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  1. Article ; Online: Chronotropic Incompetence During Exercise Testing as a Marker of Autonomic Dysfunction in Individuals with Early Parkinson's Disease.

    Griffith, Garett / Lamotte, Guillaume / Mehta, Niyati / Fan, Peng / Nikolich, Juliana / Springman, Victoria / Suttman, Erin / Joslin, Elizabeth / Balfany, Katherine / Dunlap, MacKenzie / Kohrt, Wendy M / Christiansen, Cory L / Melanson, Edward L / Josbeno, Deborah / Chahine, Lana M / Patterson, Charity G / Corcos, Daniel M

    Journal of Parkinson's disease

    2024  Volume 14, Issue 1, Page(s) 121–133

    Abstract: Background: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early ... ...

    Abstract Background: An attenuated heart rate response to exercise, termed chronotropic incompetence, has been reported in Parkinson's disease (PD). Chronotropic incompetence may be a marker of autonomic dysfunction and a cause of exercise intolerance in early stages of PD.
    Objective: To investigate the relationship between chronotropic incompetence, orthostatic blood pressure change (supine - standing), and exercise performance (maximal oxygen consumption, VO2peak) in individuals with early PD within 5 years of diagnosis not on dopaminergic medications.
    Methods: We performed secondary analyses of heart rate and blood pressure data from the Study in Parkinson's Disease of Exercise (SPARX).
    Results: 128 individuals were enrolled into SPARX (63.7±9.3 years; 57.0% male, 0.4 years since diagnosis [median]). 103 individuals were not taking chronotropic medications, of which 90 had a normal maximal heart rate response to exercise testing (155.3±14.0 bpm; PDnon-chrono) and 13 showed evidence of chronotropic incompetence (121.3±11.3 bpm; PDchrono, p < 0.05). PDchrono had decreased VO2peak compared to PDnon-chrono (19.7±4.5 mL/kg/min and 24.3±5.8 mL/kg/min, respectively, p = 0.027). There was a positive correlation between peak heart rate during exercise and the change in systolic blood pressure from supine to standing (r = 0.365, p < 0.001).
    Conclusions: A subgroup of individuals with early PD not on dopaminergic medication had chronotropic incompetence and decreased VO2peak, which may be related to autonomic dysfunction. Evaluation of both heart rate responses to incremental exercise and orthostatic vital signs may serve as biomarkers of early autonomic impairment and guide treatment. Further studies should investigate whether cardiovascular autonomic dysfunction affects the ability to exercise and whether exercise training improves autonomic dysfunction.
    MeSH term(s) Humans ; Male ; Female ; Exercise Test ; Parkinson Disease/complications ; Heart Failure ; Autonomic Nervous System Diseases/diagnosis ; Autonomic Nervous System Diseases/etiology ; Heart Rate/physiology
    Language English
    Publishing date 2024-02-04
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2620609-2
    ISSN 1877-718X ; 1877-7171
    ISSN (online) 1877-718X
    ISSN 1877-7171
    DOI 10.3233/JPD-230006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context.

    Joslin, Elizabeth J / Shankaran, Harish / Opresko, Lee K / Bollinger, Nikki / Lauffenburger, Douglas A / Wiley, H Steven

    Molecular bioSystems

    2010  Volume 6, Issue 7, Page(s) 1293–1306

    Abstract: Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ... ...

    Abstract Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a "non-binding" reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway.
    MeSH term(s) Cell Line ; Dose-Response Relationship, Drug ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/pharmacology ; Gefitinib ; Gene Regulatory Networks/drug effects ; Hepatocyte Growth Factor/pharmacology ; Humans ; Imidazoles/pharmacology ; Ligands ; Lysophospholipids/pharmacology ; Mammary Glands, Human/cytology ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Quinazolines/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Signal Transduction/physiology ; Transcriptional Activation/drug effects ; Transforming Growth Factor alpha/pharmacology
    Chemical Substances Flavonoids ; Imidazoles ; Ligands ; Lysophospholipids ; Pyridines ; Quinazolines ; Transforming Growth Factor alpha ; Hepatocyte Growth Factor (67256-21-7) ; ErbB Receptors (EC 2.7.10.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; SB 203580 (OU13V1EYWQ) ; lysophosphatidic acid (PG6M3969SG) ; Gefitinib (S65743JHBS) ; 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (SJE1IO5E3I)
    Language English
    Publishing date 2010-05-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2188635-0
    ISSN 1742-2051 ; 1742-206X
    ISSN (online) 1742-2051
    ISSN 1742-206X
    DOI 10.1039/c003921g
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: EGF-receptor-mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation

    Joslin, Elizabeth J / Opresko, Lee K / Wells, Alan / Wiley, H. Steven / Lauffenburger, Douglas A

    Journal of cell science. 2007 Oct. 15, v. 120, no. 20

    2007  

    Abstract: EGF family ligands are synthesized as membrane-anchored precursors whose proteolytic release yields mature diffusible factors that can activate cell surface receptors in autocrine or paracrine mode. Expression of these ligands is altered in pathological ... ...

    Abstract EGF family ligands are synthesized as membrane-anchored precursors whose proteolytic release yields mature diffusible factors that can activate cell surface receptors in autocrine or paracrine mode. Expression of these ligands is altered in pathological states and in physiological processes, such as development and tissue regeneration. Despite the widely documented biological importance of autocrine EGF signaling, quantitative relationships between protease-mediated ligand release and consequent cell behavior have not been rigorously investigated. We thus explored the relationship between autocrine EGF release rates and cell behavioral responses along with activation of ERK, a key downstream signal, by expressing chimeric ligand precursors and modulating their proteolytic shedding using a metalloprotease inhibitor in human mammary epithelial cells. We found that ERK activation increased monotonically with increasing ligand release rate despite concomitant downregulation of EGF receptor levels. Cell migration speed was directly related to ligand release rate and proportional to steady-state phospho-ERK levels. Moreover, migration speed was significantly greater for autocrine stimulation compared with exogenous stimulation, even at comparable phospho-ERK levels. By contrast, cell proliferation rates were approximately equivalent at all ligand release rates and were similar regardless of whether the ligand was presented endogenously or exogenously. Thus, in our mammary epithelial cell system, migration and proliferation are differentially sensitive to the mode of EGF ligand presentation.
    Language English
    Dates of publication 2007-1015
    Size p. 3688-3699.
    Publishing place The Company of Biologists Limited
    Document type Article
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Study in Parkinson's disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial.

    Patterson, Charity G / Joslin, Elizabeth / Gil, Alexandra B / Spigle, Wendy / Nemet, Todd / Chahine, Lana / Christiansen, Cory L / Melanson, Ed / Kohrt, Wendy M / Mancini, Martina / Josbeno, Deborah / Balfany, Katherine / Griffith, Garett / Dunlap, Mac Kenzie / Lamotte, Guillaume / Suttman, Erin / Larson, Danielle / Branson, Chantale / McKee, Kathleen E /
    Goelz, Li / Poon, Cynthia / Tilley, Barbara / Kang, Un Jung / Tansey, Malú Gámez / Luthra, Nijee / Tanner, Caroline M / Haus, Jacob M / Fantuzzi, Giamila / McFarland, Nikolaus R / Gonzalez-Latapi, Paulina / Foroud, Tatiana / Motl, Robert / Schwarzschild, Michael A / Simuni, Tanya / Marek, Kenneth / Naito, Anna / Lungu, Codrin / Corcos, Daniel M

    Trials

    2022  Volume 23, Issue 1, Page(s) 855

    Abstract: Background: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether ... ...

    Abstract Background: To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline.
    Methods: This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity.
    Discussion: SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health.
    Trial registration: ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.
    MeSH term(s) Antiparkinson Agents/therapeutic use ; Brain-Derived Neurotrophic Factor ; C-Reactive Protein ; Clinical Trials, Phase III as Topic ; Dopamine Plasma Membrane Transport Proteins/therapeutic use ; Exercise ; Exercise Therapy/methods ; Humans ; Multicenter Studies as Topic ; Parkinson Disease/diagnosis ; Parkinson Disease/drug therapy ; Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome
    Chemical Substances Antiparkinson Agents ; Brain-Derived Neurotrophic Factor ; Dopamine Plasma Membrane Transport Proteins ; C-Reactive Protein (9007-41-4)
    Language English
    Publishing date 2022-10-06
    Publishing country England
    Document type Clinical Trial Protocol ; Journal Article
    ZDB-ID 2040523-6
    ISSN 1745-6215 ; 1468-6694 ; 1745-6215
    ISSN (online) 1745-6215
    ISSN 1468-6694 ; 1745-6215
    DOI 10.1186/s13063-022-06703-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: EGF-receptor-mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation.

    Joslin, Elizabeth J / Opresko, Lee K / Wells, Alan / Wiley, H Steven / Lauffenburger, Douglas A

    Journal of cell science

    2007  Volume 120, Issue Pt 20, Page(s) 3688–3699

    Abstract: EGF family ligands are synthesized as membrane-anchored precursors whose proteolytic release yields mature diffusible factors that can activate cell surface receptors in autocrine or paracrine mode. Expression of these ligands is altered in pathological ... ...

    Abstract EGF family ligands are synthesized as membrane-anchored precursors whose proteolytic release yields mature diffusible factors that can activate cell surface receptors in autocrine or paracrine mode. Expression of these ligands is altered in pathological states and in physiological processes, such as development and tissue regeneration. Despite the widely documented biological importance of autocrine EGF signaling, quantitative relationships between protease-mediated ligand release and consequent cell behavior have not been rigorously investigated. We thus explored the relationship between autocrine EGF release rates and cell behavioral responses along with activation of ERK, a key downstream signal, by expressing chimeric ligand precursors and modulating their proteolytic shedding using a metalloprotease inhibitor in human mammary epithelial cells. We found that ERK activation increased monotonically with increasing ligand release rate despite concomitant downregulation of EGF receptor levels. Cell migration speed was directly related to ligand release rate and proportional to steady-state phospho-ERK levels. Moreover, migration speed was significantly greater for autocrine stimulation compared with exogenous stimulation, even at comparable phospho-ERK levels. By contrast, cell proliferation rates were approximately equivalent at all ligand release rates and were similar regardless of whether the ligand was presented endogenously or exogenously. Thus, in our mammary epithelial cell system, migration and proliferation are differentially sensitive to the mode of EGF ligand presentation.
    MeSH term(s) ADAM Proteins/metabolism ; Autocrine Communication ; Cell Line ; Cell Movement ; Epithelial Cells/physiology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Ligands ; MAP Kinase Signaling System ; Mammary Glands, Human/cytology ; Phosphorylation ; Receptor, Epidermal Growth Factor/metabolism
    Chemical Substances Ligands ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; ADAM Proteins (EC 3.4.24.-)
    Language English
    Publishing date 2007-10-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.010488
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1200: Show issues Location:
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    Zs.MG 14: Show issues

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  6. Article: Ligand accumulation in autocrine cell cultures.

    Monine, Michael I / Berezhkovskii, Alexander M / Joslin, Elizabeth J / Wiley, H Steven / Lauffenburger, Douglas A / Shvartsman, Stanislav Y

    Biophysical journal

    2005  Volume 88, Issue 4, Page(s) 2384–2390

    Abstract: Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and analysis of experiments with autocrine cells, we develop a biophysical theory of ligand ...

    Abstract Cell-culture assays are routinely used to analyze autocrine signaling systems, but quantitative experiments are rarely possible. To enable the quantitative design and analysis of experiments with autocrine cells, we develop a biophysical theory of ligand accumulation in cell-culture assays. Our theory predicts the ligand concentration as a function of time and measurable parameters of autocrine cells and cell-culture experiments. The key step of our analysis is the derivation of the survival probability of a single ligand released from the surface of an autocrine cell. An expression for this probability is derived using the boundary homogenization approach and tested by stochastic simulations. We use this expression in the integral balance equations, from which we find the Laplace transform of the ligand concentration. We demonstrate how the theory works by analyzing the autocrine epidermal growth factor receptor system and discuss the extension of our methods to other experiments with cultured autocrine cells.
    MeSH term(s) Autocrine Communication ; Biological Transport ; Biophysics/methods ; Breast/cytology ; Cell Culture Techniques ; Cells, Cultured/cytology ; Culture Media/chemistry ; Enzyme-Linked Immunosorbent Assay ; Epidermal Growth Factor/metabolism ; Epithelial Cells/cytology ; Humans ; Kinetics ; Ligands ; Models, Biological ; Models, Theoretical ; Nitric Oxide/chemistry ; Physiological Phenomena ; Receptor, Epidermal Growth Factor/metabolism ; Time Factors
    Chemical Substances Culture Media ; Ligands ; Nitric Oxide (31C4KY9ESH) ; Epidermal Growth Factor (62229-50-9) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
    Language English
    Publishing date 2005-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1529/biophysj.104.051425
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    Zs.MO 2: Show issues

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