK2 versus the closely related JAK1/2/3. Deucravacitinib has demonstrated safety and efficacy in moderate-to-severe chronic plaque psoriasis in two phase 3 pivotal trials (POETYK PSO-1 and PSO-2). Psoriasis Area Severity Index (PASI) 75 and static Physician's Global Assessment (sPGA) 0/1 response rates were significantly higher with deucravacitinib versus placebo or apremilast. In this activity, based on a recent live symposium, expert faculty discuss the clinical implications of targeting TYK2 in psoriasis, as well as strategies to identify patients for whom inhibition of TYK2 would be an appropriate treatment option based on available data. In addition, the faculty delve into the importance of shared decision-making in formulating personalized management plans for patients with psoriasis. Upon completion of this activity, participants should be better able to: Describe the pathophysiology of moderate-to-severe psoriasis as it relates to selective targeting of TYK2; Identify patients with psoriasis for whom inhibition of TYK2 would be an appropriate treatment option based on available efficacy and safety data and practice guidelines; and Develop personalized management plans for patients with psoriasis using principles and tools of shared decision-making, empowering patients to participate in treatment decisions and remain adherent to therapies

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

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

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

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

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

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

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

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

A review of the latest and most pertinent information from EULAR 2021 regarding COVID-19 for patients with rheumatic musculoskeletal diseases. This includes an overview of the topic, from an assessment of the safety profile of vaccines, to the impact of biologic or targeted synthetic disease-modifying anti-rheumatic drug treatment on COVID-19 outcomes. The discussion then shifts to a review of research presented at EULAR 2021 examining the promise demonstrated in clinical trials for small molecule JAK1 inhibitors in the treatment of patients with ankylosing spondylitis. Furthermore, the episode features an expert analysis of how drugs traditionally used to treat RA have been repurposed to battle the COVID-19 pandemic. This podcast is supported by Janssen Pharmaceutical Companies of Johnson & Johnson. The views expressed in this podcast are those of the individual speaker and do not necessarily reflect the views of Janssen Pharmaceutical Companies of Johnson & Johnson.

1. The Ugly Truth About Lockdowns Pt1  - 14 mins    Lycopene found to inhibit pathway involved in Helicobacter pylori-induced gastric cancer Yonsei University (South Korea), April 6, 2021 In this study, researchers at Yonsei University in South Korea evaluated the effects of lycopene on hyperproliferation induced by Helicobacter pylori infection. They reported their findings in an article published in the journal Nutrition Research. H. pylori is known to colonize the human stomach and is linked to an increased risk of gastric diseases, including gastric cancer. According to studies, H. pylori increases the generation of reactive oxygen species (ROS), which activate Janus-activator kinase 1 (Jak1)/signal transducers and activators of transcription 3 (Stat3) in gastric epithelial cells. ROS also mediate hyperproliferation — a hallmark of carcinogenesis — by activating Wnt/B-catenin signaling in various cells. The researchers hypothesized that lycopene, a potent antioxidant with anti-cancer properties, may be able to suppress hyperproliferation by inhibiting the ROS-mediated activation of Jak1/Stat3 and Wnt/B-catenin signaling, as well as the expression of B-catenin target genes. To test their hypothesis, they measured the ROS levels and viability of H. pylori-infected gastric epithelial AGS cells before and after lycopene treatment. The Jak1/Stat3 inhibitor AG490 served as the control treatment. They also measured the protein levels of the following: Total and phosphorylated Jak1/Stat3 Wnt/B-catenin signaling molecules Wnt-1 Lipoprotein-related protein 5 B-catenin target oncogenes (c-Myc and cyclin E) The researchers found that lycopene, like AG490, reduced ROS levels and inhibited the activation of Jak1/Stat3, alterations in the levels of Wnt/B-catenin multiprotein complex molecules, the expression of c-Myc and cyclin E and the proliferation of H. pylori-infected gastric epithelial AGS cells. Lycopene and AG490 also inhibited the increase in Wnt-1 and lipoprotein-related protein 5 expression caused by H. pylori infection. Based on these findings, the researchers concluded that lycopene can be used to prevent H. pylori-associated gastric diseases, thanks to its inhibitory effects on gastric cell hyperproliferation.   Less sugar, please! New studies show low glucose levels might assist muscle repair Skeletal muscle satellite cells found to grow better with less glucose in vitro Tokyo Metropolitan University, April 3, 2021 Researchers from Tokyo Metropolitan University have shown that skeletal muscle satellite cells, key players in muscle repair, proliferate better in low glucose environments. This is contrary to conventional wisdom that says mammalian cells fare better when there is more sugar to fuel their activities. Because ultra-low glucose environments do not allow other cell types to proliferate, the team could produce pure cultures of satellite cells, potentially a significant boost for biomedical research. Healthy muscles are an important part of a healthy life. With the wear and tear of everyday use, our muscles continuously repair themselves to keep them in top condition. In recent years, scientists have begun to understand how muscle repair works at the cellular level. Skeletal muscle satellite cells have been found to be particularly important, a special type of stem cell that resides between the two layers of sheathing, the sarcolemma and basal lamina, that envelopes myofiber cells in individual muscle fibers. When myofiber cells get damaged, the satellite cells go into overdrive, multiplying and finally fusing with myofiber cells. This not only helps repair damage, but also maintains muscle mass. To understand how we lose muscles due to illness, inactivity, or age, getting to grips with the specific mechanisms involved is a key challenge for medical science. A team of scientists from Tokyo Metropolitan University led by Assistant Professor Yasuro Furuichi, Associate Professor Yasuko Manabe and Professor Nobuharu L Fujii have been studying how skeletal muscle satellite cells multiply outside the body. Looking at cells multiplying in petri dishes in a growth medium, they noticed that higher levels of glucose had an adverse effect on the rate at which they grew. This is counterintuitive; glucose is considered to be essential for cellular growth. It is converted into ATP, the fuel that drives a lot of cellular activity. Yet, the team confirmed that lower glucose media led to a larger number of cells, with all the biochemical markers expected for greater degrees of cell proliferation. They also confirmed that this doesn't apply to all cells, something they successfully managed to use to their advantage. In experiments in high glucose media, cultures of satellite cells always ended up as a mixture, simply due to other cell types in the original sample also multiplying. By keeping the glucose levels low, they were able to create a situation where satellite cells could proliferate, but other cell types could not, giving a very pure culture of skeletal muscle satellite cells. This is a key prerequisite for studying these cells in a variety of settings, including regenerative medicine. So, was the amount of glucose in their original experiment somehow "just right"? The team added glucose oxidase, a glucose digesting enzyme, to get to even lower levels of glucose, and grew the satellite cells in this glucose-depleted medium. Shockingly, the cells seemed to fare just fine, and proliferated normally. The conclusion is that these particular stem cells seem to derive their energy from a completely different source. Work is ongoing to try to pin down what this is. The team notes that the sugar levels used in previous experiments matched those found in diabetics. This might explain why loss of muscle mass is seen in diabetic patients, and may have significant implications for how we might keep our muscles healthier for longer.   Higher plasma glutathione levels associated with decreased risk of Alzheimer disease Kapodistrian University (Greece), March 31, 2021 According to news reporting originating in Athens, Greece,research stated, “Potential links between oxidative stress and the pathophysiology of Alzheimer’s disease (AD) have been reported in the existing literature. Biological markers of oxidative stress, such as the reduced form of glutathione (GSH), may have a potential role as predictive biomarkers for AD development.” Funders for this research include Alzheimer’s Association, ESPA-EU program Excellence Grant (ARISTEIA), Ministry for Health and Social Solidarity (Greece). The news reporters obtained a quote from the research from the National and Kapodistrian University of Athens, “The aim of the present study was to explore the longitudinal associations between plasma GSH and the risk of developing AD or cognitive decline, in a sample of community-dwelling, non-demented older adults. Participants from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present prospective study. The sample used in the analyses consisted of 391 non-demented individuals over the age of 64 (mean age = 73.85 years; SD = 5.06), with available baseline GSH measurements and longitudinal follow-up. Plasma GSH was treated both as a continuous variable and as tertiles in our analyses. Cox proportional hazards models were used to evaluate the hazard ratio (HR) for AD incidence as a function of baseline plasma GSH. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline plasma GSH and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Supplementary exploratory models were also adjusted for mild cognitive impairment (MCI) at baseline, risk for malnutrition, physical activity and adherence to the Mediter-ranean dietary pattern. A total of 24 incident AD cases occurred during a mean (SD) of 2.99 (0.92) years of follow-up. Individuals in the highest GSH tertile group (highest baseline plasma GSH values) had a 70.1% lower risk for development of AD, compared to those in the lowest one [HR = 0.299 (0.093-0.959); p = 0.042], and also demonstrated a slower rate of decline of their executive functioning over time (5.2% of a standard deviation less decline in the executive composite score for each additional year of follow-up; p = 0.028). The test for trend was also significant suggesting a potential dose-response relationship.” According to the news reporters, the research concluded: “In the present study, higher baseline plasma GSH levels were associated with a decreased risk of developing AD and with a better preservation of executive functioning longitudinally.” This research has been peer-reviewed.     Citrus fruit found to decrease risk of stroke University of East Anglia (UK),  March 31, 2021    We’ve all heard how good citrus fruit is for us due to its vitamin C content and immune system-boosting properties. Now research is showing that citrus fruit can also help to reduce stroke risk.   A study conducted at the University of East Anglia in Norwich, UK reveals that eating citrus fruit, especially oranges, lowers the risk of ischemic stroke significantly. The researchers compared the health of women who ate both oranges and grapefruit regularly versus those who did not.   Compounds in citrus fruit improve circulation and blood flow, reducing stroke risk   The study looked at the flavonoid content of citrus fruits and how they impacted blood vessel health. Previous studies have found that specific orange phytochemicals are protective against intracerebral hemorrhage and considerably improve blood flow in the brain.   Researchers reviewed around 14 years of Nurse’s Health Study data tracking the health and diets of about 70,000 women. Correlations between six flavonoid sub-classes from citrus fruits were assessed related to risks of hemorrhagic, ischemic or complete stroke.   Women who consumed the highest amounts of orange and grapefruit as well as juices from these fruits had much better blood circulation, as well as a 19 percent lowered risk of stroke related to blood clotting as compared with women who didn’t eat much citrus fruit.   Why an orange alongside that apple – each day – is a powerful combination   The women who favored citrus fruit showed a substantially reduced risk of stroke and associated risks. Indeed, if an apple a day keeps the doctor away, an orange a day can keep strokes away.   Other studies of flavonoids in fruit substantiate these results regarding a reduction in stroke risk. Higher intake of all kinds of fruit has a positive impact on stroke risk as well as many other areas of health.   A 2011 study by Western University in London, Ontario found that an additional benefit of flavonoid intake was the prevention of weight gain. A tangerine flavonoid called Nobiletin was shown to reduce the risk of both type 2 diabetes and obesity in mice. The mice given the Nobiletin flavonoid avoided these issues, while those that did not became obese, developed type 2 diabetes, and had atherosclerosis and fatty liver issues.   A 2012 Japanese study found the pulp and juice from satsuma mandarin oranges inhibited tumor growth in cancers of the colon, lung and tongue. Vitamin C is a potent antioxidant known for inhibiting free radical damage in the cells. The Nobiletin in citrus fruit has also been linked with apoptosis, or programmed cell death of cancer cells.   Oregon Health & Science University researchers found a connection between eye health and the vitamin C found in citrus fruit. Retinal nerve cells benefited from the compound, and it’s likely brain and nervous system health are positively impacted as well. While fruit juice packs a potent nutritional punch, there are advantages to eating whole oranges, grapefruits and other fruits instead. Whole fruits tend to be richer in vitamins and nutrients, lower in sugar, and higher in fiber.     For older patients, focusing on what matters is often the best medicine Yale University, April 4, 2021 A woman in her 80s wanted to play with her great-grandchildren when they came to visit, but knee pain made it difficult for her. A man in his late 70s said he enjoyed going out to dinner, but was constrained by the meal preparation guidelines that he needed to follow because of his diabetes. Both people have multiple chronic conditions. They also have life goals, things they want to do to live their lives fully, like playing with grandchildren and going out to eat. Understanding these goals and barriers to them, helps doctors align care with what matters most to their patients while eliminating unwanted health care, said the authors of a report that was published March 24 in JAMA Network Open. The report, the first systematic description of older adults' health care priorities, describes a structured process called Patient Health Priorities that health care providers can follow to identify the life goals of older adults with multiple chronic conditions as well as their health care preferences. "There is growing awareness of the need to transition health care, particularly for people with multiple chronic conditions, from treating single diseases in isolation to health care that is aligned with patients' priorities," said Mary Tinetti, MD, the principal investigator of the Patient Priorities Care study, and the Gladys Phillips Crofoot Professor of Medicine (Geriatrics) at Yale School of Medicine (YSM). During the study, health care providers asked 163 patients who were 65 and older and have multiple chronic conditions to identify what they value most in life such as connecting with family, being productive, or remaining independent. They then asked what specific and realistic activities they most wanted to be able to do that reflected their values. The participants also were asked to describe the barriers that prevented them from achieving their goals, such as unnecessary doctors' visits, taking too many medications, or health concerns such as fatigue and shortness of breath. "The medications, health care visits, testing, procedures, and self-management tasks entailed in treating multiple chronic conditions require investments of time and effort that may be burdensome and conflict with what patients are willing and able to do," Tinetti said. The study was conducted among patients of 10 primary care doctors from a multi-site practice in Connecticut who invited patients to participate during routine visits. Participants had to be 65 or older and have at least three chronic health conditions that were treated with at least 10 prescription medications. They also had to be under the care of two or more specialists, or have visited the emergency room at least two times, or had been hospitalized once, during the past year. Of the 236 patients at the practice, 163 agreed to participate. Most participants were white, female, about 78 years old, and had four chronic conditions. Nearly half had high school-level or less education. Participants were asked to identify their values with questions such as, "What does enjoying life mean to you?" and "When you have a good day, what happens?" Their health care providers then worked with them to make sure their care was focused on achieving those goals. Participants also were asked what health issues most interfered with their goals, and what aspects of their health care they found helpful and which they felt were unhelpful to too burdensome. The 163 participants identified 459 outcome goals, the most common of which were sharing meals with friends and family (7.8%); visiting with grandchildren (16.3%); going shopping (6.1%), and exercising (4.6%). Twenty participants (4.4%) said they wanted to be able to stay in their homes and live independently. Common barriers to their goals were pain (41%); fatigue, lack of energy or poor sleep (14.4%); unsteadiness (13.5%); and shortness of breath and dizziness (6.1%). Thirty-two participants (19.8%) felt they were taking too many medications, while 57 (35.0%) reported having bothersome symptoms from their medications but did not mention specific drugs. Also, 43 (26%) participants said that visits to their primary care physicians and specialists were helpful, although 15 (9%) said they have too many visits or doctors. "I'm tired of going to so many doctors." Understanding what's important to patients can help with patient-doctor communication and decision-making, Tinetti said. "If a patient's outcome goals are not achievable or realistic given their health status, a conversation might include, "I worry that you might not be able to continue driving your friends to the theater. I wonder if there are other ways to fulfill your desire to see shows and connect with your friends that could be more achievable." Participants were drawn from a single practice with a homogeneous patient population; results may not generalize to other populations, and identifying the priorities of diverse groups is essential, the report's authors noted. "While further research is needed, the study suggests the feasibility of asking people about their goals and preferences, and getting responses that can inform decision-making," Tinetti said. A newly launched website, MyHealthPriorities.org, grew out of the Patient Priorities Care initiative. People can use the website to identify their priorities so they can discuss them with their health care team. "When there isn't a healthcare provider available to do the health priorities identification, there is now this option of the self-directed website," said Jessica Esterson, MPH, project director in the Section of Geriatrics at YSM. "We want to spread this capability to as many older adults as possible. By providing the website directly to individuals we greatly expand its reach and potential." The website walks people through the Patient Priorities Care health priorities identification process. At the end they will have a summary to bring to their doctors that outlines their health priorities—the activities they want their health care to help them achieve based on what they are willing and able to do. Tinetti encourages people of all ages, particularly older adults with multiple health conditions, to use MyHealthPriorities.org. "It will help you think about things you haven't thought about before, and better understand what matters most to you about your health and health care," Tinetti said. "It's important to you, your family, and your doctors."   Paleopharmaceuticals from Baltic amber might fight drug-resistant infections University of Minnesota, April 5, 2021 For centuries, people in Baltic nations have used ancient amber for medicinal purposes. Even today, infants are given amber necklaces that they chew to relieve teething pain, and people put pulverized amber in elixirs and ointments for its purported anti-inflammatory and anti-infective properties. Now, scientists have pinpointed compounds that help explain Baltic amber's therapeutic effects and that could lead to new medicines to combat antibiotic-resistant infections. The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30. Live sessions will be hosted April 5-16, and on-demand and networking content will continue through April 30. The meeting features nearly 9,000 presentations on a wide range of science topics.  Each year in the U.S., at least 2.8 million people get antibiotic-resistant infections, leading to 35,000 deaths, according to the U.S. Centers for Disease Control and Prevention. "We knew from previous research that there were substances in Baltic amber that might lead to new antibiotics, but they had not been systematically explored," says Elizabeth Ambrose, Ph.D., who is the principal investigator of the project. "We have now extracted and identified several compounds in Baltic amber that show activity against gram-positive, antibiotic-resistant bacteria." Ambrose's interest originally stemmed from her Baltic heritage. While visiting family in Lithuania, she collected amber samples and heard stories about their medicinal uses. The Baltic Sea region contains the world's largest deposit of the material, which is fossilized resin formed about 44 million years ago. The resin oozed from now-extinct pines in the Sciadopityaceae family and acted as a defense against microorganisms such as bacteria and fungi, as well as herbivorous insects that would become trapped in the resin. Ambrose and graduate student Connor McDermott, who are at the University of Minnesota, analyzed commercially available Baltic amber samples, in addition to some that Ambrose had collected. "One major challenge was preparing a homogeneous fine powder from the amber pebbles that could be extracted with solvents," McDermott explains. He used a tabletop jar rolling mill, in which the jar is filled with ceramic beads and amber pebbles and rotated on its side. Through trial and error, he determined the correct ratio of beads to pebbles to yield a semi-fine powder. Then, using various combinations of solvents and techniques, he filtered, concentrated and analyzed the amber powder extracts by gas chromatography-mass spectrometry (GC-MS). Dozens of compounds were identified from the GC-MS spectra. The most interesting were abietic acid, dehydroabietic acid and palustric acid -- 20-carbon, three-ringed organic compounds with known biological activity. Because these compounds are difficult to purify, the researchers bought pure samples and sent them to a company that tested their activity against nine bacterial species, some of which are known to be antibiotic resistant. "The most important finding is that these compounds are active against gram-positive bacteria, such as certain Staphylococcus aureus strains, but not gram-negative bacteria," McDermott says. Gram-positive bacteria have a less complex cell wall than gram-negative bacteria. "This implies that the composition of the bacterial membrane is important for the activity of the compounds," he says. McDermott also obtained a Japanese umbrella pine, the closest living species to the trees that produced the resin that became Baltic amber. He extracted resin from the needles and stem and identified sclarene, a molecule present in the extracts that could theoretically undergo chemical transformations to produce the bioactive compounds the researchers found in Baltic amber samples. "We are excited to move forward with these results," Ambrose says. "Abietic acids and their derivatives are potentially an untapped source of new medicines, especially for treating infections caused by gram-positive bacteria, which are increasingly becoming resistant to known antibiotics."     Complementary effects of pine bark extract supplementation on inattention, impulsivity, and antioxidative status in children with ADHD Taipei Medical University (Taiwan), April 1, 2021 The purpose of this study was to investigate the complementary effects of polyphenolic compounds from pine bark extract (PE) as a strong antioxidative substrate on the symptoms of inattention and impulsivity in children with attention‐deficit hyperactivity disorder (ADHD). This was a randomized, double‐blind, crossover, placebo‐controlled study that included two experimental units (4 weeks with PE supplementation and 4 weeks with placebo supplementation) separated by a 2‐week washout period. ADHD participants were supplemented with 25 mg or 50 mg PE. We recruited 20 participants (17 boys and 3 girls) with a mean age of 10.0 ± 2.1 years. PE supplementation caused a significant reduction in the inattention and hyperactivity‐impulsivity items of SNAP‐IV. During the period of PE supplementation, the item of commissions in the Continuous Performance Test III (CPT III) significantly decreased, which was used to evaluate the symptoms of inattention and impulsivity. In addition, the erythrocytic reduced glutathione/oxidized glutathione ratio significantly increased, and the plasma TBARs level significantly decreased after 4 weeks of PE supplementation. However, there was no significant correlation between CPT III (commission) and antioxidative status indictors. PE supplementation may have potential effects of ameliorating inattention and impulsivity, and elevating the antioxidative status in children with ADHD.

In this episode, Hanny Al-Samkari, MD; Sujit Sheth, MD; and Mark A. Schroeder, MD, provide their clinical perspectives on new data from ASH 2020 on nonmalignant hematologic disorders, with topics including:Use of mycophenolate mofetil plus corticosteroids vs standard corticosteroid treatment in patients with ITP from the phase III FLIGHT study Analysis of an ongoing phase I/II trial of rilzabrutinib reporting safety and efficacy in the long-term extension for adult patients with relapsed/refractory ITPNew data from the phase III HOPE-B study of etranacogene dezaparvovec gene therapy, using an AAV5-vector to deliver the Padua variant of the factor IX gene in patients with hemophilia B An update from the phase I/II CLIMB THAL-111/SCD-121 studies reporting safety and efficacy on the first 10 patients receiving CTX001 with at least 3 months of follow-upPrimary analysis from the phase III REACH3 trial evaluating ruxolitinib, an oral JAK1/2 inhibitor, in combination with steroids and calcineurin inhibitors, as a treatment for steroid-refractory or steroid-dependent chronic GVHDTop-line results from the phase II ROCKstar study of belumosudil, a ROCK2 kinase inhibitor, in patients with heavily pretreated chronic GVHDPhase I data from the GRAVITAS-119 study of JAK1 inhibitor itacitinib plus calcineurin inhibitors as prophylaxis treatment for acute GVHDPresenters:Hanny Al-Samkari, MDInstructorDepartment of MedicineHarvard Medical SchoolAttending Hematologist and Clinical InvestigatorDivision of Hematology OncologyMassachusetts General HospitalBoston, MassachusettsSujit Sheth, MDProfessorDepartment of PediatricsWeill Cornell MedicineNew York, New YorkMark A. Schroeder, MDAssociate Professor of MedicineDivision of OncologyDepartment of MedicineWashington University School of Medicine in St LouisSt Louis, MissouriContent supported by educational grants from Amgen; AstraZeneca; Bristol-Myers Squibb; Epizyme, Inc.; GlaxoSmithKline; Incyte Corporation; Janssen Biotech; Karyopharm Therapeutics Inc.; Novartis; PharmaEssentia Corp.; Seattle Genetics; and Takeda Oncology. Link to full program, including downloadable slidesets, and on-demand Webcasts:http://bit.ly/3tyQ9nG

The anti-inflammatory IL-10 pathway in the CNS can lead to Glioblastoma which is a disease presented 3-4 fold higher in people ≥65 years old, and with a mortality rate for the same age group some 7 fold higher. Activation of the IL-10 Receptor bound ligand induces the JAK1 signal transducer and activator of transcription 3 (STAT3) pathway in APCs. This results in the subsequent translocation of STAT3 homodimers into the nucleus. This STAT3 homodimer binds to STAT-binding elements which promotes the expression of the suppressor of cytokine signaling 3 (SOCS-3) and IL-1 receptor antagonist (IL-1RN). IL-10 reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor alpha) and diminished expression of both major histocompatibility complex II. The anti-inflammatory MiDAS phenotype can also induce heart failure in the aging population. References: Front Pharmacol. 2019; 10: 200 Aging Cell. 2018 Oct;17(5) Int Heart J. 2018 Jul 31;59(4):837-844 Front. Immunol., 19 March 2018 Neuro Oncol . 2020 Mar 5;22(3):333-344 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

A pair of biomarkers are being used to guide treatment and predict mortality in patients with graft-versus-host disease (GVHD), according to James L.M. Ferrara, MD, DSc, of the Icahn School of Medicine at Mount Sinai, New York. In this episode, Dr. Ferrara explains how measuring these biomarkers – REG3-alpha and ST2 – can prevent over- and undertreatment of acute GVHD. The biomarkers have also been shown to predict nonrelapse mortality more accurately than a change in clinical symptoms. Before reviewing these findings, Dr. Ferrara tells host David H. Henry, MD, what GVHD is, how to recognize it, and how it’s typically treated. GVL and GVHD GVHD is “very tightly associated” with the graft-versus-leukemia (GVL) effect, Dr. Ferrara explained. The GVL effect refers to the ability of donor immune cells to eliminate host malignant cells after allogeneic hematopoietic stem cell transplant (allo-HSCT). The donor T cells respond to minor histocompatibility antigens on malignant cells but also on normal cells. When the donor T cells attack the normal cells, the patient develops GVHD. To prevent GVHD, patients may receive cyclosporin, tacrolimus, methotrexate, sirolimus, or other drugs in various combinations. Despite prophylaxis, slightly under half of allo-HSCT recipients will still develop some form of GVHD, Dr. Ferrara said. Acute GVHD Acute GVHD typically occurs in the first month or two after transplant, and about 50% of cases happen in the first month, Dr. Ferrara said. There are three primary targets – the skin, liver, and GI tract. The rash observed with skin GVHD is vesiculopapular, and the extent of the rash determines the stage of GVHD in the skin. Increase in total bilirubin is used to measure the stages of liver disease. GVHD in the GI tract is characterized by persistent nausea and vomiting or diarrhea (up to liters a day). Evaluating the skin, liver, and GI tract together can provide the overall GVHD grade, between 1 and 4. Grade 4 GVHD is the most severe, and grade 1 is a skin rash that usually affects less than 50% of the body surface area. Over- and undertreatment When GVHD is mild and limited to the skin, topical steroid creams are adequate treatment. When GVHD progresses into the GI tract and liver, patients require systemic immunosuppression. However, it’s difficult to tell whether GVHD is going to be mild, moderate, or severe. So when patients with acute GVHD receive systemic steroids at a starting dose of 1 mg/kg, many of these patients are overtreated “and a fair number of them are undertreated because we don't actually know which patients are going to progress and which patients are going to respond to treatment,” Dr. Ferrara said. He noted that the JAK1/2 inhibitor ruxolitinib was approved to treat steroid-refractory acute GVHD last year. Prior to that, the only approved treatment for GVHD was systemic steroids. Biomarkers signal disease severity Through their research, Dr. Ferrara and colleagues identified two biomarkers of GVHD severity – REG3-alpha and ST2. “When the GI tract is damaged early, these proteins flood into the systemic circulation, and they can actually tell us who's got a damaged GI tract very early, even before one has symptoms like diarrhea,” Dr. Ferrara explained. The biomarkers can be used to assess, at the onset of GVHD, whether or not a patient has crypt damage and needs more intensive treatment. Biomarkers guide treatment, predict outcomes Dr. Ferrara and colleagues used serum samples collected by the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop MAGIC Algorithm Probability (MAP). MAP is calculated from patients’ levels of REG3-alpha and ST2 and can be used to predict the risk of severe GVHD. “You put these two biomarkers into an equation, you get a single number, and that number tells you whether [the patient is] high risk, low risk, or intermediate risk,” Dr. Ferrara explained. He and his colleagues found they could use MAP to predict patients’ response to treatment and mortality. In fact, MAP was able to predict nonrelapse mortality more accurately than a change in clinical symptoms (Blood Adv. 2019. 3[23]:4034-42. https://bit.ly/39QNUVn). Standard practice, ongoing trials MAP is increasingly becoming a part of standard practice, Dr. Ferrara said. A company called Viracor Eurofins Clinical Diagnostics licensed MAP and provides tests for consumer use (https://bit.ly/33RhRBa). Centers can send blood samples to Viracor to test. More than 50 centers in the United States sent at least 1,000 samples to Viracor for testing in 2019, Dr. Ferrara said. He and his colleagues are also utilizing MAP in ongoing clinical trials: A phase 2 study of natalizumab plus standard steroid treatment for high-risk acute GVHD (NCT02133924; https://bit.ly/3grvsUK). A pilot trial of alpha1-antitrypsin for preemption of steroid-refractory acute GVHD (NCT03459040; https://bit.ly/3qy48c9). A phase 2 trial of itacitinib for low-risk GVHD (NCT03846479; https://bit.ly/37GkaYK). Disclosures: Dr. Ferrara has a patent for serum biomarkers of acute GVHD and receives royalties from Viracor. Dr. Henry has no relevant disclosures. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.16.385971v1?rss=1 Authors: Hernandez, L. M., Montersino, A., Niu, J., Guo, S., Thomas, G. Abstract: Janus Kinase-1 (JAK1) plays key roles in pro-survival signaling during neurodevelopment and in responses to neuronal injury. JAK1 was identified as a potential palmitoyl-protein in high-throughput studies, but the importance of palmitoylation for roles of JAK1 in neurons has not been addressed. Here, we report that JAK1 is endogenously palmitoylated in cultured Dorsal Root Ganglion (DRG) neurons and, using an shRNA knockdown/rescue approach, reveal that JAK1 palmitoylation is important for neuropoietic cytokine-dependent signaling and neuronal survival. We further identify the related palmitoyl acyltransferases (PATs) ZDHHC3 and ZDHHC7 as dominant regulators of JAK1 palmitoylation in transfected non-neuronal cells and endogenously in neurons. At the molecular level, palmitoylation is critical for JAK1 kinase activity in transfected cells and even in vitro, likely because palmitoylation facilitates transphosphorylation of key sites in the JAK1 activation loop. These findings provide new insights into palmitoylation-dependent control of neuronal development and survival. Copy rights belong to original authors. Visit the link for more info

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

Finally got around to tackling the JAKi this week.  I decided to focus on SELECT-COMPARE, which pitted upadacitinib (selective JAK1 inhibitor) against adalimumab and placebo.  I briefly discuss other JAKs and my thoughts on the future of this area. Get the paper and others at ebrheum.com and follow me @ebrheum! 

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

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

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center of Singapore and Duke National University of Singapore. Our featured discussion today is a wake-up call because despite substantial efforts to promote cardiac rehabilitation in guidelines and performance measures only a small percentage of patients are receiving this and there is a remarkable regional variation. Lots of lessons to be learned here coming right up after these summaries.                                                 More children with congenital heart disease are surviving into adulthood, and congenital heart disease is associated with risk factors for dementia. But what is the actual risk of dementia in congenital heart disease adults? Well, in this first paper from first and corresponding author Dr. Bagge from Aarhus University Hospital in Denmark, the authors used medical registries and a medical record review of all Danish hospitals to identify more than 10,600 adults with congenital heart disease diagnosed between 1963 and 2012 and followed up until the hospital diagnosis of dementia or death, emigration, or the end of the study in the end of December 2012.                                                 For each individual with congenital heart disease the authors identified 10 members of the Danish general population matched on sex and birth year. They found that the risk of all-cause dementia was increased by about 60% in congenital heart disease adults compared with the matched general population. The risk was higher for early onset dementia, that is dementia at less than 65 years of age, in which the risk was more than double. The risk was also elevated for all levels of congenital heart disease complexity, including those with cyanotic potential. The relative risk remained increased for those without extra cardiac defect or acquired cardiovascular diseases.                                                 These results really underscore the importance of understanding the risk of adverse long-term neurologic outcomes in the growing and aging population with congenital heart diseases.                                                 The next paper suggests that patient outcomes after lower limb revascularization have improved in England over recent times. This paper from first and corresponding author Dr. Heikkila from London School of Hygiene and Tropical Medicine used individual patient records from hospital episode statistics to identify almost 104,000 patients who underwent endovascular or surgical lower limb revascularization for infrainguinal peripheral artery disease in England between 2006 and 2015. During this 10-year period the estimated one-year risks of major amputation and death reduced after both endovascular and surgical lower limb revascularization in England. These trends were observed for all categories of peripheral artery disease severity, with the largest reductions seen among patients with the most severe underlying disease.                                                 These encouraging trends coincided with a period of centralization and specialization of vascular services in England, although the current findings cannot be interpreted as resulting directly from this reconfiguration of services.                                                 The next paper presents experimental data showing that targeting the Janus kinase and signal transducer and activator of transcription or JAK-STAT pathway may represent a disease-modifying strategy in inflammatory vasculopathy. First author Dr. Zhang, corresponding author Dr. Weyand from Stanford University School of Medicine examined whether persistent vessel wall inflammation in giant-cell arthritis is maintained by lesional T cells and whether such T cells are sensitive to the cytokine signaling inhibitor tofacitinib, which is a JAK inhibitor that targets JAK3 and JAK1.                                                 To do this, vascular inflammation was induced in human arteries and grafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant-cell arthritis. Mice carrying inflamed human arteries were then treated with tofacitinib or vehicle. They found that tofacitinib suppressed T cell invasion into the artery, inhibited proliferation and cytokine production of vasculitogenic T cells and curbed survival of artery resident T cells. Tofacitinib treatment prevented neoangiogenesis and intimal hyperplasia in these inflamed arteries. Thus, inhibition of JAK-STAT signaling with tofacitinib effectively targeted multiple disease-relevant processes in inflammatory vasculopathy and thus represents a potential disease-modifying agent.                                                 The next paper provides important insights into how coronary artery calcification burden and cardiorespiratory fitness, which are actually two independent predictors of cardiovascular disease but may interact with each other to impact cardiovascular risk. First author Dr. Radford, corresponding author Dr. Levine from the Institute of Exercise and Environmental Medicine Texas Health Presbyterian Hospital and UT Southwestern Medical Center studied 8,425 men without clinical cardiovascular disease who underwent preventive medical examinations that included an objective measurement of coronary artery calcification and cardiorespiratory fitness between 1998 and 2007.                                                 They found that cardiovascular disease events increased with increasing coronary artery calcification and decreased with increasing cardiorespiratory fitness. Adjusting for coronary artery calcification levels for each additional MET of fitness there was an 11% lower risk of cardiovascular disease events. When both coronary artery calcification and cardiorespiratory fitness were considered together there was a strong association between continuous cardiorespiratory fitness and cardiovascular disease incident rates in all coronary artery calcium groups. Thus, the take-home message is for any baseline age and level of coronary artery calcification greater fitness is associated in a continuous fashion with lower risks of cardiovascular disease events.                                                 And that wraps up our summaries. Now for our feature discussion.                                                 We all know how cardiac rehabilitation is. It's strongly advocated in guidelines, it's very well highlighted in performance measures. But how well are we actually doing? Well, today's feature paper really gives us some very valuable information and really kind of holds a mirror in our face, doesn't it? I'm so pleased to have with us the first and corresponding author of the paper Dr. Alexis Beatty from VA Puget Sound Health Care System and University of Washington as well as Jarett Berry, our associate editor from UT Southwestern. Alexis, could you tell us what did you see when you looked at cardiac rehabilitation among the Medicare and VA populations? Dr Alexis Beatty:               Overall participation in cardiac rehab after an MI or a PCI or a bypass surgery is pretty low, only about 16% of people in Medicare and about 10% of people on the VA actually participate in cardiac rehab. But the interesting thing is that we saw pretty wide variations from state to state in participation. So some states had pretty high participation, upwards of 40% of patients, and some states had only 1, 2, 3% of people participating. Dr Carolyn Lam:                Were there any patterns to this, any factors that you teased apart? Dr Alexis Beatty:               We did observe that some regions of the country appeared to be doing better than others. So for instance, the West North Central region of the United States, Nebraska, South Dakota area has high participation in both populations and other regions like the Pacific, California, Oregon, Washington, Hawaii, Alaska, have lower participation in both populations. Dr Carolyn Lam:                And any postulations on why this may be the case? Dr Alexis Beatty:               Yeah, I have some theories. We did try to look at whether it was due to patient characteristics, hospital characteristics, socioeconomic status, and it doesn't really seem to be any of those things that are driving the differences, which leads me to believe that it's actual practice variations. So I think that literally the systems are set up better in some areas of the country than others to get patients into cardiac rehab. Dr Carolyn Lam:                And as you beautifully wrote in your paper, that means that there may be an opportunity here to identify best practices here, isn't it? Jarett, you've been thinking about this a lot. What do you think? Dr Jarett Berry:                 Yeah, I was curious, Alexis, it is interesting that the hospital variation that you saw, the on-site cardiac rehab was fairly consistent across cardiac rehab participation rates in Medicare but there was quite a bit of variability in the access to an on-site cardiac rehab site in the VA patients. I thought that was an interesting observation because it does suggest perhaps that what's driving regional variability looks to be fairly complex as you point out in your paper. But I just wanted to have you speculate a little bit or think a little bit about strategies for how we might think about improving cardiac rehab participation given the fact that there doesn't seem to be one particular answer to this problem. And so as you think about this longstanding challenge, how would you think about the future, about how we could actually really move the needle in increasing cardiac rehab participation? Dr Alexis Beatty:               There's a lot of different ways that I think that we can work to start moving the needle. And as you point out, not every VA location has a cardiac rehab center on-site and sites that do have cardiac rehab on-site do tend to do better at getting their patients into cardiac rehab. And I think it may just be that there are people there who are interested in cardiac rehab and are promoting it to patients. And then there probably are some access issues as well. But I think it's not just kind of an "if you build it they will come" sort of proposition. Having cardiac rehab centers is important but then having systems in place to get people into cardiac rehab and get people going to cardiac rehab are just as important.                                                 And so I've talked to a lot of the VAs that have centers, don't have centers, do a good job of getting people in, don't do a good job of getting people in. And even in these places that don't have cardiac rehab on-site, if they have a system in place that helps get patients into cardiac rehab they're still able to achieve pretty high rates. And so a lot of that is just doing kind of setting it up as an automatic order and having a nurse or exercise physiologist or somebody be a navigator for the patients through the process.                                                 And then the other thing I really want to stress is the importance of providers recommending it to patients. I think that's the strength with which the providers sell cardiac rehab can really make a big difference. Dr Jarett Berry:                 It's interesting, I just took over cardiac rehab as a medical director here at Southwestern about a year and a half ago and I've been struggling with this. And one of the interesting things that I just would love to get your thoughts on that I noted, which doesn't seem to get a lot of attention in the literature to me, is the role of co-payments. I don't know if most physicians who aren't involved in this space appreciate that for most insurance and for Medicare, it may not be the case for VA, I can't speak to that, but the co-payment amount for each time you come, for each visit is between $30 and $50 per visit. That seems to me in some ways ... I know you didn't address it at all in your paper, but just keeping this conversational ... What do you think the role of some of these other less discussed factors are such as just co-payment amounts that might actually be having a bigger effect on participation? Because I know if I had to pay a 1,000 bucks to go to cardiac rehab I might think twice about it. Dr Alexis Beatty:               Yeah, and I think the co-payment issue is a very real issue too and there's a lot of policy level things that makes cardiac rehab difficult. So one is this co-pay issue, there also then other changes to the way it's administered like where the location of the cardiac rehab can be and how hospitals get reimbursed for that. It has to be prescribed by a physician, it can't be prescribed by a nurse practitioner or a PA, it has to be supervised by a physician. There's a lot of restrictions on cardiac rehab that can just, practically speaking, make it difficult to deliver both from the patient and the provider and health system level.                                                 And what I tell my patients when I am trying to get them to go to cardiac rehab, and we do have co-payers in the VA too that are kind of on a sliding scale depending on patients' means. And so I tell them that it's an investment. You are making this upfront investment of your time and money and effort to get yourself healthy and learn how to be healthy in the long term. So we know that people who attend cardiac rehab are less likely to be hospitalized and are less likely to die from their heart disease, and so it's an important investment to make and that's sometimes the hard message to sell and I wish it were easier to sell. Dr Jarett Berry:                 I totally agree with you. My own patients and also the patients that I helped manage through cardiac rehab have received such benefit in many different areas from the participation. But yeah, it is an investment.                                                 I wanted to ask another question, if I may Carolyn, about the future. And you alluded to this in your paper, I know your work with Mary Whooley, you guys have done great work thinking about rolling out home-based cardiac rehab. And I think personally that the future of cardiac rehab for most patients, that we're really going to move the needle—I mean some of the policy issues are really important—but can you comment on just telling us what home-based cardiac rehab is and to what extent you think that is a potential solution to deal with these persistently low participation rates? Dr Carolyn Lam:                Actually Jarett, if I may just butt in before Alexis answers, I was about to ask that because I was just placing myself in the patient's point of view. And I mean even me, I hate going to gyms now and much rather work with a home app instructing me what to do and I can just do it here, you know what I mean? So I think that's a great question. Alexis? Dr Alexis Beatty:               I agree, the future is home cardiac rehab and using all the tools that we have at our disposal to make it easy to deliver home cardiac rehab. The evidence isn't quite as strong for home cardiac rehab but the existing evidence does suggest that it's equally effective to center-based cardiac rehab, it's just not reimbursed in the United States. So functionally it only exists in sort of integrated health systems like the VA.                                                 The VA, for instance, has started delivering home-based cardiac rehab programs. I think it's now at over 30 centers in the US. And this has basically started in the last five years. And the programs are pretty similar to a center-based cardiac rehab program in that patients come in and they get an in-depth assessment from cardiac rehab professionals. But then the difference is that they go and exercise on their own at home and they check in with the cardiac rehab professionals usually on a weekly basis over the telephone. And so it ends up being more of like a coaching relationship between the cardiac rehab professionals and the patients who are exercising on their own at home. And a lot of patients really like it because, as you pointed out, it's much more convenient for them, they don't like going to a gym, they'd rather be walking around in their neighborhood or going to their local community pool to swim. So it just sort of addressed a lot of these patient issues and they don't have to pay a co-payment. So it can take some of these other barriers that are there. Dr Jarett Berry:                 Like a Peloton bike for cardiac rehab, right? Dr Alexis Beatty:               Yeah. I mean you could even do that. For instance, in HF-ACTION they actually gave people exercise equipment for a HF-ACTION study for the home segment of the HF-ACTION study. So there certainly are models whereby we could just be giving exercise equipment. And in the VA I can mail people these little exercise paddlers that they can put on their floor or their table and you can use them with your legs or your arms. So certainly being able to send some of this exercise equipment to your patients may help them get them into doing things. But I think home cardiac rehab is the future.                                                 And then also I do work on using technology to help deliver home cardiac rehab and I view technology for this space not as the solution but as a tool to help you deliver home cardiac rehab. And now that technology is so ubiquitous, I think that we need to now learn how to use the technology to help us better deliver cardiac rehab in a way that meets the patients' needs. Dr Carolyn Lam:                Wow. Jarett, I've actually got a question for you. You were just saying that you run the rehab unit there, so what messages did you take home from this paper? Dr Jarett Berry:                 What I took home from this was exactly what we've been discussing, this issue of low uptake of cardiac rehab even in the scenario where you have a model where you're delivering this through Medicare or the VA we still see very low participation, albeit there is some variability. And so my interpretation after doing cardiac rehab here at Southwestern for the last year and half is exactly what Alexis is saying, is that we need to be really thinking more creatively about how we can deliver cardiac rehab where the patients are and not requiring them to participate in centers of cardiac rehab that are maybe 30, 40 miles from their home and in the middle of the workday, all of which just really makes such a model inefficient.                                                 So I just think what this paper does really solidify is that we really need to be thinking broadly and creatively about how to bring cardiac rehab to more patients because the way we're doing this now I think unfortunately is just ineffective. Dr Carolyn Lam:                Anything to add, Alexis? This is great. Dr Alexis Beatty:               So one other point that I would like to mention. I think about 10 years ago there was another paper that used a very similar method, and we based a lot of our methods off of that paper by Suaya about 10 years ago. And they found that the rate of participation in cardiac rehab was somewhere very close to ours, I think it was 18% and we observed 16%. And since that paper was published cardiac rehab got included in guidelines, included as a performance measure, and there has been a big push and a lot of attention to try to get people into cardiac rehab and we have moved the needle zero since that time. So I think clearly something new is needed to move the needle for cardiac rehab just as Jarett was pointing out. So we got to do something because what we're doing isn't working. Dr Carolyn Lam:                That's a great call and thank you for showing that to us so clearly in your paper. Dr Jarett Berry:                 Yeah, thanks Alexis and thanks for being so responsive in the revision process, it was a real pleasure to work with you all on this really important paper. Dr Alexis Beatty:               Thank you so much for publishing this paper. I feel I've been working on this for like five years. Dr Carolyn Lam:                Well you heard it here, listeners. Thank you for joining us today. Don't forget to tune in again next week.

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

Al Singer, Gil Katz, and Leonid A. Pobezinsky talk about how signaling through the T cell receptor inhibits interleukin-7 receptor signaling.

Igerész: Jakab1,21-25 Lelkész: Charles Warren Lejátszás közvetlen fájlból (hiba esetén): https://krek.hu/media/files/igehirdetesek/130915 9h Charles Warren_gedeon konf.zaro it_Engedd be Ot, hadd valtoztasson_Jak1,21_25.mp3 Becsült hossz: 3249 mp Generálta: ScrapeCast by Fodor Benedek UUID: 058f6f4b-6577-4849-a3bb-f9fbddc2e2ba

Claire Harrison, DM, Guy's and St Thomas' NHS Foundation Trust discusses the role of JAK1/2 Inhibitors in the treatment of chronic myeloproliferative neoplasms.

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

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

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

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

Hintergrund und Fragestellung Eines der schwerwiegenden Probleme der interventionellen Kardiologie stellte bislang die koronare Restenose im Stent dar. Erst durch die Einführung eines Rapamycin- freisetzenden-Stents konnte die Restenoserate erheblich gesenkt werden. Trotz dieses therapeutischen Erfolges sind die transkriptionellen pathophysiologischen Mechanismen der Neointimahyperplasie, die zu über 90% für den Lumenverlust nach koronarer Stentimplantation verantwortlich ist, sowie deren Beeinflussung durch Rapamycin nur teilweise verstanden. Methodik Die vorliegende Arbeit untersuchte deshalb in einem humanen Organkulturmodell auf genregulatorischer Ebene die molekularen Mechanismen, die der Neointimaformation im Menschen zu Grunde liegen, sowie die Beeinflussung dieser Mechanismen durch eine Behandlung mit Rapamycin. Ergebnisse Es konnte gezeigt werden, dass (1) die Veränderungen in der Genexpression einem zeitlichen Muster folgen mit maximalen Veränderungen 21 Tage nach Ballondilatation; (2) die inflammatorische Komponente zu den frühen Zeitpunkten eine wichtigere Rolle spielt während Proliferation und Apoptose die späteren Veränderungen in der Genexpression dominieren; (3) die Ballonangioplastie ein Genexpressionsprofil induziert, welches die Rekrutierung und Aktivierung sowohl inflammatorischer als auch hämatopoetischer Vorläuferzellen erleichtert; (4) Rapamycin die Induktion eines solchen pro-adhäsiven, proinflammatorischen Genexpressionsmusters als auch die Induktion von HPC-stimulierenden Genen verhindert. Diskussion Eine zeitlich gestaffelte Genexpressionsanalyse menschlicher Arterien nach Ballonangioplastie ist bisher nicht veröffentlicht worden. In dieser Arbeit zeigte sich, dass die Veränderungen in der Genexpression einem zeitlichen Muster folgen mit einer maximalen Alteration nach 21 Tagen und nur wenigen ausschließlich nach 56 Tagen regulierten Genen. Somit lässt sich schlussfolgern, dass eine spätere Restenose die Folge einer frühen, gestörten Wundheilung ist. Diese Auffassung wird durch die beeindruckende Verminderung der In-Stent-Restenose durch Rapamycin-freisetzende Stents unterstützt, da diese Stents etwa 80% der totalen Medikamentendosis innerhalb der ersten 30 Tage freisetzen. Während die Proliferation bekanntermassen eine wichtige Rolle für die Neointimaformation spielt, wurde die Bedeutung inflammatorischer Prozesse, welche zur Rekrutierung von Leukozyten und hämatopoetischen Vorläuferzellen führen, erst später vermehrt beschrieben. Die koordinierte Induktion eines in dieser Arbeit nachgewiesenen proinflammatorischen Genexpressionsmusters stellt eine beeindruckende Rationale für eine umfangreiche Rekrutierung von Leukozyten nach Ballondilatation dar. Zytokine wie IL-8, EMAP-II, NAP-2 oder GCP-2 waren nach Angioplastie vermehrt exprimiert und verstärken die Migration von Granulozyten. Die mechanisch induzierte Aktivierung dieses Genexpressionsmusters begünstigt somit die Leukozytenrekrutierung und dadurch auch die Restenose, da die Dichte inflammatorischer Zellen in der Neointima mit dem Ausmass der Restenose korreliert. Als weiterer Mechanismus der Neointimaformation wurde kürzlich die Rekrutierung hämatopoetischer Vorläuferzellen im Tiermodell nachgewiesen. Es war jedoch bisher nicht bekannt, ob sich diese Beobachtungen auf den Menschen übertragen lassen. Im Organkulturmodell zeigte sich nach Angioplastie die vermehrte Expression von einigen mit hämatopoetischen Vorläuferzellen assoziierten Genen. Dies weist daraufhin, dass diese Mechanismen auch im Menschen eine Rolle spielen. Im zweiten Teil dieser Arbeit wurde der Einfluss des Makrolidantibiotikums Rapamycin auf die transkriptionellen Mechanismen nach Ballonangioplastie untersucht. Zunächst spiegelten sich die bekannten antiproliferativen Effekte von Rapamycin in einer deutlich verminderten Expression von wachstumsassoziierten Genen wie verschiedenen Transkriptionsfaktoren und Kinasen wie JAK1 oder AKT1 wieder. Darüberhinaus führte die Rapamycinbehandlung zu einer koordinierten Hemmung der CXC Chemokine 6-8 (GCP-2, β- Thromboglobulin, IL-8) und von EMAP-II, welche alle eine wichtige Rolle in der Adhäsion, der Migration und der Aktivierung von Neutrophilen und Monozyten spielen. Folglich könnte eine durch Rapamycin veminderte Rekrutierung und Aktivierung dieser Zellen ein wesentlicher Mechanismus in der Reduktion der Neointimaformation sein. Zusätzlich unterstützt diese Arbeit die Hypothese, dass Rapamycin auch direkte Effekte auf hämatopoetische Vorläuferzellen hat. Im Organkulturmodell führte eine Rapamycinbehandlung zur veminderten Expression verschiedener Gene wie des Oncostatin M Rezeptors beta und JAK1, welche das Wachstum immaturer, noch differenzierender Zellen in der Gefässwand fördern. Es lässt sich zusammenfassen, dass Rapamycin neben seiner anti-proliferativen Wirkung nach Ballonangioplastie tiefgreifende hemmende Effekte auf das pro-inflammatorische Genexpressionsmuster und auf Promotoren hämatopoetischer Vorläuferzellen verübt. Somit zeigt diese Arbeit erstmals eine Rationale auf, wie Rapamycin auch im Menschen die Rekrutierung hämatopoetischer Vorläuferzellen in die Gefässwand verhindern könnte. Dies vermag möglicherweise seine hohe Effektivität in der Reduzierung der Restenose erklären.