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  1. Article: Pregabalin as a Pain Therapeutic: Beyond Calcium Channels.

    Alles, Sascha R A / Cain, Stuart M / Snutch, Terrance P

    Frontiers in cellular neuroscience

    2020  Volume 14, Page(s) 83

    Abstract: Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin ("gabapentinoids") were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA ... ...

    Abstract Initially developed to generate new treatments for epilepsy, gabapentin, and pregabalin ("gabapentinoids") were engineered to mimic the action of GABA and to modulate GABA metabolism. Rather than their intended pharmacological action on GABA neurotransmission, instead, they exhibit a high affinity for the α2δ-1 and α2δ-2 subunits of voltage-activated calcium channels, wherein binding of gabapentinoids inhibits cellular calcium influx and attenuates neurotransmission. Despite a lack of activity on GABA levels, gabapentin and pregabalin are effective at suppressing seizures and subsequently approved as a new class of antiepileptic therapy for partial-onset epilepsy. Through the same hypothesized molecular mechanism and by controlling neuronal hyperexcitability, gabapentinoids demonstrate clear efficacy in pain management, which has arguably been their most extensively prescribed application to date. In this review, we focus on pregabalin as a second-generation gabapentinoid widely employed in the treatment of a variety of pain conditions. We also discuss the wider functional roles of α2δ subunits and the contributions that pregabalin might play in affecting physiological and pathophysiological processes.
    Language English
    Publishing date 2020-04-15
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2020.00083
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  2. Article ; Online: Latent TGFβ complexes are transglutaminase cross-linked to fibrillin to facilitate TGFβ activation.

    Lockhart-Cairns, Michael P / Cain, Stuart A / Dajani, Rana / Steer, Ruth / Thomson, Jennifer / Alanazi, Yasmene F / Kielty, Cay M / Baldock, Clair

    Matrix biology : journal of the International Society for Matrix Biology

    2022  Volume 107, Page(s) 24–39

    Abstract: TGFβ superfamily members are potent growth factors in the extracellular matrix with essential roles in all aspects of cellular behaviour. Latent TGFβ binding proteins (LTBPs) are co-expressed with TGFβ, essential for correct folding and secretion of the ... ...

    Abstract TGFβ superfamily members are potent growth factors in the extracellular matrix with essential roles in all aspects of cellular behaviour. Latent TGFβ binding proteins (LTBPs) are co-expressed with TGFβ, essential for correct folding and secretion of the growth factor, to form large latent complexes. These large latent complexes bind extracellular proteins such as fibrillin for sequestration of TGFβ in the matrix, essential for normal tissue function, and dysregulated TGFβ signalling is a hallmark of many fibrillinopathies. Transglutaminase-2 (TG2) cross-linking of LTBPs is known to play a role in TGFβ activation but the underlying molecular mechanisms are not resolved. Here we show that fibrillin is a matrix substrate for TG2 and that TG2 cross-linked complexes can be formed between fibrillin and LTBP-1 and -3, and their latent TGFβ complexes. The structure of the fibrillin-LTBP1 complex shows that the two elongated proteins interact in a perpendicular arrangement which would allow them to form distal interactions between the matrix and the cell surface. Formation of the cross-link with fibrillin does not change the interaction between latent TGFβ and integrin αVβ6 but does increase TGFβ activation in cell-based assays. The activating effect may be due to direction of the latent complexes to the cell surface by fibrillin, as competition with heparan sulphate can ameliorate the activating effect. Together, these data support that TGFβ activation can be enhanced by covalent tethering of LTBPs to the matrix via fibrillin.
    MeSH term(s) Extracellular Matrix/metabolism ; Fibrillin-1/genetics ; Fibrillin-1/metabolism ; Fibrillin-2/metabolism ; Fibrillins/metabolism ; Latent TGF-beta Binding Proteins/genetics ; Latent TGF-beta Binding Proteins/metabolism ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Transforming Growth Factor beta/metabolism ; Transglutaminases/genetics ; Transglutaminases/metabolism
    Chemical Substances Fibrillin-1 ; Fibrillin-2 ; Fibrillins ; Latent TGF-beta Binding Proteins ; Microfilament Proteins ; Transforming Growth Factor beta ; Transglutaminases (EC 2.3.2.13)
    Language English
    Publishing date 2022-02-03
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1183793-7
    ISSN 1569-1802 ; 0945-053X
    ISSN (online) 1569-1802
    ISSN 0945-053X
    DOI 10.1016/j.matbio.2022.01.005
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  3. Article ; Online: The clinical educator's guide to fostering learner motivation: AMEE Guide No. 137.

    Lyons, Kayley M / Cain, Jeff J / Haines, Stuart T / Gasevic, Danijela / Brock, Tina P

    Medical teacher

    2020  Volume 43, Issue 5, Page(s) 492–500

    Abstract: Motivation theory and research remain underused by health professions educators. Some educators say it can seem too abstract. To address this, we applied health care language to learner motivation theories. Using a familiar metaphor, we examined the ... ...

    Abstract Motivation theory and research remain underused by health professions educators. Some educators say it can seem too abstract. To address this, we applied health care language to learner motivation theories. Using a familiar metaphor, we examined the indications, mechanism of action, administration, and monitoring of learner motivation interventions. Similar to the treatment monographs in medicine compendia, we summarized each motivation intervention in the form of a monograph. The purpose of this guide is for health professions educators to develop an understanding of when (i.e. indication) and how (i.e. mechanism of action) learner motivation interventions work. With this information, they can then access ready-to-implement strategies (i.e. administration) to increase their learner interest and assess the effects of these interventions (i.e. monitoring).
    MeSH term(s) Health Occupations ; Humans ; Motivation
    Language English
    Publishing date 2020-11-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 424426-6
    ISSN 1466-187X ; 0142-159X
    ISSN (online) 1466-187X
    ISSN 0142-159X
    DOI 10.1080/0142159X.2020.1837764
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  4. Article ; Online: Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1.

    Cain, Stuart M / Alles, Sascha R A / Gopaul, Ray / Bernier, Louis-Philippe / Yung, Andrew C / Bauman, Andrew / Yang, Yi / Baker, Glen B / Kozlowski, Piotr / MacVicar, Brian A / Snutch, Terrance P

    Molecular brain

    2023  Volume 16, Issue 1, Page(s) 76

    Abstract: Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium ... ...

    Abstract Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Ca
    MeSH term(s) Mice ; Animals ; Migraine with Aura/drug therapy ; Migraine with Aura/genetics ; Pregabalin/pharmacology ; Pregabalin/therapeutic use ; Migraine Disorders/drug therapy ; Migraine Disorders/genetics ; Mice, Transgenic ; Hippocampus
    Chemical Substances Pregabalin (55JG375S6M)
    Language English
    Publishing date 2023-11-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2436057-0
    ISSN 1756-6606 ; 1756-6606
    ISSN (online) 1756-6606
    ISSN 1756-6606
    DOI 10.1186/s13041-023-01062-6
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  5. Article ; Online: Extracellular Matrix Molecule-Based Capture of Mesenchymal Stromal Cells Under Flow.

    Massam-Wu, Teresa / Cain, Stuart A / Kielty, Cay M

    Methods in molecular biology (Clifton, N.J.)

    2017  Volume 1722, Page(s) 249–260

    Abstract: We present a method to capture mesenchymal stromal cells (MSCs) by adhesion to extracellular matrix (ECM) molecules under flow conditions. The technique simulates a physiological system and exploits the natural biological interactions of cells, through ... ...

    Abstract We present a method to capture mesenchymal stromal cells (MSCs) by adhesion to extracellular matrix (ECM) molecules under flow conditions. The technique simulates a physiological system and exploits the natural biological interactions of cells, through integrin receptors, with their ECM. The system offers an insight into how MSCs could be targeted/localized to the site of interest (graft) following intravenous injection.
    MeSH term(s) Cell Adhesion/physiology ; Cell Differentiation/physiology ; Cells, Immobilized/metabolism ; Extracellular Matrix/physiology ; Fibronectins/metabolism ; Flow Cytometry/methods ; Fluorescent Antibody Technique ; Humans ; Image Processing, Computer-Assisted ; Integrins/metabolism ; Laminin/metabolism ; Mesenchymal Stem Cells/classification ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Microscopy, Video ; RNA ; Single-Cell Analysis
    Chemical Substances Fibronectins ; Integrins ; Laminin ; RNA (63231-63-0)
    Language English
    Publishing date 2017-05-23
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-7553-2_16
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  6. Article: Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

    Allen, Kevin J H / Kwon, Ohyun / Hutcheson, Matthew R / Grudzinski, Joseph J / Cain, Stuart M / Cruz, Frederic A / Vinayakamoorthy, Remitha M / Sun, Ying S / Fairley, Lindsay / Prabaharan, Chandra B / Dickinson, Ryan / MacDonald-Dickinson, Valerie / Uppalapati, Maruti / Bednarz, Bryan P / Dadachova, Ekaterina

    Pharmaceuticals (Basel, Switzerland)

    2023  Volume 16, Issue 7

    Abstract: Background: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we ... ...

    Abstract Background: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS.
    Methods: [
    Results: PET/CT revealed that only the liver, bone marrow, and adrenal glands had high uptake. Clearance was initially through renal and hepatobiliary excretion in the first 72 h followed by primarily physical decay. RAPID analysis showed bone marrow to be the dose-limiting organ with a therapeutic range for
    Conclusions: Image-based dosimetry has defined a safe therapeutic range for canine clinical trials, while immunohistochemistry has suggested that the antibody will not cross-react with healthy human tissues.
    Language English
    Publishing date 2023-07-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16070979
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  7. Article ; Online: Hyperexcitable superior colliculus and fatal brainstem spreading depolarization in a model of Sudden Unexpected Death in Epilepsy.

    Cain, Stuart M / Bernier, Louis-Philippe / Zhang, Yiming / Yung, Andrew C / Kass, Jennifer / Bohnet, Barry / Yang, Yi / Gopaul, Rayshad / Kozlowski, Piotr / MacVicar, Brian A / Snutch, Terrance P

    Brain communications

    2022  Volume 4, Issue 2, Page(s) fcac006

    Abstract: Cardiorespiratory arrest and death in mouse models of sudden unexpected death in epilepsy occur when spreading depolarization is triggered by cortical seizures and then propagates to the brainstem. However, the critical brain regions and the specific ... ...

    Abstract Cardiorespiratory arrest and death in mouse models of sudden unexpected death in epilepsy occur when spreading depolarization is triggered by cortical seizures and then propagates to the brainstem. However, the critical brain regions and the specific changes required to allow spreading depolarization to propagate to the brainstem under the relatively rare circumstances leading to a fatal seizure are unknown. We previously found that following cortical seizure-inducing electrical stimulation, spreading depolarization could occur in both the superior and inferior colliculi in Cacna1a
    Language English
    Publishing date 2022-01-19
    Publishing country England
    Document type Journal Article
    ISSN 2632-1297
    ISSN (online) 2632-1297
    DOI 10.1093/braincomms/fcac006
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  8. Article ; Online: The type 1 cannabinoid receptor positive allosteric modulators GAT591 and GAT593 reduce spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg.

    McElroy, Dan L / Roebuck, Andrew J / Greba, Quentin / Garai, Sumanta / Brandt, Asher L / Yilmaz, Orhan / Cain, Stuart M / Snutch, Terrance P / Thakur, Ganesh A / Laprairie, Robert B / Howland, John G

    IBRO neuroscience reports

    2022  Volume 12, Page(s) 121–130

    Abstract: Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current ... ...

    Abstract Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS.
    Language English
    Publishing date 2022-01-24
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2667-2421
    ISSN (online) 2667-2421
    DOI 10.1016/j.ibneur.2022.01.006
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  9. Article: T-type calcium channels in burst-firing, network synchrony, and epilepsy.

    Cain, Stuart M / Snutch, Terrance P

    Biochimica et biophysica acta

    2013  Volume 1828, Issue 7, Page(s) 1572–1578

    Abstract: Low voltage-activated (LVA) T-type calcium channels are well regarded as a key mechanism underlying the generation of neuronal burst-firing. Their low threshold for activation combined with a rapid and transient calcium conductance generates low- ... ...

    Abstract Low voltage-activated (LVA) T-type calcium channels are well regarded as a key mechanism underlying the generation of neuronal burst-firing. Their low threshold for activation combined with a rapid and transient calcium conductance generates low-threshold calcium potentials (LTCPs), upon the crest of which high frequency action potentials fire for a brief period. Experiments using simultaneous electroencephalography (EEG) and intracellular recordings demonstrate that neuronal burst-firing is a likely causative component in the generation of normal sleep patterns as well as some pathophysiological conditions, such as epileptic seizures. However, less is known as to how these neuronal bursts impact brain behavior, in particular network synchronization. In this review we summarize recent findings concerning the role of T-type calcium channels in burst-firing and discuss how they likely contribute to the generation of network synchrony. We further outline the function of burst-firing and network synchrony in terms of epileptic seizures. This article is part of a Special Issue entitled: Calcium channels.
    MeSH term(s) Action Potentials/physiology ; Animals ; Calcium/metabolism ; Calcium Channels, T-Type/physiology ; Epilepsy, Absence/physiopathology ; Humans ; Nerve Net/physiology
    Chemical Substances Calcium Channels, T-Type ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2013-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamem.2012.07.028
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  10. Article: Generation of Human Mesenchymal Stem Cell 3D Spheroids Using Low-binding Plates.

    Redondo-Castro, Elena / Cunningham, Catriona J / Miller, Jonjo / Cain, Stuart A / Allan, Stuart M / Pinteaux, Emmanuel

    Bio-protocol

    2018  Volume 8, Issue 16

    Abstract: The 3D culture of human mesenchymal stem cells (hMSCs) represents a more physiological environment than classical 2D culture and has been used to enhance the MSC secretome or extend cell survival after transplantation. Here we describe a simple and ... ...

    Abstract The 3D culture of human mesenchymal stem cells (hMSCs) represents a more physiological environment than classical 2D culture and has been used to enhance the MSC secretome or extend cell survival after transplantation. Here we describe a simple and affordable method to generate 3D spheroids of hMSCs by seeding them at high density in a low-binding 96-well plate. Spheroids of hMSCs cultured in low-binding 96-well plates can be used to study the basic biology of the cells and to generate conditioned media or spheroids to be used in transplantation therapeutic approaches. These MSCs or their secretome can be used as a regenerative therapy and for tissue repair across multiple disease areas, including neurodegeneration. In comparison to other methods (hanging drop, use of gels or biomaterials, magnetic levitation,
    Language English
    Publishing date 2018-10-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2833269-6
    ISSN 2331-8325
    ISSN 2331-8325
    DOI 10.21769/BioProtoc.2968
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