Podcasts about s1p

Dr. Edward A. Botchwey is a Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. His research focuses on advancing regenerative medicine and immunoengineering through a convergence approach that integrates various disciplines and techniques for tissue repair and regeneration. Dr. Botchwey's lab has made significant contributions in investigating S1P signaling in tissue repair and engineering in vivo gradients for microvascular remodeling, as well as developing regenerative immunotherapies using specialized pro-resolving lipid mediators (SPMs) and hydrogel-based delivery systems. This talk will mainly focus on targeting S1P signaling to promote tissue repair and regeneration, including the use of sphingosine kinase inhibitors (SK1i) to reduce local S1P levels and promote muscle fiber regeneration. Additionally, the development and application of ApoM-Fc-S1P, a novel S1P chaperone that enhances S1P receptor 1 signaling, will be discussed, highlighting its role in reducing fibrosis and improving muscle healing, particularly in aged animals. Advanced drug delivery systems such as nanofiber scaffolds and hydrogels, which provide localized and sustained release of therapeutic agents like FTY720, will also be introduced. These delivery systems enhance the efficacy of S1P-targeted therapies by ensuring higher drug concentration at the injury site, facilitating better integration and healing. The presentation will cover the use of ultrasound elastography as a noninvasive imaging technique to monitor tissue stiffness and fibrosis, providing valuable insights into the therapeutic efficacy of these approaches. Dr. Botchwey aims to develop innovative, equity-centered solutions to complex challenges in regenerative medicine, with potential applications in diverse fields such as regenerative immunotherapies, metabolic and hematologic disorders, and cell and tissue transplantation. Additionally, he is actively involved in promoting diversity and outreach through programs like SURE (Summer Undergraduate Research Experience) and ENGAGES (Engaging New Generations at Georgia Tech through Engineering and Science), which aim to provide underrepresented students with research opportunities and inspire the next generation of scientists and engineers. ---- Note: The views of this podcast represent those of my guest(s) and I. Note: Purpose of these episodes- not at all, for advice or medical suggestions. These are aimed to provide support for peer pharmacists in training in educational and intellectually stimulating ways. Again, these are not at all for medical advice, or for medical suggestions. Please see your local state and board-certified physician, PA or NP, and pharmacist for medical advice and suggestions.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/advancements-in-mri-technology-improved-diagnosis-and-monitoring-of-ms/17839/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/missed-opportunities-in-multiple-sclerosis-care-increasing-hcp-awareness-of-early-diagnostic-delays/17836/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/what-do-clinicians-need-to-know-utilizing-clinically-validated-diagnostic-tools-to-diagnose-ms-earlier/17837/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/navigating-the-diagnostic-maze-strategies-for-excluding-ms-disease-mimics/17838/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/transforming-ms-management/17843/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/the-complexity-of-early-ms-diagnosis/17842/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/the-role-of-s1p-receptor-agonists-in-ms-strategies-for-disease-management/17841/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 1.00 Valid until: 20-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/from-prescription-to-personalization-an-hcps-guide-to-tailoring-ms-therapeutic-management/17840/ This program examines the significant challenges encompassing the management of Multiple Sclerosis (MS), including the need for quick and effective screening tools to help clinicians increase early diagnosis and the initiation of therapy. While there is currently no cure for MS, the treatment landscape is rapidly changing, and this program provides a review of best practice guidelines and emerging treatment strategies, including the S1P drug treatment class. There are also inequities relating to the level of care white patients with MS receive compared to non-white patients with MS, especially African Americans and Hispanic-Latinx. This program educates clinicians on the racial and ethnic disparities that produce barriers for minorities concerning MS diagnosis and treatment and helps close the gap.

CME credits: 0.75 Valid until: 29-11-2024 Claim your CME credit at https://reachmd.com/programs/cme/making-a-difference-patient-centered-ulcerative-colitis-care-in-the-era-of-jak-inhibitors-and-s1p-modulators/16125/ The goal of this program is to improve the overall management of patients with ulcerative colitis (UC). Specifically, we aim to improve clinician knowledge and competence with respect to the novel mechanisms of action of sphingosine-1-phosphate receptor (S1P) modulators and Janus kinase (JAK) inhibitors and their respective roles in the overall treatment paradigm of UC. We also aim to improve patient-centered approaches to the management of UC with a particular focus on underserved communities and Black, Indigenous, and people of color (BIPOC). To bolster our commitment to these patient populations, Boston University Chobanian & Avedisian School of Medicine partnered with Color of Crohn's & Chronic Illness (COCCI) for this initiative.=

CME credits: 0.50 Valid until: 12-03-2024 Claim your CME credit at https://reachmd.com/programs/cme/putting-it-into-practice-where-do-s1p-receptor-modulators-fit/16094/ This activity will have a key focus on S1P receptor modulators that will address how to select optimal therapy for ulcerative colitis based on clinical trial data, guidelines, and shared decision-making. Tune in with Dr. Jordan Axelrad, Associate Professor of Gastroenterology at the NYU Grossman School of Medicine.=

Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See the full write ups for today's episode at nascentmc.com/podcast Here are the highlights:  Velsipity (Etrasimod) for UC: The FDA has approved Velsipity (etrasimod) for treating moderate to severe active ulcerative colitis (UC) in adults. Etrasimod, an oral medication manufactured by Pfizer, was based on safety and efficacy data from the ELEVATE UC 52 and ELEVATE UC 12 trials, making it the second S1P class agent approved for UC in the United States. The first agent, ozanimod (Zeposia), received FDA approval in May 2021. Braftovi (encorafenib) and Mektovi (binimetinib) for NSCLC:The FDA has granted approval for the combination of encorafenib and binimetinib to treat BRAF V600E–mutant, metastatic non–small cell lung cancer (NSCLC). The approval, supported by the phase 2 PHAROS study, showed a 75% objective response rate (ORR) in treatment-naive patients. This combination was previously approved for unresectable or metastatic melanoma with a BRAF mutation. Edison System for Non-Invasive Destruction of Liver Tumors:The FDA has authorized the marketing of the HistoSonics Inc. Edison System for non-invasive destruction of liver tumors. The system utilizes a non-thermal, mechanical process of focused ultrasound to create small, vapor-filled cavities (cavitation) without heat, mechanically destroying and liquefying targeted liver tissue, including tumors. This technology is suitable for patients with sufficient functional liver reserve. Complete Response Letter for Patisiran ATTR amyloidosis:The FDA declined to approve patisiran for ATTR amyloidosis despite a favorable recommendation from advisers. The FDA noted that patisiran did not significantly improve the condition of patients with heart muscle issues or cardiomyopathy caused by ATTR amyloidosis. Patisiran, branded as Onpattro, is already approved to treat nerve damage in adult patients with hereditary ATTR amyloidosis. FDA Creates a Digital Health Advisory Committee:The FDA has established a Digital Health Advisory Committee to address complex issues related to digital health technologies, including AI/ML, augmented reality, virtual reality, and more. This committee will provide expertise and perspective to improve the FDA's understanding of the benefits, risks, and clinical outcomes associated with digital health technologies and is expected to be fully operational in 2024. Intro and outro music Garden Of Love by Pk jazz Collective  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.04.551943v1?rss=1 Authors: Bagley, D. C., Russell, T., Ortiz-Zapater, E., Fox, K., Redd, P. F., Joseph, M., Rice, C. D., Reilly, C. A., Parsons, M., Rosenblatt, J. Abstract: Asthma is a common disease characterized by airway constriction, excess mucus, and inflammation. Although asthma is an inflammatory disease, subclassed by different endotypes, triggers, and immune responses, the defining diagnostic symptom is mechanical bronchoconstriction from uncontrolled smooth muscle contraction. We previously discovered a conserved process that drives epithelial cell death in response to mechanical cell crowding called epithelial cell extrusion (1,2). Because modest crowding triggers extrusion to maintain constant homeostatic epithelial cell densities, we reasoned that the pathological crowding from bronchoconstriction might potentially destroy the airway epithelial barrier, causing the typical inflammatory period that follows an asthma attack. Here, using immune-primed mice, we show that the crowding of bronchoconstriction causes excess epithelial cell extrusion and damage, resulting in inflammation in distal airways, and mucus secretion in proximal airways. Surprisingly, relaxing airways following bronchoconstriction with the current rescue treatment, albuterol, did not prevent epithelial extrusion and destruction, inflammation, or mucus secretion. However, inhibiting canonical live cell extrusion signaling during bronchoconstriction with stretch-activated/TRP channel or sphingosine 1-phosphate (S1P) inhibitors blocked all downstream symptoms. Our findings propose a new etiology for asthma where the extreme mechanical crowding from a bronchoconstrictive attack causes inflammation by wounding airway epithelium. Whereas most therapies focus on modulating downstream inflammatory symptoms, our studies suggest that blocking epithelial extrusion could prevent the feed-forward asthma inflammatory cycle. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Clinicians prescribing the increasingly higher efficacy B-cell depletion or S1P modulators therapies — how aware are they of the newer concerns about safety? Which of their patients may be in greater danger of acquiring PML and/or opportunistic infections? The vaccinations commonly recommended for the general population (eg, COVID-19) — do individuals with MS respond differently, and what should clinicians do about it? What do the data say?Join us, as Dr. Le Hua and Dr. Areeba Siddiqui from the Cleveland Clinic's Lou Ruvo Center for Brain Health explore these questions in this issue of eMultipleSclerosis Review.Take our post-test to claim CME credits.Read this podcast's companion newsletter here. Hosted on Acast. See acast.com/privacy for more information.

Clinicians prescribing the increasingly higher efficacy B-cell depletion or S1P modulators therapies — how aware are they of the newer concerns about safety? Which of their patients may be in greater danger of acquiring PML and/or opportunistic infections? The vaccinations commonly recommended for the general population (eg, COVID-19) — do individuals with MS respond differently, and what should clinicians do about it? What do the data say?Join us, as Dr. Le Hua and Dr. Areeba Siddiqui from the Cleveland Clinic's Lou Ruvo Center for Brain Health explore these questions in this issue of eMultipleSclerosis Review.Take our post-test to claim CME credits.Read this podcast's companion newsletter here. Hosted on Acast. See acast.com/privacy for more information.

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

Go online to PeerView.com/FNG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Much progress has been made in defining the genetic abnormalities and associated abnormal pathophysiology underlying the spontaneous and chronic inflammation that characterizes inflammatory bowel disease (IBD). Medications that suppress or modify immune activity form the core of effective treatment for IBD. Sphingosine-1-phosphate (S1P) receptor modulators, a small-molecule therapeutic option, provide a target-specific approach with a favorable safety profile. Multiple S1P receptor modulators are in development, and ozanimod became the first agent in this class to receive FDA approval for the treatment of moderately to severely active ulcerative colitis in 2021. In this activity, based on a recent live symposium, expert faculty will discuss the therapeutic effects of S1P receptor modulators on the underlying pathophysiology of IBD and identify patients with UC who could benefit from treatment with these agents. In addition, the faculty will discuss individualizing treatment using S1P receptor modulators for appropriate patients with IBD in accordance with current evidence and guidelines. Upon completion of this activity, participants should be better able to: Explain how the therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators address the underlying pathophysiology of IBD; Identify patients with UC who could benefit from the use of therapy with S1P receptor modulators; and Individualize treatment using S1P receptor modulators for appropriate patients with UC in accordance with current evidence and guidelines

PODCASTER SENIOR: Marinella Clerico;PODCASTER JUNIOR: Gianmarco Abbadessa;RAZIONALE:Il danno neurologico inizia sin dalle fasi iniziali della Sclerosi Multipla, prima della manifestazione dei sintomi clinici. Il trattamento precoce con terapie ad alta efficacia può migliorare gli esiti clinici a lungo termine minimizzando l'accumulo di danni neurologici che si verificano nelle prime fasi della malattia. Le seguenti terapie modificanti il decorso sono approvate in Europa per il trattamento di tutte le forme di SM-recidivante, comprese la CIS, la SM-RR e, per alcuni DMT, la SM secondariamente progressiva (SM-SP) attiva: anticorpi monoclonali anti-CD20 (ofatumumab per via sottocutanea e ocrelizumab per via endovenosa), natalizumab (un antagonista del recettore dell'integrina alfa4beta2 somministrato per via endovenosa), modulatori del recettore della sfingosina 1-fosfato (S1P) (fingolimod, siponimod, ozanimod, ponesimod, tutti assunti per via orale), fumarati (dimetil, monometil, diroximel, tutti assunti per via orale), interferoni (IFNβ-1b somministrato per via sottocutanea, IFNβ-1a e IFNβ-1a pegilato somministrati per via sottocutanea o intramuscolare), teriflunomide (per via orale) e glatiramer acetato (iniezione sottocutanea).

Please visit answersincme.com/DRN860 to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, an expert in gastroenterology discusses emerging small molecule therapies in the treatment of moderate-to-severe Crohn's disease. Upon completion of this activity, participants should be better able to: Identify the clinical rationale for using emerging selective Janus kinase (JAK) inhibitors and sphingosine 1–phosphate (S1P) receptor modulators in Crohn's disease; Describe evidence from late-stage clinical trials on the use of small molecule therapies in individuals with moderate-to-severe Crohn's disease; and Outline patient-centered strategies for optimizing treatment with small molecule therapies in moderate-to-severe Crohn's disease.

Please visit answersincme.com/DRN860 to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, an expert in gastroenterology discusses emerging small molecule therapies in the treatment of moderate-to-severe Crohn's disease. Upon completion of this activity, participants should be better able to: Identify the clinical rationale for using emerging selective Janus kinase (JAK) inhibitors and sphingosine 1–phosphate (S1P) receptor modulators in Crohn's disease; Describe evidence from late-stage clinical trials on the use of small molecule therapies in individuals with moderate-to-severe Crohn's disease; and Outline patient-centered strategies for optimizing treatment with small molecule therapies in moderate-to-severe Crohn's disease.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

Go online to PeerView.com/REK860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. For individuals with multiple sclerosis (MS), “invisible symptoms” that include cognitive changes and fatigue exacerbate the burden of disease. Emerging evidence indicates that in addition to providing high efficacy, safety, tolerability, and patient convenience, sphingosine 1-phosphate receptor (S1PR) modulators may yield important benefits related to loss of cortical gray matter and whole brain volume, addressing cognition as well as multiple other aspects of MS. At a recent live event, our expert faculty reviewed the mechanism of action of S1PR modulators and their important role in MS care, with a focus on the clinically relevant distinctions among members of this class—from first-generation fingolimod to the more recently introduced siponimod, ozanimod, and ponesimod. The faculty discussed the role of agent-specific characteristics such as relative selectivity and off-target effects in individualized treatment planning—reviewing key trial data on patient outcomes and concluding with a case-based workshop addressing treatment selection, shared decision-making, and COVID-19 vaccination. Upon completion of this activity, participants should be better able to: Discuss the rationale for the modulation of S1P function as a therapeutic approach in multiple sclerosis (MS) in the context of disease pathophysiology; Individualize S1PR modulator therapy for patients with MS based on the latest evidence on safety, efficacy, and the potential impact on physical and cognitive outcomes; and Apply a patient-centered, team-based approach to treatment selection and sequencing in MS based on the patient's disease activity, treatment preferences and goals, and therapeutic options.

CME credits: 0.25 Valid until: 31-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/emerging-therapies-in-uc/13566/ There are over a half dozen newer and emerging classes of agents for ulcerative colitis. This abundance is great news for our patients, but it also increases the complexity of treatment. Listen in as Dr. Neil Nandi and Dr. Jean-Frederic Colombel explore the roles that these agents will play in the evolving treatment landscape. Since the completion of this activity, results from the ELEVATE UC 52 study, a yearlong phase 3 trial of etrasimod in moderate to severe ulcerative colitis, were announced. Etrasimod is an investigational, oral, once-a-day, selective sphingosine 1-phosphate (S1P) receptor modulator that showed positive 12- and 52-week results compared to placebo. Patients achieved statistically significant improvements in the co-primary endpoint of clinical remission at weeks 12 and 52 when compared to placebo. Statistically significant improvements were also attained in all key secondary endpoints at both 12 and 52 weeks. We will provide more data as the full results are published and presented in the future.

CME credits: 0.25 Valid until: 31-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/emerging-therapies-in-uc/13566/ There are over a half dozen newer and emerging classes of agents for ulcerative colitis. This abundance is great news for our patients, but it also increases the complexity of treatment. Listen in as Dr. Neil Nandi and Dr. Jean-Frederic Colombel explore the roles that these agents will play in the evolving treatment landscape. Since the completion of this activity, results from the ELEVATE UC 52 study, a yearlong phase 3 trial of etrasimod in moderate to severe ulcerative colitis, were announced. Etrasimod is an investigational, oral, once-a-day, selective sphingosine 1-phosphate (S1P) receptor modulator that showed positive 12- and 52-week results compared to placebo. Patients achieved statistically significant improvements in the co-primary endpoint of clinical remission at weeks 12 and 52 when compared to placebo. Statistically significant improvements were also attained in all key secondary endpoints at both 12 and 52 weeks. We will provide more data as the full results are published and presented in the future.

CME credits: 0.25 Valid until: 25-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/weighing-the-evidence-a-case-based-review-in-ulcerative-colitis/13439/ The proliferation of new classes of therapies for ulcerative colitis is affecting how we decide which treatments are most appropriate for our patients who are first- or second-line non-responders. This creates not only new challenges, but also new opportunities for all community gastroenterologists. Dr. Neil Nandi and Dr. David Rubin walk us through a case to highlight some of these challenges. Since the completion of this activity, results from the ELEVATE UC 52 study, a yearlong phase 3 trial of etrasimod in moderate to severe ulcerative colitis, were announced. Etrasimod is an investigational, oral, once-a-day, selective sphingosine 1-phosphate (S1P) receptor modulator that showed positive 12- and 52-week results compared to placebo. Patients achieved statistically significant improvements in the co-primary endpoint of clinical remission at weeks 12 and 52 when compared to placebo. Statistically significant improvements were also attained in all key secondary endpoints at both 12 and 52 weeks. We will provide more data as the full results are published and presented in the future.

CME credits: 0.25 Valid until: 25-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/weighing-the-evidence-a-case-based-review-in-ulcerative-colitis/13439/ The proliferation of new classes of therapies for ulcerative colitis is affecting how we decide which treatments are most appropriate for our patients who are first- or second-line non-responders. This creates not only new challenges, but also new opportunities for all community gastroenterologists. Dr. Neil Nandi and Dr. David Rubin walk us through a case to highlight some of these challenges. Since the completion of this activity, results from the ELEVATE UC 52 study, a yearlong phase 3 trial of etrasimod in moderate to severe ulcerative colitis, were announced. Etrasimod is an investigational, oral, once-a-day, selective sphingosine 1-phosphate (S1P) receptor modulator that showed positive 12- and 52-week results compared to placebo. Patients achieved statistically significant improvements in the co-primary endpoint of clinical remission at weeks 12 and 52 when compared to placebo. Statistically significant improvements were also attained in all key secondary endpoints at both 12 and 52 weeks. We will provide more data as the full results are published and presented in the future.

Multiple Sclerosis News Today's multimedia associate, Price Wooldridge, reads a news article about how S1P receptor modulators such as Mayzent and Gilenya may be associated with a greater likelihood of skin cancer. He also reads “The Supplements of Mice and Men”, from John Connor's regular column "Fall Down, Get Up Again". =================================== Are you interested in learning more about multiple sclerosis? If so, please visit: https://multiplesclerosisnewstoday.com/ ===================================== To join in on conversations regarding multiple sclerosis, please visit: https://multiplesclerosisnewstoday.com/forums/

In this podcast, expert clinicians discuss the latest updates on anti-integrin therapy and S1P receptor modulators in IBD management.

This month on Episode 26 of Discover CircRes, host Cindy St. Hilaire highlights four original research articles featured in the June 25th and July 9th issues of Circulation Research. This episode also features an in-depth conversation with Dr Hirofumi Watanabe, Dr Ariel Gomez, and Dr Maria Luisa Sequeira-Lopez from the University of Virginia about their study, The Renin Cell Baroreceptor, A Nuclear Mechanotransducer Central for Homeostasis.   Article highlights:   Mesirca, et al. Electrical Remodeling of the AV Node in Athletes   Yang, et al. Macrophage-Mediated Inflammation in COVID-19 Heart   Örd, et al. Functional Fine-Mapping of CAD/MI GWAS Variants   Akhter, et al. EC-S1PR1 Activity Directs Vascular Repair     Cindy St. Hilaire:        Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'll be highlighting the articles presented in our June 25th and July 9th issues of Circulation Research. I'm also going to speak with Dr Hirofumi Watanabe, Dr Ariel Gomez and Dr Maria Luisa Sequeira-Lopez from the University of Virginia about their study, The Renin Cell Baroreceptor, A Nuclear Mechanotransducer Central for Homeostasis. Cindy St. Hilaire:        The first article I want to share comes from the June 25th issue of Circ Res and is titled Intrinsic Electrical Remodeling Underlies Atrial Ventricular Block in Athletes. The first authors are Pietro Mesirca, Shu Nakao, Sarah Dalgas Nissen, and the corresponding author is Alicia D'Souza. And they're from the University of Manchester in the UK. Cindy St. Hilaire:        Endurance training has cardiovascular benefits, but when taken to extremes, it can elicit heart problems such as atrial ventricular block or AV block. AV block is the impaired conduction through the AV node. In fact, some endurance athletes require pacemakers later in life due to AV block. One hypothesis for this conundrum is that the problem stems from disruptions in the autonomic nervous system. This study shows that in fact, the intrinsic electrophysiology of the heart is to blame. They used trained race horses, as well as mice, subjected to endurance swimming as models for human endurance athletes. Electrocardiograms on the animals showed that just like human athletes, the race horses and the swim-trained mice exhibited signs of AV node dysfunction that is not seen in sedentary controls. Cindy St. Hilaire:        Because the dysfunction also persisted when the autonomic nervous system was blocked, the team examined molecular changes within the heart itself. They found that ion channels, HCN4 and Cav1.2, were less abundant in the AV nodes of trained animals than those of the controls. The team went on to identify two microRNAs regulating HCN4 and Cav1.2 production and showed that suppression of these microRNAs restored normal heart electrophysiology in the mice. If the result holds true for humans, this could pave the way for novel treatments for AV block. Cindy St. Hilaire:        The second article I want to share is titled An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts. The first authors are Liuliu Yang, Yuling Han, Fabrice Jafre, Benjamin Nilson-Payant and Yaron Bram. And the corresponding author is Shuibing Chen. And they're from Cornell University Medical Center. Cindy St. Hilaire:        COVID-19 is primarily a respiratory disease, but cardiac complications are common and appear to be linked with worsening outcomes. Post-mortem examinations of COVID-19 patients' hearts have revealed abnormally high numbers of macrophages, suggesting that these cells have a role in the heart pathology. To investigate this possibility, this group co-cultured macrophages and cardiomyocytes, both which were derived from human induced pluripotent stem cells and infected the cultures with SARS-CoV-2 virus. Upon infection, both cell types increased their rates of apoptosis. However, the number of cardiomyocytes succumbing to the cell death process was far higher than that of macrophages. When cardiomyocytes were infected with the virus in the absence of macrophages, their rate of apoptosis dropped. Cindy St. Hilaire:        The team showed that macrophages produced large amounts of the inflammatory cytokines, IL-6 and TNF, in response to the virus and that trading the cardiomyocytes directly with the cytokines could similarly induce apoptosis. Blocking IL-6 and TNF alpha signaling prevented the macrophage-driven cardiomyocyte death. The team then identified two FDA approved drugs, ranolazine and tofacitinib, that prevented the virus-induced cardiomyocyte death in vitro and suggest that these drugs now be investigated in larger animal models. Cindy St. Hilaire:        The next article I want to share is titled Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci. The first author is Tiit Ord, and the corresponding author is Minna Kaikkonen, from the University of Eastern Finland. Cindy St. Hilaire:        Genome-wide association studies, or GWAS studies, have identified hundreds of genetic loci associated with coronary artery disease and myocardial infarction. And many of these genes likely play a role in atherosclerotic development. However, most of these loci are located in non-coding intergenic regions of the genome. Thus, their functional effects on atherosclerosis development are not clear. Non-coding regions of the genome may contain gene regulatory elements, including cell type specific enhancers. And because such enhancer elements often have open chromatin structures, this team profiled the chromatin accessibility of single cells in human atherosclerotic plaques. Cindy St. Hilaire:        They found that many cell type-specific assessable regions overlapped with both transcription factor binding motifs, as well as GWAS-identified coronary artery disease loci. Using an algorithm called Cicero, the team was able to predict likely genes under the control of these accessible intergenic regions. They found that in more than 30 cases, they were able to confirm these intergenic regions control gene expression in in vitro assays. This work highlights the power of chromatin accessibility mapping for homing in on GWAS loci with transcriptional effects, and for identifying the likely genes they regulate. Cindy St. Hilaire:        The last article I want to share is titled Programming to S1PR1+ Endothelial Cells Promote Restoration of Vascular Integrity. The first author is Mohammed Zahid Akhter, and the corresponding author is Dolly Mehta, and they're from the University of Illinois College of Medicine. Cindy St. Hilaire:        Endothelial cells line the lumen of our blood vessels, forming a barrier that regulates the transport of nutrients, fluids and circulating cells to and from tissues. The lipid signaling molecule, sphingosine-1-phosphate, or S1P, and its receptor, S1PR1, promote endothelial barrier integrity. But how S1P and S1PR1 signaling might restore barrier function to inflammation-induced leaky vessels is unclear. Cindy St. Hilaire:        Using mice with fluorescently tagged S1PR1, this group showed that when mice are given a dose of the bacterial endotoxin, LPS, which induces lung inflammation, there's a dramatic boost in the proportion of growing lung endothelial cells. This boost in S1PR1+ endothelial cells is due to their increase in proliferation. Cindy St. Hilaire:        The authors go on to show that this proliferation is accompanied by increased production of the transcription factors involved in S1P synthesis and secretion. When they transplanted S1PR1+ cells into mice whose endothelial cells lacked the receptor, they could rescue the leaky blood vessels. By detailing the cells and molecular players responsible for vessel recovery after inflammation, this work may inform repair boosting therapies for chronic inflammatory conditions. Cindy St. Hilaire:        So today with me, I have Dr Hirofumi Watanabe, Dr Ariel Gomez and Dr Maria Luisa Sequeira-Lopez, from the University of Virginia. And they are all with me to discuss their study, The Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis. And this article is in our July 9th issue of Circulation Research. So thank you all for joining me today. I think we're spanning 13 time zones, so I appreciate you all making the effort. Maria Luisa Sequeira-Lopez:  It's our pleasure. Thank you. Ariel Gomez:               Thank you. Hirofumi Watanabe:   Thank you. Cindy St. Hilaire:        I won't lie, the Renin-Angiotensin-Aldosterone System is quite complex, so we're not going to try to break it all down here, but it is essential for the regulation of fluid balance and blood pressure in the body. Without it, things go quite awry. And your study is focusing on the kidney cell that produces renin in response to the minute changes in the blood pressure and the composition and the volume of the extracellular fluid in the body. So I'm wondering if, before we jump into the study, if you can give us a bit of background about these renin-producing cells and what is known about the renal pressure sensing system? Maria Luisa Sequeira-Lopez:  So in the adult mammalian kidney, renin cells are located at the tip of the afferent arterioles at the entrance to the glomeruli. So that's why they are called juxtaglomerular cells. They synthesize and release renin. This is then, as you mentioned, the rate-limiting enzyme for the renin-angiotensin system that controls blood pressure and fluid-electrolyte homeostasis. However, during early embryonic development, as demonstrated many years ago, renin cells are widely distributed along the renal arterial tree and inside the glomerulus and the interstitium. And with maturation they differentiated to vascular smooth muscle cells and they end up being located in the juxtaglomerular area. Maria Luisa Sequeira-Lopez:  But in response to a homeostatic challenge, such as hypertension, dehydration, hemorrhage, there is an increase in the number of renin-expressing cells along the renal arterial tree, resembling the embryonic counter. And this occurs mostly by re-expression of renin from vascular smooth muscle cells that descended from originally renin-expressing cells. And when the challenge passes, then they stop expressing renin and become vascular smooth muscle cells again. So renin cells are extremely plastic and they can switch back and forth from an endocrine to a contractile phenotype.   Cindy St. Hilaire:        I'm really glad you mentioned the vascular smooth muscle cell angle because I actually have a question about that later on. But before I get to that question, one of the things that I love reading in studies is when a current paper references much older work that often has a really intricate or insightful observation. And in your paper you cited, I believe it was in 1957, was the first real hypothesis that there is an existence of this pressure sensing mechanism in the kidney, what we're calling this baroreceptor. Yet, that was a long time ago and the identity has really been elusive. So I was wondering why has it just been so difficult to really pin down this baroreceptor and how this pressure and fluid sensing works in these cells? Ariel Gomez:               So it was elusive, as you said. The reason is the researchers didn't have the tools to actually study it. It really requires an evolution, conceptual evolution, and scientific evolution, as well as technical development. And so we were fortunate over time, over the years. We developed ways to mark the cells endogenously with the appropriate fluorescent markers, genetically engineer, then develop models that allowed to drop the blood pressure in a consistent manner, and so forth. And we could follow the lineage of these cells and study them as they move back and forth from their phenotypes. So I think it was a matter of even Dr Tovian, who is the person that you mentioned, Lou Tovian, who I actually met a long time ago. So he even postulated that maybe it was a stretch mechanism, and that's one of the great contributions of Hirofumi who figure out how to stretch the cells using different ways of doing that. Cindy St. Hilaire:        So in your quest to identify this baroreceptor, you use several murine models. A surgical tool, but also several genetic tools. And I was wondering if you could share a little bit about that initial surgical model, that aortic constriction and maybe the pros and cons about that method? Hirofumi Watanabe:   And so we established surgical model of in mice. We created inductation between the roots of the right and left renal arteries. By the surgery, and our right kidney receives high pathogen pressure, and the left kidney receives low pathogen pressure. And this surgery model resulted in a marked difference in the expression of renin in each kidney. And by RT2 PCR and in situ hybridization, renin was decreased in the right kidneys and increased in the left kidneys. Cindy St. Hilaire:        Excellent. So it's a really powerful model because you can use the same mouse to look at the same... Ariel Gomez:               Right. So the beauty of that is that, Hirofumi, by doing that, he got rid of any genetic variation between the mice. Because you are doing the high and low pressure in the same mouse. Maria Luisa Sequeira-Lopez:  And another question I can think that we have said was when, if you calculate the number of cells that increase in one kidney and decreases in the other one, if you add them, it ends up being the number of cells in a non-aortic coarctation mouse. So it looks like- Cindy St. Hilaire:         It's a literal seesaw. That's beautiful. At least the math works out in your favor in the end. That's great. Maria Luisa Sequeira-Lopez:  And that's something that Luis Tovian didn't see, because what he did is he increased the perfusion pressure in an isolated kidney and what he observed was less granulation. So it was an indirect method to find less renin in those kidneys. But with a low pressure, he didn't observe an increase in renin, or increase in granulation. What we know that really happens. Cindy St. Hilaire:        So you mentioned smooth muscle cells in the beginning of our discussion and my training has been in smooth muscle cells, vascular smooth muscle cells, mostly though focused on the aorta, especially in mice. A lot of times we just say smooth muscle cells, but people are really talking about the aortic smooth muscle cells in the mice. And in humans, in the coronaries. But we use the mouse aortic smooth muscle cells as the model, which you can obviously see when you frame it out like that, some issues. And one of the things we talk about at least in athero is the cell plasticity and this phenotype switching from the contractile quiescent state to one that's associated with disease processes. Cindy St. Hilaire:        And we've really evolved on what we've known about that. It used to be just about the migration and proliferation. Now it's about the actual phenotypic switching into different kinds of cells. Macrophage-like cells, for one. And yours really was the first to bring to my eyes that there's probably many more regarding that. So could you maybe expand a little bit on these renal smooth muscle cells or renin-like cells maybe, and what's happening in that disease process? And do we know the point at which it can switch and make renin and go back versus switches and doesn't return? Is that part of the disease process? Ariel Gomez:               We describe the plasticity of the smooth muscle cells from the renal arterioles long time ago. I mean, I think, I would say that even at the beginning of my career. And at that time people didn't use that term so much, plasticity. We didn't know how to call it because it was a switch back and forth from a smooth muscle contractile phenotype to endocrine without, at the moment, without causing disease. And the cells were able to come back to be smooth muscle cells. But the period of the stimulation was only a week or so. So during that time, the cells can go back and forth. And now we know that they do that. But if you create a persistent stimulation, and this is another paper that we are working with Hirofumi and Maria Luisa, if you create a knockout renin or knockout of angiotensin receptors or so forth, the stimulation doesn't stop because there is no angiotensin. Ariel Gomez:               And so under those conditions, the cells reach a point in which they become very aggressive, almost embryonic-like. They are constantly stimulated. They are attempting to reestablish the phenotype and in doing so, they create these concentric vascular hypertrophy. And I don't know whether we are going to send the paper to Circulation Research or to where, but we are still writing it. After that, we don't know whether they can come back because they are so seriously sick. And we know that they are responsible for this, but this is another paper. Maria Luisa Sequeira-Lopez:  Another thing that I wanted to add is that these cells have been extremely difficult to study. Ariel has been developing many, many tools that allow him to dissect them and cover many secrets of the cells. But if you... First because they are very, very few in the kidney. And there were no markers to isolate them. And if you put them in culture, now that we can have them live with a person marker, they stop expressing renin and making renin within 24-48 hours. So it's difficult to study. So that's why Hirofumi [inaudible 00:19:21] how the system works. Stimulating them with cyclic AMP, they go back like renin. If not, they differentiate into vascular smooth muscle cells. It looks like that's their default pathway. So they need to sense that there is a need for renin to increase the blood pressure and electrolyte homeostasis. So that's one of the characteristics of the cells. But if you stimulate constantly, as Ariel said, then they may be hard to… They cannot come back. Cindy St. Hilaire:        It's over the tipping point a bit. Maria Luisa Sequeira-Lopez:  Yes. Cindy St. Hilaire:        In your discussion you mentioned another study from your group that kind of took more of a developmental angle. And you mentioned that you had identified unique chromatin structures of renin-producing cells, and you also identified what are called super enhancers that help dictate the differentiation of these running progenitor cells into renin producing cells. And then in your mechanical stimuli experiments, you mentioned identifying similar chromatin signatures. And I was wondering what this might suggest in regards to the disease pathogenesis. And I guess I'm thinking about it in terms of in many diseased states, we see this activation of developmental programs that either are not stopped or just go on and are even higher expressed than in developmental programs. And is that you think is happening in these renin cells? A developmental program gone awry? Ariel Gomez:               Yeah, definitely. I definitely think so. I think we all, the three of us think that way. Yeah. I think it's an exaggeration of a developmental program. One thing that we didn't mention and why the vessels get so sick is because during development, these cells contribute to the formation of the vasculature. And so when they regress so much trying to make renin... And they make it. I mean, they go from 20,000 units to 2 million of renin, right? And they never stop. But when they regress so much, they regressed on embryonic stage and they think that they need to make more blood vessels to actually increase the flow and the oxygenation of the tissue. But in doing so, they create more pathology. So maybe, Hirofumi, I don't know if you're going to ask him, but one of those super enhancers is the Lamin A/C gene. And he has studied that in this Circulation Research paper that we are talking about. Maria Luisa Sequeira-Lopez:  I just wanted to add that they also make lots of angiogenic factors to make the vessels. Cindy St. Hilaire:        Got it. So developmentally, they're activating more production of renin but they're also producing these pro angiogenic cytokines and really driving that… Ariel Gomez:               BGF. They produce a type of BGF or angiopoietins. Cindy St. Hilaire:        Interesting. Ariel Gomez:               Yeah. And things like that. Cindy St. Hilaire:        I really liked reading about this magnetic bead experiment that you used as the mechanical stimuli. Frankly, I saw the picture and I brought it to my lab and said, "Guys, figure out how to do this." Can you explain a little bit about it? It seemed really nice, really elegant and very tuneable. So I'm excited. I'm sure many more people are excited to hear about it. Hirofumi Watanabe:   So we applied coated magnetic beads to the cultured ring cells. Then we placed a magnet above the cells so we can pull the cells by magnetic force. Cindy St. Hilaire:        How strong is the magnet that it doesn't just rip everything up? Hirofumi Watanabe:   Yeah. We cannot observe the shapes of the cells, but yeah, I hope it's just stretch. Cindy St. Hilaire:        Yeah. Well, it certainly elicited an effect. So, in terms of future translational potential, what do you think about these findings that suggest either potential future therapies or even targets that we can use to develop therapies? Is there a future therapeutic angle to these really interesting biomechanical findings? Ariel Gomez:               Discovering or knowing the structure of these pressure sensing mechanism, I think we'll eventually have many applications because it will be applicable to hypertension, of course. And maybe we can begin to think... Not yet because it's really a fundamental discovery, it's not yet at that stage. But eventually the information can be used to start thinking about treatments that are addressing those particular structures that are involved from the beta one, integrating all the way to the nucleus. And little by little people started developing epigenetic therapies, right? And we are testing some of these compounds in our lower authority. Not with this model, with other models. But I think eventually we will be able to do what was the dream. It was really a dream years ago, was to do molecular therapy, right? And so a small compound development will play an important role. And eventually driving the molecules to the exact place in the genome is... So it would be not only patient-oriented, personalized medicine, but local specific. That should be the goal of medicine in the future. I won't be there when we get there. Cindy St. Hilaire:        I don't know. CRISPR is moving things rather fast, so that's great. Ariel Gomez:               Oh, yeah. You're right. You're right. You're right about that. Okay. Cindy St. Hilaire:        So what's next in this project? What do you think is the next low hanging fruit? Now that you've identified this baroreceptor or maybe a component of a larger baroreceptor family, what do you think is the next most important question? Maria Luisa Sequeira-Lopez:  We want to know what is in-between. And the bigger one integrating and the Lamin A/C. And also, we want to see how fast this reacts. So we'll be doing experiments with the constriction for just a few hours, and harvest both kidneys and we will try to do single cell RNA-seq and a from those vials. Hirofumi Watanabe:   I think we want to study how Lamin A/C regulates renin expression in renin cells, so chromatic modification initiated by changes in particle pressure more. Ariel Gomez:               And I think the... What I've been now pushing a little bit is to remember that there is another cell in there that is in between the pressure and the JG cells. And that is the endothelium cell. Right? And so, they are communicating with one another. So we are going to engage some... In fact, it's already happening. A member of the lab is already working with the same model that Hirofumi used, looking at endothelial cells label also using aninterfering promoter linked to a fluorescent protein. So we want to know what happens to the endothelial cells, because they are receiving the brunt of the pressure. And we don't know how they sense. We described the mechanosensing capability of the JG cells, the renin cells, but the whole system is probably a lot more complex than what we think. Cindy St. Hilaire:        I think that's the lesson of renin angiotensin signaling. It's always more complex. Ariel Gomez:               Yeah. Exactly. Cindy St. Hilaire:        Well, thank you all so much for joining me today. This is a beautiful study, very elegant. And I liked the new kind of in vitro models with this bead system. And congratulations on a whole lot of work. The amount of mice was probably a lot. I look forward to your future studies and learning what's happening at this endothelial renin cell junction. Maria Luisa Sequeira-Lopez:  Thank you. And we feel honored that you chose us. Ariel Gomez:               Yeah. Well, so I want to thank you for interviewing us. But I want to say that Hirofumi spent three years in the lab and he did a magnificent amount of work. Cindy St. Hilaire:        Wow. Yeah. I would have guessed a lot longer. Ariel Gomez:               Yeah. So he did a lot of work. And I'm very, very proud of what he has accomplished. Maria Luisa Sequeira-Lopez:  Yes. And I would like to add also that we were very lucky to have an expert in integrins, Dr DeSimone, who is the chair of Cell Biology at UVA and when we went and told him that we thought that this could be part of a mechanism sensing receptor, he started collaborating with us and opened his lab for us and trained Hirofumi with some experiments. It was really highly collaborative. Cindy St. Hilaire:        That's it for the highlights from our June 25th and July 19th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Hirofumi Watanabe, Dr Ariel Gomez, and Dr Maria Luisa Sequeira-Lopez. Cindy St. Hilaire:        This podcast was produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors of the American Heart Association. For more information, please visit ahajournals.org.  

Drs Freedman and Wiendl engage in an up-to-the-minute face-off on S1P modulation. Credit available for this activity expires: [04/29/22] Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/949968?src=mkm_podcast_addon_949968

In this podcast, expert clinicians will discuss new evidence on investigational agents, the anti-integrin and S1P-1 receptor modulators, that are in late-stage development for treating moderate to severe CD.

In today's episode we discuss: —Epidemiology: Pediatric cardiologists from the Association for European Pediatric and Congenital Cardiology's COVID-19 Rapid Response Team evaluated 286 children with symptoms of multisystem inflammatory syndrome in children (MIS-C) and found 65% had laboratory evidence of current or past COVID-19 infection, 93% had cardiac involvement, and all had elevated inflammatory markers, suggesting pediatric patients with MIS-C should be monitored for cardiovascular complications and rising biomarkers. · A literature review conducted by an international panel of pediatric dermatologists describes documented skin manifestations of COVID-19 in children including chilblain-like lesions, erythema multiforme, urticaria (10-20% of cutaneous manifestation reports), vesicular exanthema, and Kawasaki disease-like inflammatory syndrome (pediatric inflammatory multisystem syndrome with nonspecific skin symptoms and cardiovascular involvement). —Understanding the Pathology: A retrospective cohort study by cardiac pathologists from the Mayo Clinic of post-mortem reviews of 15 patients with COVID-19, six patients with influenza, and six patients with no viral pathology found patients with COVID-19 were significantly more likely to have fibrin microthrombi (12/12 [100%] of COVID-19 vs 2/6 [33%] of influenza and control patients; p=0.006) and that these were found in a higher proportion of arterioles (p=0.003). One-third (33%) of COVID-19 patients had evidence of myocarditis and 26.7% evidence of amyloidosis. · Investigators mainly from the Institute of Physiology in Berlin compared the respective plasma disruption to the lung epithelium between the plasma of 19 patients with severe COVID-19 (requiring intubation), 14 patients with moderate COVID-19 (requiring hospitalization but not intubation), and 15 healthy controls and found that addition of plasma from COVID-19 patients to healthy endothelial monolayers correlated with "significant endothelial gap formation and loss of junctional VE-cadherin". Additionally, when compared to the heathy control plasma, the plasma from COVID-19 patients not only resulted in increased severity of endothelial permeability but also rapid (within 1-2 hours) and long lasting (over 6 hours) effects, suggesting that endothelial-barrier-stabilizing adjunctive therapies administered to patients exhibiting signs of moderate to severe COVID-19 may delay progression to acute respiratory distress syndrome. —Management: Neurosurgeons at the Laboratory of Experimental Neurosurgery and Cell Therapy in Milan, Italy compared blood samples from 47 healthy patients to samples from 111 SARS-CoV-2 positive patients and found sphingosine-1-phosphate (S1P) and apolipoprotein M (apoM; a carrier of S1P) levels were significantly decreased in COVID-19 patients compared to healthy patients (p

Dr Guerra explains how there is a cumulative balance between S1P and Ceramide will influence apoptosis and change the regulation of autophagy by the complex interplay between mTOR, beclin, and Bcl-2 where S1P-dependent autophagy is thought to be a homeostatic, pro-survival response involved in the clearance of intra-cellular debris.Describing these systems within the context of inflammation and pathobiochemistry will be obtained. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

In this podcast, Patricia K. Coyle, MD, and Clyde E. Markowitz, MD, will focus on sphingosine-1-phosphate (S1P) receptor modulators for RRMS.

Inflammatory bowel disease, which includes ulcerative colitis (UC) and Crohn’s disease, affects an estimated 3 million adults in the United States. Although numerous therapies are available for the treatment of moderate to severe UC, many patients still suffer poor quality of life and suboptimal outcomes. Therefore, safer and more effective UC therapies are needed. In this CME podcast activity, Dr. Peter Higgins and Dr. William Sandborn will discuss investigational Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators for treating UC. For the transcript of this podcast, click here. To obtain CME credit, click here

Sylvain Galvani and Timothy Hla explain why the lipid S1P protects blood vessels when it is bound to HDL.

Background Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. Methods Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. Results FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). Conclusions We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

[intro music]   Host – Dan Keller Hello, and welcome to Episode Eleven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Jack Antel about remyelination and microglia. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Our latest data visualization reveals a mystery in relapsing-remitting MS. It appears that the annualized relapse rates of patients in the placebo arms of clinical trials – the placebo arms – have been decreasing since 1993. What could possibly account for this? We invite your hypotheses. Visit the MSDF website and go to our data visualizations page under “research resources.” From there you can connect to a discussion forum we’re hosting to share your opinions.   Deep brain stimulation is an extreme brain surgery that can lead to dramatic improvements in patients with Parkinson’s disease or obsessive-compulsive disorder. But in MS patients with tremor, the risk-benefit ratio varies a great deal from patient to patient. The surgery involves placing an electrode into the thalamus and stimulating the surrounding neurons to reduce tremor. However, no one is sure why the procedure works in some people with MS tremor and not in others. Last week, we published a news synthesis—including a dramatic video—on the efficacy of this surgery to treat the otherwise untreatable tremor in some MS patients.   We also reported on results from the phase 1 clinical trial of an anti-LINGO-1 remyelination agent. The drug, called BIIB033, is produced by Biogen Idec and proved safe and tolerable in healthy individuals and people with MS. In mouse models, the drug is shown to work by blocking LINGO-1. LINGO-1 prevents oligodendrocyte progenitor cells from differentiating into myelin-producing cells. The company is now conducting a phase 2 study to determine proper dosage in patients with MS.   [transition music]   Now to the interview. Dr. Jack Antel is a neurologist at the Montreal Neurological Institute and Hospital. His team studies remyelination and repair. He spoke with MSDF about how microglia and progenitor cells affect this process.   Interviewer – Dan Keller Welcome, Dr. Antel.   Interviewee – Jack Antel Thank you very much.   MSDF Where do things stand now? What is the thinking of remyelination? Is it a dynamic process? Is it something that happens all at once? Is there a balance between injury and repair?   Dr. Antel From the perspective of multiple sclerosis itself, we look to our pathologists who've examined the actual MS tissue, and they have established criteria by which they identify that remyelination has occurred, and thus this has been a major incentive to see whether one can accelerate that process. One can now somewhat question the certainty that we are distinguishing between actual remyelination and perhaps partial injury of myelin, and maybe part of what we've seen is actual injury rather than actual repair. The other side of the coin is from the experimental biologist who clearly have shown remyelination to occur and have identified progenitor cells as being the basis of remyelination in animal models. Now we have to bring the observation from the clinical pathology in humans together with those observations are we still certain that all of remyelination is dependent on new cells, or can previously myelinating cells still contribute. And in the context of the human disease, the issue is what is the total potential of the cells? Why doesn't everybody remyelinate? This is because there's intrinsic differences in the myelin cells that humans have. Could the myelin cells themselves be subject to injury? And also, the complicating feature is how much injury is there? So that, if the axons have been damaged, maybe they are not receptive to remyelination. And also, the chronic changes in the environment of all the other glial cells and their products in the human situation, which is after all a disease of months and years not of days and weeks, maybe this is an important influence as to why remyelination occurs or doesn't.   MSDF You had mentioned partial myelination or demyelination. When one looks at a path slide, is it possible to tell whether it's going up or down? Can you distinguish one from the other?   Dr. Antel So that active injury of myelin can be identified because in the active MS lesion myelin debris is freed up and picked up by the phagocytic cells – either the microglia or macrophages – so one can see that there is active injury. If one looks just at the myelin sheath itself, the criteria for remyelination is these sheaths have become rather thinned out, and the segment of the myelin sheath is shorter than in the naturally myelinated cell condition. The issue becomes whether are we absolutely sure that this is remyelination, or could one model developing this histologic feature in some way by injury? And I think that would be a very good challenge for the experimentalists to see if they can get an injury model that reproduces some myelin injury without actually killing the myelinating cells.   MSDF Besides being a target for the immune response, how do glia participate in the immune response?   Dr. Antel So the glia – we can refer both to the astrocytes and microglia – and as you mentioned one of the important issues I think with these cells is how they talk to the immune cells that are coming from the outside into the brain and modulating their properties. In addition, these glial cells themselves can influence the myelination process in several ways. One is that they can produce some of the same molecules that the immune cells produce or novel molecules that can either promote or directly inhibit the capacity of myelinating cells to function – so direct signaling effects on the myelinating cells. The other is they are producing molecules that change the environment so that processes either grow out or don't grow out from the myelinating cells. So we have to consider the glia, which are very dynamic and thus become a target for therapeutic manipulation, in terms of both their effects on immune cells but also can they be so, if you will, "good guys" or "bad guys" in terms of the promoting the myelination process.   MSDF We think of some of the present drugs as modulating the immune system and trafficking and its effect on effector cells. But do you think that some of these may be affecting bystander cells, or I suppose maybe they're not bystanders if they're actively involved. Could they have an affect on glia?   Dr. Antel I think that this is an emerging opportunity in the field because we are now having the first generation of drugs that actually access the central nervous system. The initial generation of drugs, many of the monoclonal antibodies, we felt were acting outside of the nervous system – either on immune cells themselves or on the cells that comprised the blood-brain barrier but with some particularly of the small molecule drugs that access the central nervus system – that these drugs have the capacity to interact with the neural cells. If we use as an example the family of agents that we refer to as this sphingosine-1-phosphate receptor modulators, S1P agents, there has long been data that these receptors are expressed on all cells, including all of the neural cells, and there is existing data that S1P modulators can affect the function of glial cells. Now how this translates into effects that are clinically relevant is the challenge that's ongoing now.   MSDF How does all of this relate to progressive MS?   Dr. Antel So progressive MS, I believe, is an entity that we have not totally understood yet, and we have to consider it in its parts, namely is progressive MS reflective of ongoing injury to the myelinating cells or the underlying axons? Is this a reflection of the injured cells no longer able to maintain themselves are they metabolically failing? And that can we distinguish these processes because if it's ongoing immune injury – whether related to the adaptive or innate immune system – then it makes sense to target those process. If it's an injury or metabolic failure, then that would be another approach. I think we have to consider whether progressive MS, again has evolved over many, many years, and whether one of our challenges is reducing the initial injury process can avoid many of these long-term events.   MSDF In secondary progressive MS, do you see that there's sort of a tipping point? Is there something different in secondary progressive once that occurs?   Dr. Antel It's difficult to provide an answer, and I think here is an area particularly where careful clinical studies are guiding us that the initial notion that multiple events triggered a later process would have been a very nice system to have because then stopping a process early would have predicted a beneficial later response. We are struck that the clinical data is suggesting that progression can occur perhaps even in the absence of ongoing inflammation whether the two are dissociated, at least in some cases, is a real concern. And thus, just controlling the initial immune response – because it triggers a later event – may not be sufficient. And the reverse, which I think has received perhaps less attention, is that from the clinical perspective multiple people have multiple disabling acute events and do not develop the progressive process. So it is not clear that the two are absolutely linked; whether there are genetic susceptibility factors that determine this have not yet emerged; whether it's the nature of the injury; or whether we have multiple diseases processes.   MSDF We often think of bench-to-bedside as the pathway for advancements. Now you had told me earlier that you're working with people in the opposite direction; you're finding things in the human condition and then leading to laboratory validation. Can you tell me a little bit about that?   Dr. Antel I think this is a very important aspect and why it is important that the clinical and clinical pathology experts really identify the core issues so that they can be taken to a laboratory and experimentally addressed. That in MS, we're dealing with a disease that develops over months and years making it more difficult to model it precisely. It's a disease where we have not established the initiating event. Whereas in the animal system, we usually use a arbitrary antigen if we were going to model an immune mediated disorder. We model the demyelination/remyelination process usually by acute toxins in the animal systems; whereas this is not the case in MS that specific exposure. And so I think we need to continue to develop our model systems that can induce some type of progressive disorder that is not specifically introduced perhaps by a specific antigen, at least the antigens we use currently.   MSDF Knowing that remyelination is possible, is there an implication that it may be going on in all of us in healthy brain at all times where you actually get turnover? And if so, can you capitalize on this kind of system?   Dr. Antel So the issue of turnover of myelin, I think, has not been emphasized sufficiently until recently both from the perspective if we have continuous turnover whether this may be one of the mechanisms whereby antigens are presented to the immune system. The other in terms of the turnover rate of myelin or oligodendrocytes – whether the health of these cells is damaged by the disease process, and whether a limiting factor over time is that the injury of the cells, which could be quite subtle – so that the cells are not killed, but they've impaired their function either to maintain the interaction with axons or the necessary transport of key molecules down the processes. Whether interruption of this then results in the inability of the cells to maintain their myelination properties and to continue the turnover or what might be a repair activity. And we interpret this as a later progression of the disease.   MSDF On the topics we've been discussing, is there anything important to add?   Dr. Antel I think the importance is that we now are turning our attention to these topics. That it is very timely that we do this – because until we could control the actual disease activity through immunomodulatory therapies – if that aspect was not controlled it would be much more difficult to think of trying to control the overall disease process. And also, as we couple the biology with careful clinical observations and the advances in imaging of the human brain, so that it gives us greater opportunities to bring our theories from the lab to the clinics and see whether we really impact in a positive way on the processes we've been discussing.   MSDF Very good. We appreciate it.   Dr. Antel My pleasure.   [transition music]   MSDF Thank you for listening to Episode Eleven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie [intro music]     Host – Dan Keller Hello, and welcome to Episode Eleven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Jack Antel about remyelination and microglia. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Our latest data visualization reveals a mystery in relapsing-remitting MS. It appears that the annualized relapse rates of patients in the placebo arms of clinical trials – the placebo arms – have been decreasing since 1993. What could possibly account for this? We invite your hypotheses. Visit the MSDF website and go to our data visualizations page under “research resources.” From there you can connect to a discussion forum we’re hosting to share your opinions.   Deep brain stimulation is an extreme brain surgery that can lead to dramatic improvements in patients with Parkinson’s disease or obsessive-compulsive disorder. But in MS patients with tremor, the risk-benefit ratio varies a great deal from patient to patient. The surgery involves placing an electrode into the thalamus and stimulating the surrounding neurons to reduce tremor. However, no one is sure why the procedure works in some people with MS tremor and not in others. Last week, we published a news synthesis—including a dramatic video—on the efficacy of this surgery to treat the otherwise untreatable tremor in some MS patients.   We also reported on results from the phase 1 clinical trial of an anti-LINGO-1 remyelination agent. The drug, called BIIB033, is produced by Biogen Idec and proved safe and tolerable in healthy individuals and people with MS. In mouse models, the drug is shown to work by blocking LINGO-1. LINGO-1 prevents oligodendrocyte progenitor cells from differentiating into myelin-producing cells. The company is now conducting a phase 2 study to determine proper dosage in patients with MS.   [transition music]   Now to the interview. Dr. Jack Antel is a neurologist at the Montreal Neurological Institute and Hospital. His team studies remyelination and repair. He spoke with MSDF about how microglia and progenitor cells affect this process.   Interviewer – Dan Keller Welcome, Dr. Antel.   Interviewee – Jack Antel Thank you very much.   MSDF Where do things stand now? What is the thinking of remyelination? Is it a dynamic process? Is it something that happens all at once? Is there a balance between injury and repair?   Dr. Antel From the perspective of multiple sclerosis itself, we look to our pathologists who've examined the actual MS tissue, and they have established criteria by which they identify that remyelination has occurred, and thus this has been a major incentive to see whether one can accelerate that process. One can now somewhat question the certainty that we are distinguishing between actual remyelination and perhaps partial injury of myelin, and maybe part of what we've seen is actual injury rather than actual repair. The other side of the coin is from the experimental biologist who clearly have shown remyelination to occur and have identified progenitor cells as being the basis of remyelination in animal models. Now we have to bring the observation from the clinical pathology in humans together with those observations are we still certain that all of remyelination is dependent on new cells, or can previously myelinating cells still contribute. And in the context of the human disease, the issue is what is the total potential of the cells? Why doesn't everybody remyelinate? This is because there's intrinsic differences in the myelin cells that humans have. Could the myelin cells themselves be subject to injury? And also, the complicating feature is how much injury is there? So that, if the axons have been damaged, maybe they are not receptive to remyelination. And also, the chronic changes in the environment of all the other glial cells and their products in the human situation, which is after all a disease of months and years not of days and weeks, maybe this is an important influence as to why remyelination occurs or doesn't.   MSDF You had mentioned partial myelination or demyelination. When one looks at a path slide, is it possible to tell whether it's going up or down? Can you distinguish one from the other?   Dr. Antel So that active injury of myelin can be identified because in the active MS lesion myelin debris is freed up and picked up by the phagocytic cells – either the microglia or macrophages – so one can see that there is active injury. If one looks just at the myelin sheath itself, the criteria for remyelination is these sheaths have become rather thinned out, and the segment of the myelin sheath is shorter than in the naturally myelinated cell condition. The issue becomes whether are we absolutely sure that this is remyelination, or could one model developing this histologic feature in some way by injury? And I think that would be a very good challenge for the experimentalists to see if they can get an injury model that reproduces some myelin injury without actually killing the myelinating cells.   MSDF Besides being a target for the immune response, how do glia participate in the immune response?   Dr. Antel So the glia – we can refer both to the astrocytes and microglia – and as you mentioned one of the important issues I think with these cells is how they talk to the immune cells that are coming from the outside into the brain and modulating their properties. In addition, these glial cells themselves can influence the myelination process in several ways. One is that they can produce some of the same molecules that the immune cells produce or novel molecules that can either promote or directly inhibit the capacity of myelinating cells to function – so direct signaling effects on the myelinating cells. The other is they are producing molecules that change the environment so that processes either grow out or don't grow out from the myelinating cells. So we have to consider the glia, which are very dynamic and thus become a target for therapeutic manipulation, in terms of both their effects on immune cells but also can they be so, if you will, "good guys" or "bad guys" in terms of the promoting the myelination process.   MSDF We think of some of the present drugs as modulating the immune system and trafficking and its effect on effector cells. But do you think that some of these may be affecting bystander cells, or I suppose maybe they're not bystanders if they're actively involved. Could they have an affect on glia?   Dr. Antel I think that this is an emerging opportunity in the field because we are now having the first generation of drugs that actually access the central nervous system. The initial generation of drugs, many of the monoclonal antibodies, we felt were acting outside of the nervous system – either on immune cells themselves or on the cells that comprised the blood-brain barrier but with some particularly of the small molecule drugs that access the central nervus system – that these drugs have the capacity to interact with the neural cells. If we use as an example the family of agents that we refer to as this sphingosine-1-phosphate receptor modulators, S1P agents, there has long been data that these receptors are expressed on all cells, including all of the neural cells, and there is existing data that S1P modulators can affect the function of glial cells. Now how this translates into effects that are clinically relevant is the challenge that's ongoing now.   MSDF How does all of this relate to progressive MS?   Dr. Antel So progressive MS, I believe, is an entity that we have not totally understood yet, and we have to consider it in its parts, namely is progressive MS reflective of ongoing injury to the myelinating cells or the underlying axons? Is this a reflection of the injured cells no longer able to maintain themselves are they metabolically failing? And that can we distinguish these processes because if it's ongoing immune injury – whether related to the adaptive or innate immune system – then it makes sense to target those process. If it's an injury or metabolic failure, then that would be another approach. I think we have to consider whether progressive MS, again has evolved over many, many years, and whether one of our challenges is reducing the initial injury process can avoid many of these long-term events.   MSDF In secondary progressive MS, do you see that there's sort of a tipping point? Is there something different in secondary progressive once that occurs?   Dr. Antel It's difficult to provide an answer, and I think here is an area particularly where careful clinical studies are guiding us that the initial notion that multiple events triggered a later process would have been a very nice system to have because then stopping a process early would have predicted a beneficial later response. We are struck that the clinical data is suggesting that progression can occur perhaps even in the absence of ongoing inflammation whether the two are dissociated, at least in some cases, is a real concern. And thus, just controlling the initial immune response – because it triggers a later event – may not be sufficient. And the reverse, which I think has received perhaps less attention, is that from the clinical perspective multiple people have multiple disabling acute events and do not develop the progressive process. So it is not clear that the two are absolutely linked; whether there are genetic susceptibility factors that determine this have not yet emerged; whether it's the nature of the injury; or whether we have multiple diseases processes.   MSDF We often think of bench-to-bedside as the pathway for advancements. Now you had told me earlier that you're working with people in the opposite direction; you're finding things in the human condition and then leading to laboratory validation. Can you tell me a little bit about that?   Dr. Antel I think this is a very important aspect and why it is important that the clinical and clinical pathology experts really identify the core issues so that they can be taken to a laboratory and experimentally addressed. That in MS, we're dealing with a disease that develops over months and years making it more difficult to model it precisely. It's a disease where we have not established the initiating event. Whereas in the animal system, we usually use a arbitrary antigen if we were going to model an immune mediated disorder. We model the demyelination/remyelination process usually by acute toxins in the animal systems; whereas this is not the case in MS that specific exposure. And so I think we need to continue to develop our model systems that can induce some type of progressive disorder that is not specifically introduced perhaps by a specific antigen, at least the antigens we use currently.   MSDF Knowing that remyelination is possible, is there an implication that it may be going on in all of us in healthy brain at all times where you actually get turnover? And if so, can you capitalize on this kind of system?   Dr. Antel So the issue of turnover of myelin, I think, has not been emphasized sufficiently until recently both from the perspective if we have continuous turnover whether this may be one of the mechanisms whereby antigens are presented to the immune system. The other in terms of the turnover rate of myelin or oligodendrocytes – whether the health of these cells is damaged by the disease process, and whether a limiting factor over time is that the injury of the cells, which could be quite subtle – so that the cells are not killed, but they've impaired their function either to maintain the interaction with axons or the necessary transport of key molecules down the processes. Whether interruption of this then results in the inability of the cells to maintain their myelination properties and to continue the turnover or what might be a repair activity. And we interpret this as a later progression of the disease.   MSDF On the topics we've been discussing, is there anything important to add?   Dr. Antel I think the importance is that we now are turning our attention to these topics. That it is very timely that we do this – because until we could control the actual disease activity through immunomodulatory therapies – if that aspect was not controlled it would be much more difficult to think of trying to control the overall disease process. And also, as we couple the biology with careful clinical observations and the advances in imaging of the human brain, so that it gives us greater opportunities to bring our theories from the lab to the clinics and see whether we really impact in a positive way on the processes we've been discussing.   MSDF Very good. We appreciate it.   Dr. Antel My pleasure.   [transition music]   MSDF Thank you for listening to Episode Eleven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]     Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]    

Oxidiertes “Low density Lipoprotein“ (LDL) trägt durch Aktivierung von vaskulären End othelzellen und Thrombozyten zum Fortschreiten der Atherosklerose bei. Da die durch milde oxidiertes LDL (mox-LDL) aktivierten Signalwege in Endothelzellen und Thrombozyten bisher nur unzureichend charakterisiert waren, wurden sie in dieser Arbeit näher untersucht. Weiterhin wurde ausgehend von der Beobachtung, daß es bei milder Oxidation von LDL zur Bildung von Lysophosphatidsäure (LPA) kommt, und daß LPA die spezifische Thrombozyten- aktivierende Substanz im milde oxidierten LDL ist, in dieser Arbeit in in vitro Modellen untersucht, ob LPA und das strukturell und funktionell verwandte Lysophospholipid Sphingosin- 1-Phosphat (S1P) Signalwege regulieren, die zur pathologischen Aktivierung von Thrombozyten und Endothelzellen beitragen. Als Modellsysteme wurden unter anderem die endotheliale Permeabilität und der Plättchen-“shape change“ herangezogen. Es konnte gezeigt werden, daß milde oxidiertes LDL und LPA sowohl in Endothelzellen als auch in Thrombozyten - über Membran-gebundene LPA-Rezeptoren - die GTPase Rho und deren Effektor- Molekül Rho-Kinase aktivieren. Rho-Kinase hemmt die Myosin Leichtketten Phosphatase, wodurch es zum Anstieg der Myosin Leichtketten Phosphorylierung kommt. Myosin Leichtketten Phosphorylierung führt (i) zur Kontraktion von Endothelzellen, die wiederum einen Anstieg der endothelialen Permeabilität auslöst, und (ii) zur Formveränderung (shape change) von Thrombozyten, dem ersten Anzeichen der Plättchen-Aktivierung. Das Lysophospholipid S1P dagegen induziert in Endothelzellen sequentiell (1) Rho/Rho-Kinase abhängige Myosin Leichtketten Phosphatase-Inaktivierung, Myosin Leichtketten Phosphorylierung und Endothelzellkontraktion, (2) Rac abhängige Myosin Leichtketten Phosphatase-Aktivierung, Ausbildung von “membrane ruffles“ und Endothelzellausbreitung und (3) erneute Rho/Rho- Kinase abhängige Myosin Leichtketten Phosphatase-Inaktivierung und Endothelzellkontraktion. Das durch S1P regulierte Wechselspiel zwischen Rho- und Rac-Aktivität und die dadurch regulierten Sequenzen von Zellkontraktion und -ausbreitung sind wahrscheinlich für die Endothelzellmigration im Rahmen von Angiogenese und Wundreparatur von Bedeutung. Den Lysophospholipiden könnte also eine wichtige Rolle in der Pathogenese der Atherosklerose und in der Regulation von Angiogenese und Wundreparatur zukommen. Die pharmakologische Hemmung des Rho/Rho-Kinase Signalweges könnte möglicherweise einen neuen Ansatzpunkt zur Behandlung der Atherosklerose darstellen.