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  1. Article ; Online: Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain

    Tuoxin Cao / Jessica J. Matyas / Cynthia L. Renn / Alan I. Faden / Susan G. Dorsey / Junfang Wu

    Cells, Vol 9, Iss 1194, p

    2020  Volume 1194

    Abstract: Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, ... ...

    Abstract Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.
    Keywords tyrosine receptor kinase B (TrkB) ; TrkB.T1 ; brain-derived neurotrophic factor (BDNF) ; astrocytes ; neuropathic pain ; spinal cord injury ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Racial/ethnic differences in experimental pain sensitivity and associated factors - Cardiovascular responsiveness and psychological status.

    Hee Jun Kim / Joel D Greenspan / Richard Ohrbach / Roger B Fillingim / William Maixner / Cynthia L Renn / Meg Johantgen / Shijun Zhu / Susan G Dorsey

    PLoS ONE, Vol 14, Iss 4, p e

    2019  Volume 0215534

    Abstract: This study evaluated the contributions of psychological status and cardiovascular responsiveness to racial/ethnic differences in experimental pain sensitivity. The baseline measures of 3,159 healthy individuals-non-Hispanic white (NHW): 1,637, African- ... ...

    Abstract This study evaluated the contributions of psychological status and cardiovascular responsiveness to racial/ethnic differences in experimental pain sensitivity. The baseline measures of 3,159 healthy individuals-non-Hispanic white (NHW): 1,637, African-American (AA): 1,012, Asian: 299, and Hispanic: 211-from the OPPERA prospective cohort study were used. Cardiovascular responsiveness measures and psychological status were included in structural equation modeling based mediation analyses. Pain catastrophizing was a significant mediator for the associations between race/ethnicity and heat pain tolerance, heat pain ratings, heat pain aftersensations, mechanical cutaneous pain ratings and aftersensations, and mechanical cutaneous pain temporal summation for both Asians and AAs compared to NHWs. HR/MAP index showed a significant inconsistent (mitigating) mediating effect on the association between race/ethnicity (AAs vs. NHWs) and heat pain tolerance. Similarly, coping inconsistently mediated the association between race/ethnicity and mechanical cutaneous pain temporal summation in both AAs and Asians, compared to NHWs. The factor encompassing depression, anxiety, and stress was a significant mediator for the associations between race/ethnicity (Asians vs. NHWs) and heat pain aftersensations. Thus, while pain catastrophizing mediated racial/ethnic differences in many of the QST measures, the psychological and cardiovascular mediators were distinctly restrictive, signifying multiple independent mechanisms in racial/ethnic differences in pain.
    Keywords Medicine ; R ; Science ; Q
    Subject code 150
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Whole blood transcriptomic profiles can differentiate vulnerability to chronic low back pain.

    Susan G Dorsey / Cynthia L Renn / Mari Griffioen / Cameron B Lassiter / Shijun Zhu / Heather Huot-Creasy / Carrie McCracken / Anup Mahurkar / Amol C Shetty / Colleen K Jackson-Cook / Hyungsuk Kim / Wendy A Henderson / Leorey Saligan / Jessica Gill / Luana Colloca / Debra E Lyon / Angela R Starkweather

    PLoS ONE, Vol 14, Iss 5, p e

    2019  Volume 0216539

    Abstract: The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. ...

    Abstract The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Susceptibility of different mouse strains to oxaliplatin peripheral neurotoxicity

    Paola Marmiroli / Beatrice Riva / Eleonora Pozzi / Elisa Ballarini / Dmitry Lim / Alessia Chiorazzi / Cristina Meregalli / Carla Distasi / Cynthia L Renn / Sara Semperboni / Lavinia Morosi / Federico A Ruffinatti / Massimo Zucchetti / Susan G Dorsey / Guido Cavaletti / Armando Genazzani / Valentina A Carozzi

    PLoS ONE, Vol 12, Iss 10, p e

    Phenotypic and genotypic insights.

    2017  Volume 0186250

    Abstract: Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co- ... ...

    Abstract Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Bordetella pertussis infection exacerbates influenza virus infection through pertussis toxin-mediated suppression of innate immunity.

    Victor I Ayala / John R Teijaro / Donna L Farber / Susan G Dorsey / Nicholas H Carbonetti

    PLoS ONE, Vol 6, Iss 4, p e

    2011  Volume 19016

    Abstract: Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on subsequent influenza virus (PR8) infection in mouse models and the role of pertussis ... ...

    Abstract Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on subsequent influenza virus (PR8) infection in mouse models and the role of pertussis toxin (PT) in this effect. BALB/c mice infected with a wild-type strain of B. pertussis (WT) and subsequently (up to 14 days later) infected with PR8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice similarly infected with a PT-deficient mutant strain (ΔPT) and PR8. Substitution of WT infection by intranasal treatment with purified active PT was sufficient to replicate the exacerbating effects on PR8 infection in BALB/c and C57/BL6 mice, but the effects of PT were lost when toxin was administered 24 h after virus inoculation. PT had no effect on virus titers in primary cultures of murine tracheal epithelial cells (mTECs) in vitro, suggesting the toxin targets an early immune response to increase viral titers in the mouse model. However, type I interferon responses were not affected by PT. Whole genome microarray analysis of gene expression in lung tissue from PT-treated and control PR8-infected mice at 12 and 36 h post-virus inoculation revealed that PT treatment suppressed numerous genes associated with communication between innate and adaptive immune responses. In mice depleted of alveolar macrophages, increase of pulmonary viral titers by PT treatment was lost. PT also suppressed levels of IL-1β, IL-12, IFN-γ, IL-6, KC, MCP-1 and TNF-α in the airways after PR8 infection. Furthermore PT treatment inhibited early recruitment of neutrophils and NK cells to the airways. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated influenza infection by countering protective innate immune responses that control virus titers.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2011-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Bortezomib-induced painful peripheral neuropathy

    Valentina A Carozzi / Cynthia L Renn / Michela Bardini / Grazia Fazio / Alessia Chiorazzi / Cristina Meregalli / Norberto Oggioni / Kathleen Shanks / Marina Quartu / Maria Pina Serra / Barbara Sala / Guido Cavaletti / Susan G Dorsey

    PLoS ONE, Vol 8, Iss 9, p e

    an electrophysiological, behavioral, morphological and mechanistic study in the mouse.

    2013  Volume 72995

    Abstract: Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as other hematological and solid neoplasms. Peripheral neurological complications manifesting with ... ...

    Abstract Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as other hematological and solid neoplasms. Peripheral neurological complications manifesting with paresthesias, burning sensations, dysesthesias, numbness, sensory loss, reduced proprioception and vibratory sensitivity are among the major limiting side effects associated with bortezomib therapy. Although bortezomib-induced painful peripheral neuropathy is clinically easy to diagnose and reliable models are available, its pathophysiology remains partly unclear. In this study we used well-characterized immune-competent and immune-compromised mouse models of bortezomib-induced painful peripheral neuropathy. To characterize the drug-induced pathological changes in the peripheral nervous system, we examined the involvement of spinal cord neuronal function in the development of neuropathic pain and investigated the relevance of the immune response in painful peripheral neuropathy induced by bortezomib. We found that bortezomib treatment induced morphological changes in the spinal cord, dorsal roots, dorsal root ganglia (DRG) and peripheral nerves. Neurophysiological abnormalities and specific functional alterations in Aδ and C fibers were also observed in peripheral nerve fibers. Mice developed mechanical allodynia and functional abnormalities of wide dynamic range neurons in the dorsal horn of spinal cord. Bortezomib induced increased expression of the neuronal stress marker activating transcription factor-3 in most DRG. Moreover, the immunodeficient animals treated with bortezomib developed a painful peripheral neuropathy with the same features observed in the immunocompetent mice. In conclusion, this study extends the knowledge of the sites of damage induced in the nervous system by bortezomib administration. Moreover, a selective functional vulnerability of peripheral nerve fiber subpopulations was found as well as a change in the electrical activity of wide ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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