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http://www.ncbi.nlm.nih.gov/pubmed/17644068
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1. Biochem Biophys Res Commun. 2007 Sep 14;361(1):146-50. doi:
10.1016/j.bbrc.2007.06.183. Epub 2007 Jul 17.
Polarization of endosomal SNX27 in migrating and tumor-engaged natural killer
cells.
MacNeil AJ(1), Pohajdak B.
Author information:
(1)Department of Biology, Dalhousie University, 1355 Oxford Street, Halifax, NS,
Canada B3H 4J1.
Polarization is a critical mechanism for the proper functioning of many cell
types. For lymphocytes, it is essential in a variety of processes, including
migration from the blood to other tissue sites and vice versa. In NK cells and
CTLs, the cytotoxic granule delivery mechanism requires polarization for granule
movement to the immunological synapse (IS), in killing tumor and virus-infected
cells. Recently, it has become apparent that endosomes are also involved in the
cytotoxic mechanism. Using an in vitro conjugation approach, we show that in
NK-92 cells, endosomal Sorting Nexin 27 (SNX27) polarizes to the IS during tumor
cell engagement in a distinct compartment adjacent to the cytotoxic granules. We
also show that SNX27 polarizes to the apical membrane, opposite the uropod,
during NK cell migration. These previously unreported results indicate that
SNX27 is a participant in NK cell polarization, as a mediator or target of the
mechanism.
DOI: 10.1016/j.bbrc.2007.06.183
PMID: 17644068 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22539860
|
1. J Neurosci. 2012 Apr 25;32(17):6000-13. doi: 10.1523/JNEUROSCI.5347-11.2012.
The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the
mammalian CNS.
Holmseth S(1), Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN,
Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC.
Author information:
(1)Centre for Molecular Biology and Neuroscience, Department of Anatomy,
Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
The extracellular levels of excitatory amino acids are kept low by the action of
the glutamate transporters. Glutamate/aspartate transporter (GLAST) and
glutamate transporter-1 (GLT-1) are the most abundant subtypes and are essential
for the functioning of the mammalian CNS, but the contribution of the EAAC1
subtype in the clearance of synaptic glutamate has remained controversial,
because the density of this transporter in different tissues has not been
determined. We used purified EAAC1 protein as a standard during immunoblotting
to measure the concentration of EAAC1 in different CNS regions. The highest
EAAC1 levels were found in the young adult rat hippocampus. Here, the
concentration of EAAC1 was ∼0.013 mg/g tissue (∼130 molecules μm⁻³), 100 times
lower than that of GLT-1. Unlike GLT-1 expression, which increases in parallel
with circuit formation, only minor changes in the concentration of EAAC1 were
observed from E18 to adulthood. In hippocampal slices, photolysis of
MNI-D-aspartate (4-methoxy-7-nitroindolinyl-D-aspartate) failed to elicit
EAAC1-mediated transporter currents in CA1 pyramidal neurons, and D-aspartate
uptake was not detected electron microscopically in spines. Using EAAC1
knock-out mice as negative controls to establish antibody specificity, we show
that these relatively small amounts of EAAC1 protein are widely distributed in
somata and dendrites of all hippocampal neurons. These findings raise new
questions about how so few transporters can influence the activation of NMDA
receptors at excitatory synapses.
DOI: 10.1523/JNEUROSCI.5347-11.2012
PMCID: PMC4031369
PMID: 22539860 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21300787
|
1. Mol Cell Biol. 2011 Apr;31(8):1734-47. doi: 10.1128/MCB.01044-10. Epub 2011
Feb 7.
Deficiency of sorting nexin 27 (SNX27) leads to growth retardation and elevated
levels of N-methyl-D-aspartate receptor 2C (NR2C).
Cai L(1), Loo LS, Atlashkin V, Hanson BJ, Hong W.
Author information:
(1)Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673,
Singapore.
Phox (PX) domain-containing sorting nexins (SNXs) are emerging as important
regulators of endocytic trafficking. Sorting nexin 27 (SNX27) is unique, as it
contains a PDZ (Psd-95/Dlg/ZO1) domain. We show here that SNX27 is primarily
targeted to the early endosome by interaction of its PX domain with PtdIns(3)P.
Although targeted ablation of the SNX27 gene in mice did not significantly
affect growth and survival during embryonic development, SNX27 plays an
essential role in postnatal growth and survival. N-Methyl-d-aspartate (NMDA)
receptor 2C (NR2C) was identified as a novel SNX27-interacting protein, and this
interaction is mediated by the PDZ domain of SNX27 and the C-terminal
PDZ-binding motif of NR2C. Increased NR2C expression levels, together with
impaired NR2C endocytosis in SNX27(-/-) neurons, indicate that SNX27 may
function to regulate endocytosis and/or endosomal sorting of NR2C. This is
consistent with a role of SNX27 as a general regulator for sorting of membrane
proteins containing a PDZ-binding motif, and its absence may alter the
trafficking of these proteins, leading to growth and survival defects.
DOI: 10.1128/MCB.01044-10
PMCID: PMC3126336
PMID: 21300787 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25196144
|
1. J Neurochem. 2014 Dec;131(5):573-81. doi: 10.1111/jnc.12942. Epub 2014 Sep 26.
Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases
sensitivity to kainic acid.
Shih J(1), Liu L, Mason A, Higashimori H, Donmez G.
Author information:
(1)Department of Neuroscience, Tufts University School of Medicine, Boston,
Massachusetts, USA; Neuroscience Program, Tufts University Sackler School of
Biomedical Sciences, Boston, Massachusetts, USA.
Glutamate transport is a critical process in the brain that maintains low
extracellular levels of glutamate to allow for efficient neurotransmission and
prevent excitotoxicity. Loss of glutamate transport function is implicated in
epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains
unclear whether or not glutamate transport can be modulated in these disease
conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a
mitochondrial sirtuin, is up-regulated in response to treatment with the potent
excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic
acid and decreased glutamate transporter expression and function in the brain.
Together, these results indicate a critical and novel stress response role for
SIRT4 in promoting proper glutamate transport capacity and protecting against
excitotoxicity.
© 2014 International Society for Neurochemistry.
DOI: 10.1111/jnc.12942
PMID: 25196144 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17351151
|
1. Mol Cell Proteomics. 2007 Jun;6(6):1073-87. doi: 10.1074/mcp.M700047-MCP200.
Epub 2007 Mar 9.
Proteomics identification of sorting nexin 27 as a diacylglycerol kinase
zeta-associated protein: new diacylglycerol kinase roles in endocytic recycling.
Rincón E(1), Santos T, Avila-Flores A, Albar JP, Lalioti V, Lei C, Hong W,
Mérida I.
Author information:
(1)Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC,
E-28049 Madrid, Spain.
Diacylglycerol kinase zeta is a member of the diacylglycerol kinase family of
enzymes, which generate phosphatidic acid through diacylglycerol
phosphorylation. In addition to the catalytic and cysteine-rich domains found in
all diacylglycerol kinases, diacylglycerol kinase zeta has a MARCKS domain as
well as a C-terminal region containing four ankyrin repeats and a PDZ-binding
motif. Previous reports demonstrated that diacylglycerol kinase zeta interaction
with several proteins is an important mechanism for modulating the localization
and activity of this enzyme. Here we used a proteomics approach to search for
novel diacylglycerol kinase zeta-interacting proteins and identified sorting
nexin 27 (SNX27), a recently described member of a protein family involved in
intracellular trafficking, which has a PDZ domain in addition to the phox
homology domain characteristic of SNX proteins. Co-immunoprecipitation studies
and two-hybrid analysis confirmed physical, PDZ-dependent association between
SNX27 and diacylglycerol kinase zeta. Because diacylglycerol kinase zeta is
expressed abundantly in T lymphocytes, we characterized SNX27 expression and
subcellular localization in these cells. SNX27 co-localized with transferrin
receptor-positive vesicles, pointing to its participation in T cell endocytic
recycling. Expression of deletion mutants revealed that in addition to the phox
homology domain the SNX27 PDZ domain contributed to vesicle localization of this
protein, suggesting that interaction with diacylglycerol kinase zeta regulates
SNX27 localization. Analysis of cells with RNA interference-mediated knockdown
of diacylglycerol kinase zeta showed accelerated transferrin receptor exit from
the lymphocyte endocytic recycling compartment back to the plasma membrane,
further confirming diacylglycerol kinase zeta-dependent control of vesicle
trafficking. These data support a previously unreported role for diacylglycerol
kinase zeta in the modulation of membrane trafficking, which may also help to
define SNX27 function.
DOI: 10.1074/mcp.M700047-MCP200
PMID: 17351151 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17828261
|
1. Nat Neurosci. 2007 Oct;10(10):1249-59. doi: 10.1038/nn1953. Epub 2007 Sep 2.
A unique sorting nexin regulates trafficking of potassium channels via a PDZ
domain interaction.
Lunn ML(1), Nassirpour R, Arrabit C, Tan J, McLeod I, Arias CM, Sawchenko PE,
Yates JR 3rd, Slesinger PA.
Author information:
(1)Peptide Biology Laboratory, The Salk Institute for Biological Studies, 10010
North Torrey Pines Rd., La Jolla, California 92037, USA.
G protein-gated potassium (Kir3) channels are important for controlling neuronal
excitability in the brain. Using a proteomics approach, we have identified a
unique rodent intracellular protein, sorting nexin 27 (SNX27), which regulates
the trafficking of Kir3 channels. Like most sorting nexins, SNX27 possesses a
functional PX domain that selectively binds the membrane phospholipid
phosphatidylinositol-3-phosphate (PI3P) and is important for trafficking to the
early endosome. SNX27, however, is the only sorting nexin to contain a PDZ
domain. This PDZ domain discriminates between channels with similar class I
PDZ-binding motifs, associating with the C-terminal end of Kir3.3 and Kir3.2c
(-ESKV), but not with that of Kir2.1 (-ESEI) or Kv1.4 (-ETDV). SNX27 promotes
the endosomal movement of Kir3 channels, leading to reduced surface expression,
increased degradation and smaller Kir3 potassium currents. The regulation of
endosomal trafficking via sorting nexins reveals a previously unknown mechanism
for controlling potassium channel surface expression.
DOI: 10.1038/nn1953
PMID: 17828261 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21602791
|
1. Nat Cell Biol. 2011 Jun;13(6):715-21. doi: 10.1038/ncb2252. Epub 2011 May 22.
SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking
of signalling receptors.
Temkin P(1), Lauffer B, Jäger S, Cimermancic P, Krogan NJ, von Zastrow M.
Author information:
(1)Department of Psychiatry, University of California at San Francisco, San
Francisco, California 94158, USA.
Endocytic sorting of signalling receptors between recycling and degradative
pathways is a key cellular process controlling the surface complement of
receptors and, accordingly, the cell's ability to respond to specific
extracellular stimuli. The β2 adrenergic receptor (β2AR) is a prototypical
seven-transmembrane signalling receptor that recycles rapidly and efficiently to
the plasma membrane after ligand-induced endocytosis. β2AR recycling is
dependent on the receptor's carboxy-terminal PDZ ligand and Rab4. This active
sorting process is required for functional resensitization of β2AR-mediated
signalling. Here we show that sequence-directed sorting occurs at the level of
entry into retromer tubules and that retromer tubules are associated with Rab4.
Furthermore, we show that sorting nexin 27 (SNX27) serves as an essential
adaptor protein linking β2ARs to the retromer tubule. SNX27 does not seem to
directly interact with the retromer core complex, but does interact with the
retromer-associated Wiskott-Aldrich syndrome protein and SCAR homologue (WASH)
complex. The present results identify a role for retromer in endocytic
trafficking of signalling receptors, in regulating a receptor-linked signalling
pathway, and in mediating direct endosome-to-plasma membrane traffic.
DOI: 10.1038/ncb2252
PMCID: PMC3113693
PMID: 21602791 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interest Statement The authors of this
paper declare no competing financial interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/9011758
|
1. Brain Res Mol Brain Res. 1996 Feb;36(1):189-92. doi:
10.1016/0169-328x(95)00297-6.
Expression of three glutamate transporter subtype mRNAs in human brain regions
and peripheral tissues.
Nakayama T(1), Kawakami H, Tanaka K, Nakamura S.
Author information:
(1)Third Department of Internal Medicine, Hiroshima University, School of
Medicine, Japan.
We compared the expression of mRNAs for three human glutamate transporter
subtypes in human central nervous system (CNS) and other organs by Northern blot
analysis. hGLT-1 and hGLuT-1 mRNAs were most abundantly expressed in the brain,
while hEAAC1 mRNA expression (3.8 kb and 2,4 kb) was strongest in peripheral
organs. All subtype mRNAs were expressed throughout the CNS with hGLT-1
predominant in frontal lobe, striatum and limbic areas, and hGluT-1 predominant
in cerebellum.
DOI: 10.1016/0169-328x(95)00297-6
PMID: 9011758 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23313319
|
1. Neurobiol Dis. 2013 Jun;54:206-15. doi: 10.1016/j.nbd.2012.12.013. Epub 2013
Jan 8.
Astrocyte GRK2 as a novel regulator of glutamate transport and brain damage.
Nijboer CH(1), Heijnen CJ, Degos V, Willemen HL, Gressens P, Kavelaars A.
Author information:
(1)Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD),
University Medical Center Utrecht, KC03.068.0, Lundlaan 6, 3584 EA, Utrecht, The
Netherlands. C.Nijboer@umcutrecht.nl
G protein-coupled receptor (GPCR) kinase 2 (GRK2) regulates cellular signaling
via desensitization of GPCRs and by direct interaction with intracellular
signaling molecules. We recently described that ischemic brain injury decreases
cerebral GRK2 levels. Here we studied the effect of astrocyte GRK2-deficiency on
neonatal brain damage in vivo. As astrocytes protect neurons by taking up
glutamate via plasma-membrane transporters, we also studied the effect of GRK2
on the localization of the GLutamate ASpartate Transporter (GLAST). Brain damage
induced by hypoxia-ischemia was significantly reduced in GFAP-GRK2(+/-) mice,
which have a 60% reduction in astrocyte GRK2 compared to GFAP-WT littermates. In
addition, GRK2-deficient astrocytes have higher plasma-membrane levels of GLAST
and an increased capacity to take up glutamate in vitro. In search for the
mechanism by which GRK2 regulates GLAST expression, we observed increased GFAP
levels in GRK2-deficient astrocytes. GFAP and the cytoskeletal protein ezrin are
known regulators of GLAST localization. In line with this evidence,
GRK2-deficiency reduced phosphorylation of the GRK2 substrate ezrin and enforced
plasma-membrane GLAST association after stimulation with the group I
mGluR-agonist DHPG. When ezrin was silenced, the enhanced plasma-membrane GLAST
association in DHPG-exposed GRK2-deficient astrocytes was prevented. In
conclusion, we identified a novel role of astrocyte GRK2 in regulating
plasma-membrane GLAST localization via an ezrin-dependent route. We demonstrate
that the 60% reduction in astrocyte GRK2 protein level that is observed in
GFAP-GRK2(+/-) mice is sufficient to significantly reduce neonatal ischemic
brain damage. These findings underline the critical role of GRK2 regulation in
astrocytes for dampening the extent of brain damage after ischemia.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2012.12.013
PMCID: PMC3628971
PMID: 23313319 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26099588
|
1. Infect Immun. 2015 Sep;83(9):3555-67. doi: 10.1128/IAI.00654-15. Epub 2015 Jun
22.
Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM L-Glutamate
ABC Transporter in Neisseria meningitidis Internalization into Human Brain
Microvascular Endothelial Cells.
Takahashi H(1), Yanagisawa T(2), Kim KS(3), Yokoyama S(2), Ohnishi M(4).
Author information:
(1)Department of Bacteriology I, National Institute of Infectious Diseases,
Tokyo, Japan hideyuki@nih.go.jp.
(2)RIKEN Structural Biology Laboratory, Tsurumi, Yokohama, Japan.
(3)Division of Pediatric Infectious Diseases, Department of Pediatrics, School
of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
(4)Department of Bacteriology I, National Institute of Infectious Diseases,
Tokyo, Japan.
We previously reported that Neisseria meningitidis internalization into human
brain microvasocular endothelial cells (HBMEC) was triggered by the influx of
extracellular L-glutamate via the GltT-GltM L-glutamate ABC transporter, but the
underlying mechanism remained unclear. We found that the ΔgltT ΔgltM invasion
defect in assay medium (AM) was alleviated in AM without 10% fetal bovine serum
(FBS) [AM(-S)]. The alleviation disappeared again in AM(-S) supplemented with
500 μM glutamate. Glutamate uptake by the ΔgltT ΔgltM mutant was less efficient
than that by the wild-type strain, but only upon HBMEC infection. We also
observed that both GltT-GltM-dependent invasion and accumulation of ezrin, a key
membrane-cytoskeleton linker, were more pronounced when N. meningitidis formed
larger colonies on HBMEC under physiological glutamate conditions. These results
suggested that GltT-GltM-dependent meningococcal internalization into HBMEC
might be induced by the reduced environmental glutamate concentration upon
infection. Furthermore, we found that the amount of glutathione within the ΔgltT
ΔgltM mutant was much lower than that within the wild-type N. meningitidis
strain only upon HBMEC infection and was correlated with intracellular survival.
Considering that the L-glutamate obtained via GltT-GltM is utilized as a
nutrient in host cells, l-glutamate uptake via GltT-GltM plays multiple roles in
N. meningitidis internalization into HBMEC.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
DOI: 10.1128/IAI.00654-15
PMCID: PMC4534661
PMID: 26099588 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15265858
|
1. J Biol Chem. 2004 Sep 17;279(38):39505-12. doi: 10.1074/jbc.M408038200. Epub
2004 Jul 20.
A trimeric quaternary structure is conserved in bacterial and human glutamate
transporters.
Gendreau S(1), Voswinkel S, Torres-Salazar D, Lang N, Heidtmann H, Detro-Dassen
S, Schmalzing G, Hidalgo P, Fahlke C.
Author information:
(1)Department of Molecular Pharmacology, Rheinisch-Westfälische Technische
Hochschule Aachen, 52057 Aachen, Germany.
Neuronal and glial glutamate transporters play a central role in the termination
of synaptic transmission and in extracellular glutamate homeostasis in the
mammalian central nervous system. They are known to be multimers; however, the
number of subunits forming a functional transporter is controversial. We studied
the subunit stoichiometry of two distantly related glutamate transporters, the
human glial glutamate transporter hEAAT2 and a bacterial glutamate transporter
from Escherichia coli, ecgltP. Using blue native polyacrylamide gel
electrophoresis, analysis of concatenated transporters, and chemical
cross-linking, we demonstrated that human and prokaryotic glutamate transporters
expressed in Xenopus laevis oocytes or in mammalian cells are assembled as
trimers composed of three identical subunits. In an inducible mammalian cell
line expressing hEAAT2 the glutamate uptake currents correlate to the amount of
trimeric transporters. Overexpression and purification of ecgltP in E. coli
resulted in a homogenous population of trimeric transporters that were
functional after reconstitution in lipid vesicles. Our results indicate that an
evolutionarily conserved trimeric quaternary structure represents the sole
native and functional state of glutamate transporters.
DOI: 10.1074/jbc.M408038200
PMID: 15265858 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23161123
|
1. Electrophoresis. 2013 Feb;34(3):397-400. doi: 10.1002/elps.201200380. Epub
2013 Jan 3.
Modified silver staining in 2DE improves protein detection even at extremely low
sample concentration.
Liew YK(1), Neela V, Hamat RA, Nordin SA, Chong PP.
Author information:
(1)Department of Medical Microbiology and Parasitology, Universiti Putra
Malaysia, Serdang, Malaysia.
The typical concentration of protein loaded varies from 0.13 to 1.40 μg/μL for a
classical silver staining method in 2DE gel. Here, we present a simple modified
classical silver staining method by modifying the silver impregnation and
development reaction steps. This modified method detects the protein spots at
extremely low loaded concentrations, ranging from 0.0048 to 0.0480 μg/μL. We
recommend this modified silver staining as an excellent method for the limited
biological samples used for silver-stained 2DE analysis. Altogether, the
protocol takes close to two days from first dimension separation to second
dimension separation, followed by silver staining, scanning, and analysis.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/elps.201200380
PMID: 23161123 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9614067
|
1. J Biol Chem. 1998 Jun 12;273(24):14698-706. doi: 10.1074/jbc.273.24.14698.
Identification of functional domains of the human glutamate transporters EAAT1
and EAAT2.
Mitrovic AD(1), Amara SG, Johnston GA, Vandenberg RJ.
Author information:
(1)Department of Pharmacology, University of Sydney, New South Wales 2006,
Australia.
Glutamate transporters serve the important function of mediating removal of
glutamate released at excitatory synapses and maintaining extracellular
concentrations below excitotoxic levels. Excitatory amino acid transporter
subtypes EAAT1 and EAAT2 have a high degree of sequence homology and similar
predicted topology and yet display a number of functional differences. Several
recombinant chimeric transporters were generated to identify domains that
contribute to functional differences between EAAT1 and EAAT2. Wild-type
transporters and chimeric transporters were expressed in Xenopus laevis oocytes,
and electrogenic transport was studied under voltage clamp conditions. The
differential sensitivity of EAAT1 and EAAT2 to transport blockers, kainate,
threo-3-methylglutamate, and (2S, 4R)-4-methylglutamate as well as
L-serine-O-sulfate transport and chloride permeability were employed to
characterize chimeric transporters. One particular region, transmembrane domains
9 and 10, plays an important role in defining these functional differences. The
intracellular carboxyl-terminal region may also play a minor role in conferring
an effect on chloride permeability. This study provides important insight into
the identification of functional domains that determine differences among
glutamate transporter subtypes.
DOI: 10.1074/jbc.273.24.14698
PMID: 9614067 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23536889
|
1. PLoS One. 2013;8(3):e59800. doi: 10.1371/journal.pone.0059800. Epub 2013 Mar
25.
Ras-association domain of sorting Nexin 27 is critical for regulating expression
of GIRK potassium channels.
Balana B(1), Bahima L, Bodhinathan K, Taura JJ, Taylor NM, Nettleton MY, Ciruela
F, Slesinger PA.
Author information:
(1)Peptide Biology Laboratories, The Salk Institute for Biological Studies, La
Jolla, California, United States of America.
G protein-gated inwardly rectifying potassium (GIRK) channels play an important
role in regulating neuronal excitability. Sorting nexin 27b (SNX27b), which
reduces surface expression of GIRK channels through a PDZ domain interaction,
contains a putative Ras-association (RA) domain with unknown function. Deleting
the RA domain in SNX27b (SNX27b-ΔRA) prevents the down-regulation of
GIRK2c/GIRK3 channels. Similarly, a point mutation (K305A) in the RA domain
disrupts regulation of GIRK2c/GIRK3 channels and reduces H-Ras binding in vitro.
Finally, the dominant-negative H-Ras (S17N) occludes the SNX27b-dependent
decrease in surface expression of GIRK2c/GIRK3 channels. Thus, the presence of a
functional RA domain and the interaction with Ras-like G proteins comprise a
novel mechanism for modulating SNX27b control of GIRK channel surface expression
and cellular excitability.
DOI: 10.1371/journal.pone.0059800
PMCID: PMC3607560
PMID: 23536889 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
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http://www.ncbi.nlm.nih.gov/pubmed/20855639
|
1. Am J Clin Pathol. 2010 Oct;134(4):586-93. doi: 10.1309/AJCP55KQYWSGZRKC.
Combination of an aptamer probe to CD4 and antibodies for multicolored cell
phenotyping.
Zhang P(1), Zhao N, Zeng Z, Chang CC, Zu Y.
Author information:
(1)Department of Pathology, The Methodist Hospital, Houston, TX 77030, USA.
Comment in
Am J Clin Pathol. 2010 Oct;134(4):529-31. doi: 10.1309/AJCPFU4CG2WGJJKS.
Aptamers have emerged as a new class of small molecule ligands. These short,
single-stranded oligonucleotides can be produced through simple chemical
synthesis, making them easier and less costly to produce than antibodies. We
synthesized an RNA aptamer probe specific for human CD4 using a reported
sequence and investigated the potential use of this probe in cell phenotyping.
Studies in cultured cells demonstrated that the synthetic CD4 aptamer had a
nearly identical cell-binding specificity as the standard CD4 antibody.
Fluorescent microscopy confirmed that the aptamer and antibody generated the
same CD4 staining pattern in cells without competing with one another.
Multicolored flow cytometry analysis revealed that the CD4 aptamer could be
combined with antibodies to phenotype cells from bone marrow, lymph nodes, and
pleural fluid, suggesting that the aptamer probe has value for clinical use.
DOI: 10.1309/AJCP55KQYWSGZRKC
PMID: 20855639 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18708826
|
1. Cardiol Rev. 2008 Sep-Oct;16(5):250-9. doi: 10.1097/CRD.0b013e3181804336.
Investigational antiplatelet drugs for the treatment and prevention of coronary
artery disease.
Zeidner JF(1), Frishman WH, Lerner RG.
Author information:
(1)Department of Medicine, Johns Hopkins School of Medicine/Johns Hopkins
Hospital, Baltimore, Maryland, USA.
Antiplatelet therapy for the prevention and treatment of coronary artery disease
(CAD) has undergone dramatic changes and improvements. Aspirin remains the
first-line antiplatelet drug for clinical use. Newer platelet inhibitors such as
the thienopyridine agents, ticlopidine and clopidogrel, have also been shown to
be effective in treating CAD. There have been ongoing efforts to evaluate newer
antiplatelet drugs, with the potential to improve clinical efficacy and safety.
Some of the more promising antiplatelet agents include new adenosine diphosphate
receptor antagonists such as prasugrel, cangrelor, and ticagrelor (AZD6140). In
addition, a new thromboxane receptor antagonist, NCX-4016, a newly discovered
protease-activated receptor antagonist that targets thrombin-induced platelet
aggregation, and anti-von Willebrand factor aptamers show tremendous promise in
refining antiplatelet therapy by targeting different receptors and molecules.
DOI: 10.1097/CRD.0b013e3181804336
PMID: 18708826 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20733053
|
1. J Cell Biol. 2010 Aug 23;190(4):565-74. doi: 10.1083/jcb.201004060.
SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane.
Lauffer BE(1), Melero C, Temkin P, Lei C, Hong W, Kortemme T, von Zastrow M.
Author information:
(1)Program in Pharmaceutical Sciences and Pharmacogenomics, University of
California-San Francisco, San Francisco, CA 94158, USA.
Postsynaptic density 95/discs large/zonus occludens-1 (PDZ) domain-interacting
motifs, in addition to their well-established roles in protein scaffolding at
the cell surface, are proposed to act as cis-acting determinants directing the
molecular sorting of transmembrane cargo from endosomes to the plasma membrane.
This hypothesis requires the existence of a specific trans-acting PDZ protein
that mediates the proposed sorting operation in the endosome membrane. Here, we
show that sorting nexin 27 (SNX27) is required for efficient PDZ-directed
recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes. SNX27
mediates this sorting function when expressed at endogenous levels, and its
recycling activity requires both PDZ domain-dependent recognition of the
beta(2)AR cytoplasmic tail and Phox homology (PX) domain-dependent association
with the endosome membrane. These results identify a discrete role of SNX27 in
PDZ-directed recycling of a physiologically important signaling receptor, and
extend the concept of cargo-specific molecular sorting in the recycling pathway.
DOI: 10.1083/jcb.201004060
PMCID: PMC2928020
PMID: 20733053 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/21926430
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1. J Biol Chem. 2011 Nov 11;286(45):39403-16. doi: 10.1074/jbc.M111.260802. Epub
2011 Sep 18.
Sorting nexin 27 protein regulates trafficking of a p21-activated kinase (PAK)
interacting exchange factor (β-Pix)-G protein-coupled receptor kinase
interacting protein (GIT) complex via a PDZ domain interaction.
Valdes JL(1), Tang J, McDermott MI, Kuo JC, Zimmerman SP, Wincovitch SM,
Waterman CM, Milgram SL, Playford MP.
Author information:
(1)Cell Biology and Physiology Center, NHLBI, National Institutes of Health,
Bethesda, Maryland 20982, USA.
Sorting nexin 27 (SNX27) is a 62-kDa protein localized to early endosomes and
known to regulate the intracellular trafficking of ion channels and receptors.
In addition to a PX domain, SNX27 is the only sorting family member that
contains a PDZ domain. To identify novel SNX27-PDZ binding partners, we
performed a proteomic screen in mouse principal kidney cortical collecting duct
cells using a GST-SNX27 fusion construct as bait. We found that β-Pix
(p21-activated kinase-interactive exchange factor), a guanine nucleotide
exchange factor for the Rho family of small GTPases known to regulate cell
motility directly interacted with SNX27. The association of β-Pix and SNX27 is
specific for β-Pix isoforms terminating in the type-1 PDZ binding motif (ETNL).
In the same screen we also identified Git1/2 as a potential SNX27 interacting
protein. The interaction between SNX27 and Git1/2 is indirect and mediated by
β-Pix. Furthermore, we show recruitment of the β-Pix·Git complex to endosomal
sites in a SNX27-dependent manner. Finally, migration assays revealed that
depletion of SNX27 from HeLa and mouse principal kidney cortical collecting duct
cells significantly decreases cell motility. We propose a model by which SNX27
regulates trafficking of β-Pix to focal adhesions and thereby influences cell
motility.
DOI: 10.1074/jbc.M111.260802
PMCID: PMC3234764
PMID: 21926430 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/22427946
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1. PLoS One. 2012;7(3):e33058. doi: 10.1371/journal.pone.0033058. Epub 2012 Mar
13.
Position of the third Na+ site in the aspartate transporter GltPh and the human
glutamate transporter, EAAT1.
Bastug T(1), Heinzelmann G, Kuyucak S, Salim M, Vandenberg RJ, Ryan RM.
Author information:
(1)School of Physics, The University of Sydney, Sydney, Australia.
Glutamate transport via the human excitatory amino acid transporters is coupled
to the co-transport of three Na(+) ions, one H(+) and the counter-transport of
one K(+) ion. Transport by an archaeal homologue of the human glutamate
transporters, Glt(Ph), whose three dimensional structure is known is also
coupled to three Na(+) ions but only two Na(+) ion binding sites have been
observed in the crystal structure of Glt(Ph). In order to fully utilize the
Glt(Ph) structure in functional studies of the human glutamate transporters, it
is essential to understand the transport mechanism of Glt(Ph) and accurately
determine the number and location of Na(+) ions coupled to transport. Several
sites have been proposed for the binding of a third Na(+) ion from electrostatic
calculations and molecular dynamics simulations. In this study, we have
performed detailed free energy simulations for Glt(Ph) and reveal a new site for
the third Na(+) ion involving the side chains of Threonine 92, Serine 93,
Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also
studied the transport properties of alanine mutants of the coordinating residues
Threonine 92 and Serine 93 in Glt(Ph), and the corresponding residues in a human
glutamate transporter, EAAT1. The mutant transporters have reduced affinity for
Na(+) compared to their wild type counterparts. These results confirm that
Threonine 92 and Serine 93 are involved in the coordination of the third Na(+)
ion in Glt(Ph) and EAAT1.
DOI: 10.1371/journal.pone.0033058
PMCID: PMC3302783
PMID: 22427946 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
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http://www.ncbi.nlm.nih.gov/pubmed/23977684
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1. Electrophoresis. 2013 Jul;34(13):1972-5. doi: 10.1002/elps.201300087.
Staining of proteins for 2D SDS-PAGE using Coomassie Blue--speed versus
sensitivity?
Májek P(1), Riedelová-Reicheltová Z, Suttnar J, Dyr JE.
Author information:
(1)Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
pavel.majek@uhkt.cz
Several new fast staining protocols for the visualization of proteins separated
by SDS-PAGE utilizing Coomassie Blue staining (CBS) have been described in
literature. The sensitivity of a newly designed staining protocol is usually
estimated using 1D SDS-PAGE of serially diluted protein samples. However, this
approach is not predictive and satisfactory for 2D SDS-PAGE capable of resolving
hundreds or thousands of different proteins in a single analysis. In this work,
a new fast staining protocol recently introduced by Dong et al. (PLoS One 2011,
6, e22394) was compared to colloidal CBS. The number of detectable spots in 2D
SDS-PAGE of identical blood plasma samples in repeated runs was chosen as a
sensitivity criterion. Further, the influence of gel boiling on the subsequent
protein identification by MS was investigated. In spite of its advantages, the
staining protocol according to Dong et al. (PLoS One 2011, 6, e22394) seems to
be less sensitive than colloidal Coomassie staining when the number of detected
spots is the evaluating criterion. No obvious influence of gel boiling on the
protein identification was observed.
DOI: 10.1002/elps.201300087
PMID: 23977684 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/23738000
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1. PLoS One. 2013 May 30;8(5):e64781. doi: 10.1371/journal.pone.0064781. Print
2013.
An RNA aptamer provides a novel approach for the induction of apoptosis by
targeting the HPV16 E7 oncoprotein.
Nicol C(1), Cesur Ö, Forrest S, Belyaeva TA, Bunka DH, Blair GE, Stonehouse NJ.
Author information:
(1)School of Molecular and Cellular Biology, Faculty of Biological Sciences and
Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds,
United Kingdom.
BACKGROUND: Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus,
which is a major causative agent of cervical cancer. Cellular transformation is
associated with deregulated expression of the E6 and E7 oncogenes. E7 has been
shown to bind a number of cellular proteins, including the cell cycle control
protein pRb. In this study, RNA aptamers (small, single-stranded
oligonucleotides selected for high-affinity binding) to HPV16 E7 were employed
as molecular tools to further investigate these protein-protein interactions.
METHODOLOGY/PRINCIPAL FINDINGS: This study is focused on one aptamer (termed
A2). Transfection of this molecule into HPV16-transformed cells resulted in
inhibition of cell proliferation (shown using real-time cell electronic sensing
and MTT assays) due to the induction of apoptosis (as demonstrated by Annexin
V/propidium iodide staining). GST-pull down and bead binding assays were used to
demonstrate that the binding of A2 required N-terminal residues of E7 known to
be involved in interaction with the cell cycle control protein, pRb. Using a
similar approach, A2 was shown to disrupt the interaction between E7 and pRb in
vitro. Furthermore, transfection of HPV16-transformed cells with A2 appeared to
result in the loss of E7 and rise in pRb levels, as observed by immunoblotting.
CONCLUSIONS/SIGNIFICANCE: This paper includes the first characterisation of the
effects of an E7 RNA aptamer in a cell line derived from a cervical carcinoma.
Transfection of cells with A2 was correlated with the loss of E7 and the
induction of apoptosis. Aptamers specific for a number of cellular and viral
proteins have been documented previously; one aptamer (Macugen) is approved for
clinical use and several others are in clinical trials. In addition to its role
as a molecular tool, A2 could have further applications in the future.
DOI: 10.1371/journal.pone.0064781
PMCID: PMC3667794
PMID: 23738000 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
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http://www.ncbi.nlm.nih.gov/pubmed/24136520
|
1. Methods Mol Biol. 2014;1072:141-54. doi: 10.1007/978-1-62703-631-3_11.
2DE analysis of forest tree proteins using fluorescent labels and multiplexing.
Renaut J(1), Leclercq C, Planchon S.
Author information:
(1)Department of Environment and Agrobiotechnologies (EVA), Proteomics Platform,
Centre de Recherche Public-Gabriel Lippmann, Belvaux, Luxembourg.
Although proteomists working with gel-free methods are considering the gels as
coming from the past, proteomics based on gels has still a lot of opportunities
to offer and acquisition of images on which thousands of spots may be resolved
is still largely performed. Nowadays, two-dimensional electrophoresis remains a
powerful tool to explore the plant proteome and to unravel changes in protein
abundance between samples. Some weak points can be pointed out, as for any
method, as for example the lack of reproducibility, or the detection of
low-abundance proteins. The use of the technique called "difference gel
electrophoresis" or "DIGE" can help to overcome or at least to reduce these
inconveniences. DIGE requires the labelling of proteins by fluorochromes prior
to their separation on 2DE gels. This technique may be applied to a wide array
of plant stress studies, among others to trees. Accurate quantitative results
can then be obtained and proteins presenting an interest in the studied stress
are subsequently subjected to an enzymatic digestion (usually with trypsin) and
identified using electrospray ionization, matrix-assisted laser
desorption/ionization-time-of-flight-MS, and/or tandem MS.
DOI: 10.1007/978-1-62703-631-3_11
PMID: 24136520 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21651459
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1. Expert Opin Investig Drugs. 2011 Aug;20(8):1073-86. doi:
10.1517/13543784.2011.592139. Epub 2011 Jun 9.
Opioid modulators for alcohol dependence.
Hillemacher T(1), Heberlein A, Muschler MA, Bleich S, Frieling H.
Author information:
(1)Hannover Medical School, Center for Addiction Research (CARe) , Department
for Psychiatry , Socialpsychiatry and Psychotherapy, Carl-Neuberg-Str. Germany.
hillemacher.thomas@mh-hannover.de
INTRODUCTION: Studies have shown that opioid antagonists like naltrexone are
efficient in reducing heavy drinking. The neurobiological mechanism by which
opioid modulators affect drinking behavior is based on the strong connection
between the endogenous opioid system, the dopamine system and the influence of
the CNS stress response.
AREAS COVERED: This review provides an overview of the pathophysiological role
of the opioid system in alcohol dependence and the neurobiological mechanisms of
possible pharmacological interventions. An extensive Medline and Internet
research was performed to retrieve information on existing and currently
investigated opioid modulators. The findings were assessed critically and
interpreted with regard to an individualized therapy for alcohol dependence.
EXPERT OPINION: The opioid system is of crucial importance in the genesis and
maintenance of alcohol dependence. Naltrexone- and to a lesser extent nalmefene-
is an agent that modulates opioidergic transmission in the CNS and it shows a
limited but well-studied efficacy in treating alcohol dependence. Several agents
(LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase
III studies are of interest but first their efficacy must be proved in clinical
practice.
DOI: 10.1517/13543784.2011.592139
PMID: 21651459 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24105977
|
1. Mol Pharmacol. 2014 Jan;85(1):1-10. doi: 10.1124/mol.113.089755. Epub 2013 Oct
8.
Valproic acid is a novel activator of AMP-activated protein kinase and decreases
liver mass, hepatic fat accumulation, and serum glucose in obese mice.
Avery LB(1), Bumpus NN.
Author information:
(1)Department of Pharmacology and Molecular Sciences, The Johns Hopkins
University School of Medicine, Baltimore, Maryland.
Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of
epilepsy. Here we demonstrate that VPA is a novel activator of AMP-activated
protein kinase (AMPK), a key regulator of cellular metabolism, using primary
mouse and human hepatocytes. Incubation of primary mouse hepatocytes with VPA
resulted in increased levels of phosphorylated AMPK and acetyl-CoA carboxylase
(ACC). This finding was recapitulated using primary human hepatocytes.
Pretreatment of mouse hepatocytes with a small-molecule inhibitor of AMPK,
Compound C
(6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine),
abrogated the phosphorylation of ACC following treatment with VPA. The
cytochrome P450 inhibitor 1-aminobenzotriazole blocked the VPA-stimulated
phosphorylation of AMPK, suggesting a requirement for biotransformation of VPA.
In line with this, treatment of hepatocytes with metabolites of VPA resulted in
increased phosphorylation of AMPK/ACC as compared with VPA. Treatment of ob/ob
mice with VPA for 14 days resulted in decreased liver masses, hepatic fat
accumulation, and serum glucose. These results paralleled those observed in mice
treated with metformin. In addition, a targeted mass spectrometry-based
metabolomics assay revealed several small molecules that were differentially
abundant in the serum of ob/ob mice treated with VPA as compared with
vehicle-treated mice. These studies are the first to establish VPA and its
metabolites as in vitro activators of AMPK.
DOI: 10.1124/mol.113.089755
PMCID: PMC3868906
PMID: 24105977 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21291870
|
1. Biochem Pharmacol. 2011 Apr 15;81(8):996-1003. doi: 10.1016/j.bcp.2011.01.015.
Epub 2011 Feb 1.
Opioid-like compound exerts anti-fibrotic activity via decreased hepatic
stellate cell activation and inflammation.
Day SA(1), Lakner AM, Moore CC, Yen MH, Clemens MG, Wu ES, Schrum LW.
Author information:
(1)Department of Biology, University of North Carolina at Charlotte, Charlotte,
NC 28223, USA.
Hepatic fibrosis is characterized by excess type I collagen deposition and
exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist
used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic
animal models, which can be accompanied by deleterious side effects.
Additionally, opioid neurotransmission is upregulated in patients with
inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal)
and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does
not show significant opioid receptor antagonism. To delineate the potential
hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal
could modulate activation of hepatic stellate cells (HSCs), primary effector
cells that secrete type I collagen and inflammatory mediators during liver
injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth
muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite
decreased collagen mRNA expression, both compounds increased intracellular
collagen protein expression; however, inhibition of collagen secretion was
observed. To address a possible mechanism for suppressed collagen secretion or
retention of intracellular collagen, endoplasmic (ER) protein expression and
matrix metalloproteinase (MMP) activity were examined. While no change in ER
protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was
dramatically increased. In an acute LPS inflammatory injury animal model,
JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver
infiltration. Overall, these results suggest that JKB-119 can directly inhibit
HSC activation attributed to anti-inflammatory activity and may, therefore,
attenuate inflammation associated with HSC activation and liver disease.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bcp.2011.01.015
PMID: 21291870 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9780908
|
1. J Craniofac Surg. 1998 Sep;9(5):417-22. doi: 10.1097/00001665-199809000-00003.
Bilambdoid and posterior sagittal synostosis: the Mercedes Benz syndrome.
Moore MH(1), Abbott AH, Netherway DJ, Menard R, Hanieh A.
Author information:
(1)Australian Craniofacial Unit, North Adelaide, Australia.
A consistent pattern of craniosynostosis in the sagittal and bilateral lambdoid
sutures is described in three patients. The external cranial ridging associated
with fusion of these sutures produces a characteristic triradiate, or "Mercedes
Benz," appearance to the posterior skull. Locally marked growth restriction is
evident in the posterior fossa with compensatory secondary expansion of the
anterior fossa manifesting a degree of frontal bossing which mimics bicoronal
synostosis. Although this appearance could lead to inadvertent surgery in the
frontal region, attention to the occipital region with wide early suture
excision and vault shaping is indicated.
DOI: 10.1097/00001665-199809000-00003
PMID: 9780908 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20463739
|
1. Nature. 2010 May 13;465(7295):227-30. doi: 10.1038/nature08999.
Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA
decay.
Pastor F(1), Kolonias D, Giangrande PH, Gilboa E.
Author information:
(1)Department of Microbiology & Immunology, Dodson Interdisciplinary
Immunotherapy Institute, University of Miami Miller School of Medicine Miami,
Florida 33134, USA.
The main reason why tumours are not controlled by the immune system is that,
unlike pathogens, they do not express potent tumour rejection antigens (TRAs).
Tumour vaccination aims at stimulating a systemic immune response targeted to,
mostly weak, antigens expressed in the disseminated tumour lesions. Main
challenges in developing effective vaccination protocols are the identification
of potent and broadly expressed TRAs and effective adjuvants to stimulate a
robust and durable immune response. Here we describe an alternative approach in
which the expression of new, and thereby potent, antigens are induced in tumour
cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small
interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the
expression of new antigenic determinants and their immune-mediated rejection. In
subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD
factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to
significant inhibition of tumour growth that was superior to that of vaccination
with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing
irradiated tumour cells, and could be further enhanced by co-stimulation.
Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and
clinically feasible approach to enhance the antigenicity of disseminated tumours
leading to their immune recognition and rejection. The cell-free chemically
synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of
immunogenicity and enhances the feasibility of generating reagents suitable for
clinical use.
DOI: 10.1038/nature08999
PMCID: PMC3107067
PMID: 20463739 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25242375
|
1. Comput Biol Chem. 2014 Dec;53 Pt A:84-96. doi:
10.1016/j.compbiolchem.2014.08.013. Epub 2014 Sep 16.
Orphan and gene related CpG Islands follow power-law-like distributions in
several genomes: evidence of function-related and taxonomy-related modes of
distribution.
Tsiagkas G(1), Nikolaou C(2), Almirantis Y(3).
Author information:
(1)Institute of Biosciences and Applications, National Center for Scientific
Research "Demokritos", 15310 Athens, Greece.
(2)Computational Genomics Group, Department of Biology, University of Crete,
71409 Heraklion, Greece.
(3)Institute of Biosciences and Applications, National Center for Scientific
Research "Demokritos", 15310 Athens, Greece. Electronic address:
yalmir@bio.demokritos.gr.
CpG Islands (CGIs) are compositionally defined short genomic stretches, which
have been studied in the human, mouse, chicken and later in several other
genomes. Initially, they were assigned the role of transcriptional regulation of
protein-coding genes, especially the house-keeping ones, while more recently
there is found evidence that they are involved in several other functions as
well, which might include regulation of the expression of RNA genes, DNA
replication etc. Here, an investigation of their distributional characteristics
in a variety of genomes is undertaken for both whole CGI populations as well as
for CGI subsets that lie away from known genes (gene-unrelated or "orphan"
CGIs). In both cases power-law-like linearity in double logarithmic scale is
found. An evolutionary model, initially put forward for the explanation of a
similar pattern found in gene populations is implemented. It includes segmental
duplication events and eliminations of most of the duplicated CGIs, while a
moderate rate of non-duplicated CGI eliminations is also applied in some cases.
Simulations reproduce all the main features of the observed inter-CGI
chromosomal size distributions. Our results on power-law-like linearity found in
orphan CGI populations suggest that the observed distributional pattern is
independent of the analogous pattern that protein coding segments were reported
to follow. The power-law-like patterns in the genomic distributions of CGIs
described herein are found to be compatible with several other features of the
composition, abundance or functional role of CGIs reported in the current
literature across several genomes, on the basis of the proposed evolutionary
model.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.compbiolchem.2014.08.013
PMID: 25242375 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19396832
|
1. Am J Med Genet A. 2009 May;149A(5):1024-32. doi: 10.1002/ajmg.a.32782.
Bilateral lambdoid and sagittal synostosis (BLSS): a unique craniosynostosis
syndrome or predictable craniofacial phenotype?
Hing AV(1), Click ES, Holder U, Seto ML, Vessey K, Gruss J, Hopper R, Cunningham
ML.
Author information:
(1)Department of Pediatrics, University of Washington, Seattle, Washington
98195-6320, USA. ahing@u.washington.edu
Multisutural craniosynostosis that includes bilateral lambdoid and sagittal
synostosis (BLSS) results in a very characteristic head shape with frontal
bossing, turribrachycephaly, biparietal narrowing, occipital concavity, and
inferior displacement of the ears. This entity has been reported both in the
genetics literature as craniofacial dyssynostosis and in the surgical literature
as "Mercedes Benz" syndrome. Craniofacial dyssynostosis was first described in
1976 by Dr. Neuhauser when he presented a series of seven patients with
synostosis of the sagittal and lambdoid sutures, short stature, and
developmental delay. Over the past 30 years nine additional patients with
craniofacial dyssynostosis have been reported in the literature adding to the
growing evidence for a distinct craniosynostosis syndrome. The term "Mercedes
Benz" syndrome was coined by Moore et al. in 1998 due to the characteristic
appearance of the fused sutures on three-dimensional CT imaging. In contrast to
the aforementioned reported cases of craniofacial dyssynostosis, all three
patients had normal development. Recently, there have been several case reports
of patients with BLSS and distinct chromosomal anomalies. These findings suggest
that BLSS is a heterogeneous disorder perhaps with syndromic, chromosomal, and
isolated forms. In this manuscript we will present the largest series of
patients with BLSS and review clinical, CT, and molecular findings.
DOI: 10.1002/ajmg.a.32782
PMID: 19396832 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23889921
|
1. CNS Neurosci Ther. 2013 Nov;19(11):871-81. doi: 10.1111/cns.12144. Epub 2013
Jul 27.
Antiepileptics topiramate and levetiracetam alleviate behavioral deficits and
reduce neuropathology in APPswe/PS1dE9 transgenic mice.
Shi JQ(1), Wang BR, Tian YY, Xu J, Gao L, Zhao SL, Jiang T, Xie HG, Zhang YD.
Author information:
(1)Department of Neurology, Nanjing First Hospital, Nanjing Medical University,
Nanjing, Jiangsu Province, China.
BACKGROUND: The close relationship between epileptic seizure and Alzheimer's
disease (AD) has been demonstrated in the past decade. Valproic acid, a
traditional first-line antiepileptic drug, exerted protective effects in
transgenic models of AD. It remains uncertain whether new antiepileptic drugs
could reverse neuropathology and behavioral deficits in AD transgenic mice.
AIMS: APPswe/PS1dE9 transgenic mice were used in this study, which over express
the Swedish mutation of amyloid precursor protein together with presenilin 1
deleted in exon 9. 7-month-old APPswe/PS1dE9 transgenic mice were treated daily
with 20 mg/kg topiramate (TPM) and 50 mg/kg levetiracetam (LEV) for 30 days by
intraperitoneal injection to explore the effects of TPM and LEV on the
neuropathology and behavioral deficits.
RESULTS: The results indicated that TPM and LEV alleviated behavioral deficits
and reduced amyloid plaques in APPswe/PS1dE9 transgenic mice. TPM and LEV
increased Aβ clearance and up-regulated Aβ transport and autophagic degradation.
TPM and LEV inhibited Aβ generation and suppressed γ-secretase activity. TPM and
LEV inhibited GSK-3β activation and increased the activation of AMPK/Akt
activation. Further, TPM and LEV inhibited histone deacetylase activity in vivo.
CONCLUSIONS: Therefore, TPM and LEV might have the potential to treat AD
effectively in patient care.
© 2013 John Wiley & Sons Ltd.
DOI: 10.1111/cns.12144
PMCID: PMC6493595
PMID: 23889921 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest
|
http://www.ncbi.nlm.nih.gov/pubmed/20048621
|
1. Plast Reconstr Surg. 2010 Jan;125(1):299-304. doi:
10.1097/PRS.0b013e3181c2a6aa.
Mercedes Benz pattern craniosynostosis.
Rhodes JL(1), Kolar JC, Fearon JA.
Author information:
(1)Richmond, Va.; and Dallas, Texas From the Division of Plastic Surgery,
Virginia Commonwealth University Medical Center, and the Children's Specialty
Center and the Craniofacial Center, Medical City Children's Hospital.
BACKGROUND: The complex craniosynostoses, which include all nonsyndromic
multiple sutural fusions, represent a small fraction of patients presenting with
craniosynostosis. Among these are a trisutural fusion, dubbed the "Mercedes Benz
pattern," involving the sagittal and both lambdoid sutures. The purpose of this
report is to review the authors' series of this unusual form of
craniosynostosis, to identify associated anomalies, and to assess treatment
outcomes.
METHODS: The authors conducted a retrospective clinical outcome assessment of
all patients presenting with Mercedes Benz pattern craniosynostosis. Growth was
assessed by direct anthropologic measurements, and significance was assessed by
the t test.
RESULTS: Over a 17-year period, 11 of 802 patients presenting with
craniosynostosis were identified with Mercedes Benz pattern synostosis (1.4
percent). Three patients had additional sutural involvement and two had
identifiable genetic syndromes. Seven of 11 (64 percent) had cerebellar
tonsillar herniation on preoperative imaging, and four symptomatic patients (36
percent) have required Chiari decompressions. Three patients have required more
than one remodeling procedure. Serial postoperative anthropologic measurements
identified progressive brachycephaly, with diminished growth in both head
circumference and skull length (mean follow-up, 3.75 years). Cognitive function
was grossly normal, except for one syndromic patient.
CONCLUSIONS: Despite fusion of the sagittal suture, the surgical treatment for
Mercedes Benz pattern craniosynostosis should include skull lengthening, not
reduction. The authors' findings for diminished postoperative growth suggest
that an overcorrection be considered. Fourth or fifth sutural involvement
correlated with additional corrections. Given the observed high incidence for
symptomatic cerebellar tonsillar herniation, routine magnetic resonance
evaluations are recommended for affected individuals.
DOI: 10.1097/PRS.0b013e3181c2a6aa
PMID: 20048621 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22352726
|
1. Curr Pharm Biotechnol. 2012 Aug;13(10):1924-34. doi:
10.2174/138920112802273137.
Antidote control of aptamer therapeutics: the road to a safer class of drug
agents.
Bompiani KM(1), Woodruff RS, Becker RC, Nimjee SM, Sullenger BA.
Author information:
(1)Department of Surgery, Duke University School of Medicine, Durham, NC 27710,
USA.
Aptamers, or nucleic acid ligands, have gained clinical interest over the past
20 years due to their unique characteristics, which are a combination of the
best facets of small molecules and antibodies. The high binding affinity and
specificity of aptamers allows for isolation of an artificial ligand for
theoretically any therapeutic target of interest. Chemical manipulations of
aptamers also allow for fine-tuning of their bioavailability, and antidote
control greatly expands their clinical use. Here we review the various methods
of antidote control of aptamer therapeutics--matched oligonucleotide antidotes
and universal antidotes. We also describe the development, recent progress, and
potential future therapeutic applications of these types of aptamer-antidote
pairs.
DOI: 10.2174/138920112802273137
PMID: 22352726 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24198064
|
1. Immunol Res. 2013 Dec;57(1-3):44-51. doi: 10.1007/s12026-013-8442-7.
Expression of new antigens on tumor cells by inhibiting nonsense-mediated mRNA
decay.
Gilboa E(1).
Author information:
(1)Department of Microbiology and Immunology, Dodson Interdisciplinary
Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of
Medicine, University of Miami, Miami, FL, 33136, USA, egilboa@med.miami.edu.
The main reason why tumors are not controlled by the immune system of the cancer
patient is that tumors do not express potent tumor antigens that can be
recognized by the immune system as "foreign." The current focus in developing
immune-based modalities is to potentiate an immune response against the
existing, albeit weak, antigens expressed in the tumor. An alternative approach
is to express new, and hence potent, antigens in tumor cells in situ. To this
end, we have developed an approach to generate new antigenic determinants in
tumor cells using siRNA technology to inhibit nonsense-mediated mRNA decay
(NMD), a surveillance mechanism which prevents the expression of mRNAs
containing a premature termination codon. Targeting siRNA inhibition to tumor
cells--an essential requisite because of the constitutive nature and
physiological roles of the NMD process--is accomplished by using a novel
targeting technology based on using oligonucleotide aptamer ligands. Aptamers or
aptamer-targeted siRNA conjugates, unlike antibodies, can be synthesized in a
chemical process providing a more straightforward and cost-effective
manufacturing and regulatory approval process to generate clinical-grade
reagents. In murine tumor models, the aptamer-targeted siRNA-mediated NMD
inhibition in tumor cells led to significant inhibition of tumor growth, which
was superior to best-in-class "conventional" cancer vaccination protocols.
Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and
clinically feasible approach to enhance the antigenicity of disseminated tumors
leading to their immune recognition and rejection. The cell-free chemically
synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of
immunogenicity and enhances the feasibility of generating reagents suitable for
clinical use.
DOI: 10.1007/s12026-013-8442-7
PMID: 24198064 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20232424
|
1. Pediatr Blood Cancer. 2010 Jul 15;55(1):35-41. doi: 10.1002/pbc.22465.
Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell
lines.
El-Sheikh A(1), Fan R, Birks D, Donson A, Foreman NK, Vibhakar R.
Author information:
(1)Department of Pediatrics, University of Iowa, Iowa, USA.
BACKGROUND: Medulloblastoma comprises approximately 20% of all primary pediatric
brain tumors. Despite recent advances, the survival rate for high-risk patients
and the morbidity associated with these treatments remains suboptimal. To
improve outcomes and decrease morbidity, more targeted therapy is required. One
possible target is the Aurora Kinase family. The objective of this study was to
evaluate the impact of Aurora Kinase A inhibition in medulloblastoma cell lines.
PROCEDURE: Cell proliferation was measured using an MTS assay after adding an
Aurora Kinase inhibitor (C1368) at different concentrations. Cell cycle analysis
was carried out by Flow Cytometry using propidium iodide (PI). RNAi experiments
were performed using siRNA oligonucleotides. Luciferase experiments were carried
out using the Cignal Finder 10 Pathway Reporter Arrays.
RESULTS: Inhibition of Aurora Kinase A induces cell death in medulloblastoma
cells and lowers the IC(50) of other chemotherapeutic agents (etoposide and
cisplatin) used in medulloblastoma treatment. Cell arrest at G2/M phase was
significantly increased in medulloblastoma cell lines treated with C1368 Sigma
at IC(30) or transfected siRNA. Inhibition of Aurora Kinase A resulted in
decreased activity of pro-proliferative signaling pathways including Wnt, Myc,
and RB as measured by luciferase reporter assays.
CONCLUSIONS: These data indicate that inhibition of Aurora Kinase A inhibits
cell growth in medulloblastoma through inhibition of pro-proliferative signaling
pathways Wnt, Myc, and RB. Additionally, combining Aurora Kinase A inhibition
with other chemotherapeutic agents significantly lowers their IC(50), which make
it a promising small molecule target for medulloblastoma therapy.
DOI: 10.1002/pbc.22465
PMID: 20232424 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21679342
|
1. Cancer Sci. 2011 Oct;102(10):1756-60. doi: 10.1111/j.1349-7006.2011.02010.x.
Epub 2011 Jul 26.
Hedgehog signaling pathway as a therapeutic target in various types of cancer.
Onishi H(1), Katano M.
Author information:
(1)Department of Cancer Therapy and Research, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan. ohnishi@surg1.med.kyushu-u.ac.jp
Hedgehog (Hh) signaling is an important factor in growth and patterning during
embryonic development. A mutation in Patched, Smoothened or Gli1, which regulate
the Hh signaling pathway, might lead to the onset of glioblastoma, basal cell
carcinoma, medulloblastoma and rhabdomyosarcoma. Recently, Hh signaling has been
reported to be activated in a ligand-dependent manner, contributing to
carcinogenesis and cancer progression. Hedgehog signaling is reactivated in
various types of cancer, and this contributes to cancer progression by
facilitating proliferation, invasion and cell survival. Moreover, Hh signaling
is associated with several other signaling pathways that contribute to cancer
progression. These observations indicate that controlling Hh signaling might
become a target for novel molecular targeting therapy.
DOI: 10.1111/j.1349-7006.2011.02010.x
PMID: 21679342 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15926872
|
1. Expert Opin Investig Drugs. 2005 May;14(5):671-82. doi:
10.1517/13543784.14.5.671.
Pegaptanib sodium for the treatment of neovascular age-related macular
degeneration.
Moshfeghi AA(1), Puliafito CA.
Author information:
(1)Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami
Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136, USA.
This article reviews pegaptanib sodium, a compound developed by Eyetech
Pharmaceuticals Inc. and Pfizer Inc., for the treatment of neovascular
age-related macular degeneration (AMD). Traditional treatment approaches to
neovascular AMD have included destructive therapies such as thermal laser
photocoagulation and photodynamic therapy; the use of pegaptanib sodium heralds
a new treatment approach that is a non-destructive therapy based on the
inhibition of vascular endothelial growth factor activity in the eye. This
diminishes the neovascular drive in the pathologically hyperpermeable state of
the diseased eye. Pegaptanib sodium is one of the first therapeutics belonging
to the class of compounds known as aptamers. The chemistry, mechanism of action,
pharmacokinetics and rationale for the clinical use of the drug are reviewed.
The article highlights and summarises the results of the multi-centre,
randomised, sham-controlled clinical trials with pegaptanib sodium to treat
subfoveal choroidal neovascularisation in AMD. In addition, the safety profile
is reviewed.
DOI: 10.1517/13543784.14.5.671
PMID: 15926872 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18651559
|
1. J Cell Physiol. 2008 Dec;217(3):577-83. doi: 10.1002/jcp.21542.
Signaling pathways in medulloblastoma.
Guessous F(1), Li Y, Abounader R.
Author information:
(1)Department of Neurology, University of Virginia, Charlottesville, Virginia
22908, USA.
Medulloblastoma is the most common brain tumor of childhood. Multiple signaling
pathways have been associated with medulloblastoma formation and growth. These
include the developmental pathways Hedgehog, (Hh) Notch, and Wnt as well as the
receptor tyrosine kinases (RTK) c-Met, erbB2, IGF-R and TrkC, and the
oncoprotein Myc. Here we review the involvement of these pathways in
medulloblastoma malignancy with a focus on their mode of deregulation,
prognostic value, functional effects, cellular and molecular mechanisms of
action, and implications for therapy.
DOI: 10.1002/jcp.21542
PMID: 18651559 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15968382
|
1. Thromb Haemost. 2005 Jun;93(6):1014-20. doi: 10.1160/TH04-12-0790.
Nucleic acid aptamers in therapeutic anticoagulation. Technology, development
and clinical application.
Becker RC(1), Rusconi C, Sullenger B.
Author information:
(1)Cardiovascular Thrombosis Research Center, Duke Clinical Research Institute,
2400 Pratt Street, Room 0311 Terrace Level, Durham, North Carolina 27715, USA.
Becke021@mc.duke.edu
The evolution of anticoagulant therapy for the prevention and treatment of
thrombotic disorders has progressed at a relatively modest pace considering the
scope of the problem and our current understanding of platelet biology,
coagulation proteases, and vascular science as they apply to protective
haemostasis and pathologic thrombosis. Recent observations, dedicated to
cellular-based models of coagulation, provide fundamental constructs,
mechanistic clarity, and potentially unparalleled opportunity for accelerating
the development and wide-scale clinical use of safe, effective, regulatable and
patient-specific therapies. The following review introduces a novel domain of
anticoagulant therapy referred to as aptamers (derived from the Latin aptus - to
fit), considering their history, development, and potential application in
patient care arenas.
DOI: 10.1160/TH04-12-0790
PMID: 15968382 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21838685
|
1. Curr Med Chem. 2011;18(27):4206-14. doi: 10.2174/092986711797189600.
Nucleic acid aptamers: clinical applications and promising new horizons.
Ni X(1), Castanares M, Mukherjee A, Lupold SE.
Author information:
(1)James Buchanan Brady Urological Institute, Johns Hopkins University School of
Medicine 600 N Wolfe St., Baltimore, MD 21287, USA.
Aptamers are a special class of nucleic acid molecules that are beginning to be
investigated for clinical use. These small RNA/DNA molecules can form secondary
and tertiary structures capable of specifically binding proteins or other
cellular targets; they are essentially a chemical equivalent of antibodies.
Aptamers have the advantage of being highly specific, relatively small in size,
and non-immunogenic. Since the discovery of aptamers in the early 1990s, great
efforts have been made to make them clinically relevant for diseases like
cancer, HIV, and macular degeneration. In the last two decades, many aptamers
have been clinically developed as inhibitors for targets such as vascular
endothelial growth factor (VEGF) and thrombin. The first aptamer based
therapeutic was FDA approved in 2004 for the treatment of age-related macular
degeneration and several other aptamers are currently being evaluated in
clinical trials. With advances in targeted-therapy, imaging, and nanotechnology,
aptamers are readily considered as potential targeting ligands because of their
chemical synthesis and ease of modification for conjugation. Preclinical studies
using aptamer-siRNA chimeras and aptamer targeted nanoparticle therapeutics have
been very successful in mouse models of cancer and HIV. In summary aptamers are
in several stages of development, from pre-clinical studies to clinical trials
and even as FDA approved therapeutics. In this review, we will discuss the
current state of aptamers in clinical trials as well as some promising aptamers
in pre-clinical development.
DOI: 10.2174/092986711797189600
PMCID: PMC3260938
PMID: 21838685 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16510586
|
1. Cancer Res. 2006 Mar 1;66(5):2666-72. doi: 10.1158/0008-5472.CAN-05-2198.
N-myc can substitute for insulin-like growth factor signaling in a mouse model
of sonic hedgehog-induced medulloblastoma.
Browd SR(1), Kenney AM, Gottfried ON, Yoon JW, Walterhouse D, Pedone CA, Fults
DW.
Author information:
(1)Department of Neurosurgery, University of Utah School of Medicine, Salt Lake
City, Utah 84132-2303, USA.
Medulloblastoma is a malignant brain tumor that arises in the cerebellum in
children, presumably from granule neuron precursors (GNP). Advances in patient
treatment have been hindered by a paucity of animal models that accurately
reflect the molecular pathogenesis of human tumors. Aberrant activation of the
Sonic hedgehog (Shh) and insulin-like growth factor (IGF) pathways is associated
with human medulloblastomas. Both pathways are essential regulators of GNP
proliferation during cerebellar development. In cultured GNPs, IGF signaling
stabilizes the oncogenic transcription factor N-myc by inhibiting glycogen
synthase kinase 3beta-dependent phosphorylation and consequent degradation of
N-myc. However, determinants of Shh and IGF tumorigenicity in vivo remain
unknown. Here we report a high frequency of medulloblastoma formation in mice
following postnatal overexpression of Shh in cooperation with N-myc.
Overexpression of N-myc, alone or in combination with IGF signaling mediators or
with the Shh target Gli1, did not cause tumors. Thus, Shh has transforming
functions in addition to induction of N-myc and Gli1. This tumor model will be
useful for testing novel medulloblastoma therapies and providing insight into
mechanisms of hedgehog-mediated transformation.
DOI: 10.1158/0008-5472.CAN-05-2198
PMID: 16510586 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16631118
|
1. Biochem Biophys Res Commun. 2006 Jun 9;344(3):792-7. doi:
10.1016/j.bbrc.2006.03.201. Epub 2006 Apr 17.
Delivery of double-stranded DNA thioaptamers into HIV-1 infected cells for
antiviral activity.
Ferguson MR(1), Rojo DR, Somasunderam A, Thiviyanathan V, Ridley BD, Yang X,
Gorenstein DG.
Author information:
(1)Division of Infectious Diseases, Department of Internal Medicine, The
University of Texas Medical Branch, 301 University Boulevard, Galveston, TX
77555, USA. mrfergus@utmb.edu
Oligonucleotide agents (ODN) are emerging as attractive alternatives to chemical
drugs. However, the clinical use of ODNs as therapeutics has been hindered by
their susceptibility to degradation by cellular enzymes and their limited
ability to penetrate intact cells. We have used various liposome-mediated
transfection agents, for the in vitro delivery of DNA thioaptamers into
U373-MAGI-CCR5 cells. Our lead thioaptamer, R12-2, targets the RNase H domain of
the HIV-1 reverse transcriptase (RT) and inhibits viral infection in
U373-MAGI-CCR5 cells. R12-2, a 62-base-pair, double-stranded DNA molecule with a
monothio-phosphate modified backbone, was selected through a novel combinatorial
selection method. We studied the use of oligofectamine (OF), TFX-20,
Transmessenger (TM), and Gene Jammer (GJ) for transfection of the thio-modified
DNA aptamers. OF-transfected U373-MAGI-CCR5 cells resulted in 68% inhibition of
HIV infection in the treated cells compared to the untreated control. Inhibition
was observed in a dose-dependent manner with maximal inhibition of 83%. In this
report, we demonstrate that monothioate-modified DNA duplex oligonucleotides can
be efficiently delivered into cells by liposome-based transfection agents to
inhibit HIV replication.
DOI: 10.1016/j.bbrc.2006.03.201
PMID: 16631118 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9973222
|
1. Cancer Res. 1999 Feb 1;59(3):711-9.
Activation of neurotrophin-3 receptor TrkC induces apoptosis in
medulloblastomas.
Kim JY(1), Sutton ME, Lu DJ, Cho TA, Goumnerova LC, Goritchenko L, Kaufman JR,
Lam KK, Billet AL, Tarbell NJ, Wu J, Allen JC, Stiles CD, Segal RA, Pomeroy SL.
Author information:
(1)Department of Neurology, Children's Hospital, Boston, Massachusetts 02115,
USA.
Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood
medulloblastomas is associated with favorable clinical outcome. Here, we provide
evidence that TrkC is more than simply a passive marker of prognosis. We
demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in
the presence of NT-3; (b) overexpression of TrkC inhibits the growth of
intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c)
trkC expression by individual tumor cells is highly correlated with apoptosis
within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling
promotes apoptosis by activating multiple parallel signaling pathways and by
inducing immediate-early gene expression of both c-jun and c-fos. Considered
collectively, these results support the conclusion that the biological actions
of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth
through the promotion of apoptosis.
PMID: 9973222 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19574499
|
1. Genome Res. 2009 Sep;19(9):1570-8. doi: 10.1101/gr.092833.109. Epub 2009 Jul
2.
Identification of rare cancer driver mutations by network reconstruction.
Torkamani A(1), Schork NJ.
Author information:
(1)The Scripps Translational Science Institute and Scripps Genomic Medicine,
Scripps Health and The Scripps Research Institute, La Jolla, California 92037,
USA.
Recent large-scale tumor resequencing studies have identified a number of
mutations that might be involved in tumorigenesis. Analysis of the frequency of
specific mutations across different tumors has been able to identify some, but
not all of the mutated genes that contribute to tumor initiation and
progression. One reason for this is that other functionally important genes are
likely to be mutated more rarely and only in specific contexts. Thus, for
example, mutation in one member of a collection of functionally related genes
may result in the same net effect, and/or mutations in certain genes may be
observed less frequently if they play functional roles in later stages of tumor
development, such as metastasis. We modified and applied a network
reconstruction and coexpression module identification-based approach to identify
functionally related gene modules targeted by somatic mutations in cancer. This
method was applied to available breast cancer, colorectal cancer, and
glioblastoma sequence data, and identified Wnt/TGF-beta cross-talk, Wnt/VEGF
signaling, and MAPK/focal adhesion kinase pathways as targets of rare driver
mutations in breast, colorectal cancer, and glioblastoma, respectively. These
mutations do not appear to alter genes that play a central role in these
pathways, but rather contribute to a more refined shaping or "tuning" of the
functioning of these pathways in such a way as to result in the inhibition of
their tumor-suppressive signaling arms, and thereby conserve or enhance
tumor-promoting processes.
DOI: 10.1101/gr.092833.109
PMCID: PMC2752121
PMID: 19574499 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20053726
|
1. Mol Cancer Res. 2010 Jan;8(1):35-45. doi: 10.1158/1541-7786.MCR-09-0220. Epub
2010 Jan 6.
Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by
inhibiting STAT3 and AKT signaling pathways.
Yang F(1), Jove V, Xin H, Hedvat M, Van Meter TE, Yu H.
Author information:
(1)Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute,
City of Hope Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Medulloblastomas are the most frequent malignant brain tumors in children.
Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical
trials as an antiangiogenic agent for cancer therapy. In this report, we show
that sunitinib induced apoptosis and inhibited cell proliferation of both a
short-term primary culture (VC312) and an established cell line (Daoy) of human
medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3
and cleavage of poly(ADP-ribose) polymerase and upregulation of proapoptotic
genes, Bak and Bim, and inhibited the expression of survivin, an antiapoptotic
protein. Sunitinib treatment also downregulated cyclin E, cyclin D2, and cyclin
D3 and upregulated p21Cip1, all of which are involved in regulating cell cycle.
In addition, it inhibited phosphorylation of signal transducer and activator of
transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells.
Dephosphorylation of STAT3 (Tyr(705)) induced by sunitinib was helped by a
reduction in activities of Janus-activated kinase 2 and Src. Additionally,
sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially
blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of
phosphorylated AKT after sunitinib treatment was accompanied by decreased
phosphorylation of downstream proteins glycogen synthase kinase-3beta and
mammalian target of rapamycin. Expression of a constitutively activated STAT3
mutant or myristoylated AKT partially blocked the effects of sunitinib in these
tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor
cells in vitro. These findings suggest the potential use of sunitinib for the
treatment of pediatric medulloblastomas.
DOI: 10.1158/1541-7786.MCR-09-0220
PMCID: PMC2808420
PMID: 20053726 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest No
potential conflicts of interest were disclosed.
|
http://www.ncbi.nlm.nih.gov/pubmed/16707597
|
1. Clin Cancer Res. 2006 May 15;12(10):3019-27. doi:
10.1158/1078-0432.CCR-05-2187.
Phosphatidylinositol 3'-kinase/AKT signaling is activated in medulloblastoma
cell proliferation and is associated with reduced expression of PTEN.
Hartmann W(1), Digon-Söntgerath B, Koch A, Waha A, Endl E, Dani I, Denkhaus D,
Goodyer CG, Sörensen N, Wiestler OD, Pietsch T.
Author information:
(1)Department of Neuropathology, University of Bonn Medical Center, Bonn,
Germany.
PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors of
childhood. They are supposed to originate from cerebellar neural precursor
cells. Recently, it has been shown that Sonic Hedgehog-induced formation of
medulloblastoma in an animal model is significantly enhanced by activation of
the phosphatidylinositol 3'-kinase (PI3K) signaling pathway.
EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the molecular
pathogenesis of human medulloblastoma, we did an immunohistochemical study of
the expression of Ser473-phosphorylated (p)-AKT protein in 22 medulloblastoma
samples: All samples displayed p-AKT expression. To investigate if an activated
PI3K/AKT pathway is required for medulloblastoma cell growth, we treated five
human medulloblastoma cell lines with increasing concentrations of the PI3K
inhibitor LY294002 and analyzed cellular proliferation and apoptosis. The
antiproliferative effect could be antagonized by overexpressing constitutively
active AKT. As the activation of PI3K/AKT signaling may be associated with
alterations of the PTEN gene located at 10q23.3, a chromosomal region subject to
frequent allelic losses in medulloblastoma, we screened PTEN for mutations and
mRNA expression.
RESULTS: Proliferation of all of the medulloblastoma cell lines was dependent on
PI3K/AKT signaling, whereas apoptosis was not prominently affected. Allelic loss
was detected in 16% of the cases. One medulloblastoma cell line was found to
carry a truncating mutation in the PTEN coding sequence. Even more important,
PTEN mRNA and protein levels were found to be significantly lower in
medulloblastomas compared with normal cerebellar tissue of different
developmental stages. Reduction of PTEN expression was found to be associated
with PTEN promoter hypermethylation in 50% of the tumor samples.
CONCLUSIONS: We conclude that activation of the PI3K/AKT pathway constitutes an
important step in the molecular pathogenesis of medulloblastoma and that
dysregulation of PTEN may play a significant role in this context.
DOI: 10.1158/1078-0432.CCR-05-2187
PMID: 16707597 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17545597
|
1. Cancer Res. 2007 Jun 1;67(11):5179-85. doi: 10.1158/0008-5472.CAN-06-4177.
Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic
hedgehog-dependent medulloblastoma formation in mice.
McCall TD(1), Pedone CA, Fults DW.
Author information:
(1)Department of Neurosurgery, University of Utah School of Medicine, Salt Lake
City, Utah 84132, USA.
Medulloblastomas are malignant brain tumors that arise in the cerebellum in
children. Aberrant activation of the Sonic hedgehog (Shh) signaling pathway,
which normally stimulates proliferation of granule neuron precursors (GNP)
during cerebellar development, induces tumors in mice that closely mimic human
medulloblastomas. Shh-dependent medulloblastoma formation is enhanced by
hyperactive insulin-like growth factor (IGF) signaling and ectopic expression of
Myc oncogenes. This enhanced tumorigenesis stems from the sensitivity of GNPs to
IGF and Myc levels in regulating proliferation. An emerging theme in cancer
research is that oncogene-induced cell proliferation cannot initiate neoplastic
transformation unless cellular programs that mediate apoptosis are disabled.
Here, we report a high frequency of medulloblastoma formation in mice after
postnatal overexpression of the antiapoptotic protein Bcl-2 in cooperation with
Shh. Ectopic expression of Bcl-2 alone or in combination with N-Myc did not
induce tumors, indicating that Shh has essential transforming functions in GNPs
not supplied by the mitogenic stimulus of N-Myc combined with a strong
antiapoptotic signal provided by Bcl-2. Expression of endogenous Bcl-2 was not
up-regulated in Shh-induced tumors. Instead, elevated levels of phosphorylated
Akt were found, suggesting that activated phosphatidylinositol 3-kinase
signaling is one intrinsic mechanism for suppressing apoptosis in Shh-dependent
medulloblastomas. Thus, blockade of apoptosis cooperates with Shh-stimulated
proliferation to transform GNPs and induce aggressive medulloblastomas. These
findings provide insights into the molecular signals that initiate
medulloblastoma formation and they support the importance of blocking apoptosis
in carcinogenesis.
DOI: 10.1158/0008-5472.CAN-06-4177
PMID: 17545597 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21358093
|
1. J Cancer Res Ther. 2010 Oct-Dec;6(4):521-9. doi: 10.4103/0973-1482.77072.
Distinctive microRNA signature of medulloblastomas associated with the WNT
signaling pathway.
Gokhale A(1), Kunder R, Goel A, Sarin R, Moiyadi A, Shenoy A, Mamidipally C,
Noronha S, Kannan S, Shirsat NV.
Author information:
(1)Advanced Centre for Treatment, Research and Education in Cancer, Tata
Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India.
AIM: Medulloblastoma is a malignant brain tumor that occurs predominantly in
children. Current risk stratification based on clinical parameters is inadequate
for accurate prognostication. MicroRNA expression is known to be deregulated in
various cancers and has been found to be useful in predicting tumor behavior. In
order to get a better understanding of medulloblastoma biology, miRNA profiling
of medulloblastomas was carried out in parallel with expression profiling of
protein-coding genes.
MATERIALS AND METHODS: miRNA profiling of medulloblastomas was carried out using
Taqman Low Density Array v 1.0 having 365 human microRNAs. In parallel,
genome-wide expression profiling of protein-coding genes was carried out using
Affymetrix gene 1.0 ST arrays.
RESULTS: Both the profiling studies identified four molecular subtypes of
medulloblastomas. Expression levels of select protein-coding genes and miRNAs
could classify an independent set of medulloblastomas. Twelve of 31
medulloblastomas were found to overexpress genes belonging to the canonical WNT
signaling pathway and carry a mutation in CTNNB1 gene. A number of miRNAs like
miR-193a, miR-224/miR-452 cluster, miR-182/miR-183/miR-96 cluster, and miR-148a
having potential tumor/metastasis suppressive activity were found to be
overexpressed in the WNT signaling associated medulloblastomas. Exogenous
expression of miR-193a and miR-224, two miRNAs that have the highest WNT pathway
specific upregulation, was found to inhibit proliferation, increase radiation
sensitivity and reduce anchorage-independent growth of medulloblastoma cells.
CONCLUSION: Expression level of tumor/metastasis suppressive miRNAs in the WNT
signaling associated medulloblastomas is likely to determine their response to
treatment, and thus, these miRNAs would be important biomarkers for risk
stratification within the WNT signaling associated medulloblastomas.
DOI: 10.4103/0973-1482.77072
PMID: 21358093 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19738049
|
1. Cancer Res. 2009 Sep 15;69(18):7224-34. doi: 10.1158/0008-5472.CAN-09-1299.
Epub 2009 Sep 8.
Tuberous sclerosis complex suppression in cerebellar development and
medulloblastoma: separate regulation of mammalian target of rapamycin activity
and p27 Kip1 localization.
Bhatia B(1), Northcott PA, Hambardzumyan D, Govindarajan B, Brat DJ, Arbiser JL,
Holland EC, Taylor MD, Kenney AM.
Author information:
(1)Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer
Center, New York, New York 10021, USA.
During development, proliferation of cerebellar granule neuron precursors
(CGNP), candidate cells-of-origin for the pediatric brain tumor medulloblastoma,
requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF),
the pathways of which are also implicated in medulloblastoma. One of the
consequences of IGF signaling is inactivation of the mammalian target of
rapamycin (mTOR)-suppressing tuberous sclerosis complex (TSC), comprised of TSC1
and TSC2, leading to increased mRNA translation. We show that mice, in which TSC
function is impaired, display increased mTOR pathway activation, enhanced CGNP
proliferation, glycogen synthase kinase-3 alpha/beta (GSK-3 alpha/beta)
inactivation, and cytoplasmic localization of the cyclin-dependent kinase
inhibitor p27(Kip1), which has been proposed to cause its inactivation or gain
of oncogenic functions. We observed the same characteristics in wild-type
primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in
mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover,
Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation,
and the mutant TSC2 allele synergized with aberrant Shh signaling to increase
medulloblastoma incidence in mice. Driving exogenous TSC2 expression in
Shh-induced medulloblastoma cells corrected p27(Kip1) localization and reduced
proliferation. GSK-3 alpha/beta inactivation in the tumors in vivo and in
primary CGNP cultures was mTOR-dependent, whereas p27(Kip1) cytoplasmic
localization was regulated upstream of mTOR by TSC2. These results indicate that
a balance between Shh mitogenic signaling and TSC function regulating new
protein synthesis and cyclin-dependent kinase inhibition is essential for the
normal development and prevention of tumor formation or expansion.
DOI: 10.1158/0008-5472.CAN-09-1299
PMCID: PMC2745891
PMID: 19738049 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest: None
|
http://www.ncbi.nlm.nih.gov/pubmed/25052069
|
1. Cancer Med. 2014 Oct;3(5):1146-58. doi: 10.1002/cam4.314. Epub 2014 Jul 23.
Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain
in medulloblastoma.
Wolle D(1), Lee SJ, Li Z, Litan A, Barwe SP, Langhans SA.
Author information:
(1)Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for
Children, Wilmington, Delaware, 19803.
Epidermal growth factor (EGF) signaling regulates cell growth, proliferation,
and differentiation. Upon receptor binding, EGF triggers cascades of downstream
signaling, including the MAPK and phosphoinositide-3-kinase (PI3K)/Akt signaling
pathways. Aberrant expression/activation of EGFR is found in multiple human
cancers, including medulloblastoma, the most prevalent pediatric brain cancer,
and often has been associated with metastasis, poor prognosis, and resistance to
chemotherapy. Na,K-ATPase is an ion pump well known for its role in
intracellular ion homeostasis. Recent studies showed that Na,K-ATPase also
functions as a signaling platform and revealed a role in EGFR, MAPK, and PI3K
signaling. While both EGFR and Na,K-ATPase seem to modulate similar signaling
pathways, cardiac glycosides that are steroid-like inhibitors of Na,K-ATPase,
exhibit antiproliferative and proapoptotic properties in cancer cells. Thus, we
sought to better understand the relationship between EGF and cardiac glycoside
signaling. Here, we show that in medulloblastoma cells, both EGF and ouabain
activate Erk1/2 and PI3K/Akt signaling. Nevertheless, in medulloblastoma cells
ouabain did not transactivate EGFR as has been reported in various other cell
lines. Indeed, ouabain inhibited EGF-induced Erk1/2 and Akt activation and,
moreover, prevented EGF-induced formation of actin stress fibers and cell
motility, probably by activating a stress signaling response. Na,K-ATPase has
been proposed to act as a signaling scaffold and our studies suggest that in
medulloblastoma cells Na,K-ATPase might act as a check point to integrate
EGF-associated signaling pathways. Thus, Na,K-ATPase might serve as a valid
target to develop novel therapeutic approaches in tumors with aberrant
activation of the EGFR signaling cascades.
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
DOI: 10.1002/cam4.314
PMCID: PMC4302666
PMID: 25052069 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24233780
|
1. Methods Mol Biol. 2014;1101:113-34. doi: 10.1007/978-1-62703-721-1_7.
Statistical tools and R software for cancer driver probabilities.
Parmigiani G(1), Boca S, Ding J, Trippa L.
Author information:
(1)Department of Biostatistics and Computational Biology, Dana Farber Cancer
Institute, Boston, MA, USA.
This chapter provides a description and illustration of CancerMutationAnalysis
and Cancer MutationMCMC, two open source R packages specifically designed for
the analysis of somatic mutations in cancer genome studies, at both the gene and
gene-set levels.
DOI: 10.1007/978-1-62703-721-1_7
PMID: 24233780 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21169372
|
1. Bioinformatics. 2011 Jan 15;27(2):175-81. doi: 10.1093/bioinformatics/btq630.
Epub 2010 Dec 17.
Identifying cancer driver genes in tumor genome sequencing studies.
Youn A(1), Simon R.
Author information:
(1)Biometric Research Branch, National Cancer Institute, Bethesda, MD
20892-7434, USA.
MOTIVATION: Major tumor sequencing projects have been conducted in the past few
years to identify genes that contain 'driver' somatic mutations in tumor
samples. These genes have been defined as those for which the non-silent
mutation rate is significantly greater than a background mutation rate estimated
from silent mutations. Several methods have been used for estimating the
background mutation rate.
RESULTS: We propose a new method for identifying cancer driver genes, which we
believe provides improved accuracy. The new method accounts for the functional
impact of mutations on proteins, variation in background mutation rate among
tumors and the redundancy of the genetic code. We reanalyzed sequence data for
623 candidate genes in 188 non-small cell lung tumors using the new method. We
found several important genes like PTEN, which were not deemed significant by
the previous method. At the same time, we determined that some genes previously
reported as drivers were not significant by the new analysis because mutations
in these genes occurred mainly in tumors with large background mutation rates.
AVAILABILITY: The software is available at:
http://linus.nci.nih.gov/Data/YounA/software.zip.
DOI: 10.1093/bioinformatics/btq630
PMCID: PMC3018819
PMID: 21169372 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19704786
|
1. Commun Integr Biol. 2008;1(1):34-6. doi: 10.4161/cib.1.1.6622.
Nucleoid autonomy: An underlying mechanism of mitochondrial genetics with
therapeutic potential.
Gilkerson RW(1), Schon EA.
Author information:
(1)Department of Neurology; College of Physicians and Surgeons; Columbia
University; New York, New York USA.
Comment on
Gilkerson RW, Schon EA, Hernandez E, Davidson MM. Mitochondrial nucleoids
maintain genetic autonomy but allow for functional complementation. J Cell Biol.
2008;181:1117–1128.
Emerging research shows that the packaging of mitochondrial DNA (mtDNA) into
protein-DNA assemblies called nucleoids confers higher-order organization to the
mitochondrial genome. Studies of nucleoid composition, structure and dynamics
reveal the mitochondrial nucleoid to be tightly regulated in its genetic
autonomy, macromolecular organization and distribution throughout the cell. Our
recent research shows that mitochondrial nucleoids are self-contained genetic
entities that do not exchange mtDNAs with each other frequently. This suggests
that the genetic composition of a cell's nucleoids will be the key determinant
of the cell's mtDNA dynamics, and provides a mechanistic basis for therapeutic
methods to rescue dysfunction due to mutations in mtDNA.
DOI: 10.4161/cib.1.1.6622
PMCID: PMC2633794
PMID: 19704786
|
http://www.ncbi.nlm.nih.gov/pubmed/23694700
|
1. IEEE Trans Nanobioscience. 2013 Sep;12(3):150-7. doi:
10.1109/TNB.2013.2263391. Epub 2013 May 16.
Adjusting for background mutation frequency biases improves the identification
of cancer driver genes.
Evans P(1), Avey S, Kong Y, Krauthammer M.
Author information:
(1)Department of Pathology, Yale University School of Medicine, New Haven, CT
06511, USA.
A common goal of tumor sequencing projects is finding genes whose mutations are
selected for during tumor development. This is accomplished by choosing genes
that have more non-synonymous mutations than expected from an estimated
background mutation frequency. While this background frequency is unknown, it
can be estimated using both the observed synonymous mutation frequency and the
non-synonymous to synonymous mutation ratio. The synonymous mutation frequency
can be determined across all genes or in a gene-specific manner. This choice
introduces an interesting trade-off. A gene-specific frequency adjusts for an
underlying mutation bias, but is difficult to estimate given missing synonymous
mutation counts. Using a genome-wide synonymous frequency is more robust, but is
less suited for adjusting biases. Studying four evaluation criteria for
identifying genes with high non-synonymous mutation burden (reflecting
preferential selection of expressed genes, genes with mutations in conserved
bases, genes with many protein interactions, and genes that show loss of
heterozygosity), we find that the gene-specific synonymous frequency is superior
in the gene expression and protein interaction tests. In conclusion, the use of
the gene-specific synonymous mutation frequency is well suited for assessing a
gene's non-synonymous mutation burden.
DOI: 10.1109/TNB.2013.2263391
PMCID: PMC3989533
PMID: 23694700 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21865355
|
1. J Clin Endocrinol Metab. 2011 Nov;96(11):3374-80. doi: 10.1210/jc.2011-1678.
Epub 2011 Aug 24.
Continuation of amiodarone delays restoration of euthyroidism in patients with
type 2 amiodarone-induced thyrotoxicosis treated with prednisone: a pilot study.
Bogazzi F(1), Bartalena L, Tomisti L, Rossi G, Brogioni S, Martino E.
Author information:
(1)Department of Endocrinology and Metabolism, University of Pisa, Ospedale
Cisanello, Via Paradisa, 2, 56124 Pisa, Italy. fausto.bogazzi@med.unipi.it
CONTEXT: Type 2 amiodarone-induced thyrotoxicosis (AIT) is a destructive
thyroiditis usually responsive to glucocorticoids. Whether continuation of
amiodarone affects treatment outcome is unsettled.
OBJECTIVE: The objective of the study was to compare the outcome of
glucocorticoid treatment in type 2 AIT patients who continued or withdrew
amiodarone.
DESIGN: This was a matched retrospective cohort study.
SETTING: The study was conducted at a university center.
PATIENTS: Eighty-three consecutive patients with untreated type 2 AIT
participated in the study. After matching with patients continuing amiodarone
(AMIO-ON, n = 8), patients interrupting amiodarone were randomly selected in a
4:1 ratio (AMIO-OFF, n = 32).
INTERVENTION: All patients were treated with oral prednisone. Patients whose
thyrotoxicosis recurred after glucocorticoid withdrawal were treated with a
second course of prednisone.
MAIN OUTCOME MEASURE: Time and rate of cure were measured.
RESULTS: Median time to the first normalization of serum thyroid hormone levels
did not significantly differ in AMIO-ON and AMIO-OFF patients (24 and 31 d,
respectively; P = 0.326). Conversely, median time for stably restoring
euthyroidism was 140 d in AMIO-ON patients and 47 d in AMIO-OFF patients (log
rank, P = 0.011). In fact, AIT recurred in five of seven AMIO-ON patients
(71.4%) and in only three of 32 AMIO-OFF patients (9.4%, P = 0.002), requiring
readministration of prednisone. One AMIO-ON patient never reached thyroid
hormone normalization during the study period. Factors associated with
glucocorticoid failure were thyroid volume and amiodarone continuation.
CONCLUSIONS: Prednisone restores euthyroidism in most type 2 AIT patients,
irrespective of amiodarone continuation or withdrawal. However, continuing
amiodarone increases the recurrence rate of thyrotoxicosis, causing a delay in
the stable restoration of euthyroidism and a longer exposure of the heart to
thyroid hormone excess.
DOI: 10.1210/jc.2011-1678
PMID: 21865355 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19703654
|
1. Int J Biochem Cell Biol. 2009 Oct;41(10):1899-906. doi:
10.1016/j.biocel.2009.03.016. Epub 2009 Apr 9.
Mitochondrial DNA nucleoids determine mitochondrial genetics and dysfunction.
Gilkerson RW(1).
Author information:
(1)Department of Neurology, College of Physicians & Surgeons, Columbia
University, Russ Berrie Pavilion 307, 1150 St. Nicholas Ave., New York, NY
10032, USA. rg2156@columbia.edu
Mitochondrial DNA plays a crucial role in cellular homeostasis; however, the
molecular mechanisms underlying mitochondrial DNA inheritance and propagation
are only beginning to be understood. To ensure the distribution and propagation
of the mitochondrial genome, mitochondrial DNA is packaged into macromolecular
assemblies called nucleoids, composed of one or more copies of mitochondrial DNA
and associated proteins. We review current research on the mitochondrial
nucleoid, including nucleoid-associated proteins, nucleoid dynamics within the
cell, potential mechanisms to ensure proper distribution of nucleoids, and the
impact of nucleoid organization on mitochondrial dysfunction. The nucleoid is
the molecular organizing unit of mitochondrial genetics, and is the site of
interactions that ultimately determine the bioenergetic state of the cell as a
whole. Current and future research will provide essential insights into the
molecular and cellular interactions that cause bioenergetic crisis, and yield
clues for therapeutic rescue of mitochondrial dysfunction.
DOI: 10.1016/j.biocel.2009.03.016
PMID: 19703654 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21225109
|
1. Arq Bras Cardiol. 2010 Oct;95(5):e122-4. doi: 10.1590/s0066-782x2010001500022.
Amiodarone and thyrotoxicosis: case reports.
[Article in English, Portuguese, Spanish]
Tavares AB(1), Paula SK, Vaisman M, Teixeira Pde F.
Author information:
(1)Hospital Universitário Clementino Fraga Filho, UFRJ, Rio de Janeiro, RJ,
Brasil. anabeatrizwinter@yahoo.com.br
Amiodarone-induced thyroid dysfunction has been reported to affect 2-24% of
users. Despite the easy management of amiodarone-induced hypothyroidism, the
development of thyrotoxicosis leads to a difficult approach in most cases. The
aim of this study is to describe three different cases of patients with
amiodarone-induced thyrotoxicosis and discuss the clinical and laboratorial
aspects, and the different approaches to them. It is essential to carefully
evaluate patients before and during amiodarone therapy, since the prompt
diagnosis and treatment of this condition is essential in patients with high
cardiovascular risk.
DOI: 10.1590/s0066-782x2010001500022
PMID: 21225109 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23637282
|
1. Cold Spring Harb Perspect Biol. 2013 May 1;5(5):a011080. doi:
10.1101/cshperspect.a011080.
The mitochondrial nucleoid: integrating mitochondrial DNA into cellular
homeostasis.
Gilkerson R(1), Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, Quintanilla
B.
Author information:
(1)Department of Biology, University of Texas-Pan American, Edinburg, TX
78539-2999, USA. gilkersonrw@utpa.edu
The packaging of mitochondrial DNA (mtDNA) into DNA-protein assemblies called
nucleoids provides an efficient segregating unit of mtDNA, coordinating mtDNA's
involvement in cellular metabolism. From the early discovery of mtDNA as
"extranuclear" genetic material, its organization into nucleoids and integration
into both the mitochondrial organellar network and the cell at large via a
variety of signal transduction pathways, mtDNA is a crucial component of the
cell's homeostatic network. The mitochondrial nucleoid is composed of a set of
DNA-binding core proteins involved in mtDNA maintenance and transcription, and a
range of peripheral factors, which are components of signaling pathways
controlling mitochondrial biogenesis, metabolism, apoptosis, and retrograde
mitochondria-to-nucleus signaling. The molecular interactions of nucleoid
components with the organellar network and cellular signaling pathways provide
exciting clues to the dynamic integration of mtDNA into cellular metabolic
homeostasis.
DOI: 10.1101/cshperspect.a011080
PMCID: PMC3632060
PMID: 23637282 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18339846
|
1. Cancer Res. 2008 Mar 15;68(6):1675-82. doi: 10.1158/0008-5472.CAN-07-5283.
Prediction of cancer driver mutations in protein kinases.
Torkamani A(1), Schork NJ.
Author information:
(1)Graduate Program in Biomedical Sciences, Center for Human Genetics and
Genomics, University of California, San Diego, CA, USA.
A large number of somatic mutations accumulate during the process of
tumorigenesis. A subset of these mutations contribute to tumor progression
(known as "driver" mutations) whereas the majority of these mutations are
effectively neutral (known as "passenger" mutations). The ability to
differentiate between drivers and passengers will be critical to the success of
upcoming large-scale cancer DNA resequencing projects. Here we show a method
capable of discriminating between drivers and passengers in the most frequently
cancer-associated protein family, protein kinases. We apply this method to
multiple cancer data sets, validating its accuracy by showing that it is capable
of identifying known drivers, has excellent agreement with previous statistical
estimates of the frequency of drivers, and provides strong evidence that
predicted drivers are under positive selection by various sequence and
structural analyses. Furthermore, we identify particular positions in protein
kinases that seem to play a role in oncogenesis. Finally, we provide a ranked
list of candidate driver mutations.
DOI: 10.1158/0008-5472.CAN-07-5283
PMID: 18339846 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23873099
|
1. Tumour Biol. 2013 Oct;34(5):2497-506. doi: 10.1007/s13277-013-1002-x. Epub
2013 Jul 20.
Twist: a molecular target in cancer therapeutics.
Khan MA(1), Chen HC, Zhang D, Fu J.
Author information:
(1)Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical
Medicine, Luzhou Medical College, 3-319 Zhongshan Road, Luzhou, Sichuan, 646000,
China.
Twist, the basic helix-loop-helix transcription factor, is involved in the
process of epithelial to mesenchymal transitions (EMTs), which play an essential
role in cancer metastasis. Overexpression of Twist or its promoter methylation
is a common scenario in metastatic carcinomas. Twist is activated by a variety
of signal transduction pathways, including Akt, signal transducer and activator
of transcription 3, mitogen-activated protein kinase, Ras, and Wnt signaling.
Activated Twist upregulates N-cadherin and downregulates E-cadherin, which are
the hallmarks of EMT. Moreover, Twist plays an important role in some
physiological processes involved in metastasis, like angiogenesis, invadopodia,
extravasation, and chromosomal instability. Twist also protects cancer cells
from apoptotic cell death. In addition, Twist is responsible for the stemness of
cancer cells and the generation of drug resistance. Recently, targeting Twist
has gained significant interests in cancer therapeutics. The inactivation of
Twist by small RNA technology or chemotherapeutic approach has been proved
successful. Moreover, several inhibitors which are antagonistic to the upstream
or downstream molecules of Twist signaling pathways have also been identified.
Development of potential treatment strategies by targeting Twist has a great
promise in cancer therapeutics.
DOI: 10.1007/s13277-013-1002-x
PMID: 23873099 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24084849
|
1. Sci Rep. 2013 Oct 2;3:2650. doi: 10.1038/srep02650.
Comprehensive identification of mutational cancer driver genes across 12 tumor
types.
Tamborero D(1), Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand
J, Lawrence MS, Getz G, Bader GD, Ding L, Lopez-Bigas N.
Author information:
(1)1] Research Unit on Biomedical Informatics, Department of Experimental and
Health Sciences, Universitat Pompeu Fabra, Dr. Aiguader 88, Barcelona, Spain
[2].
With the ability to fully sequence tumor genomes/exomes, the quest for cancer
driver genes can now be undertaken in an unbiased manner. However, obtaining a
complete catalog of cancer genes is difficult due to the heterogeneous molecular
nature of the disease and the limitations of available computational methods.
Here we show that the combination of complementary methods allows identifying a
comprehensive and reliable list of cancer driver genes. We provide a list of 291
high-confidence cancer driver genes acting on 3,205 tumors from 12 different
cancer types. Among those genes, some have not been previously identified as
cancer drivers and 16 have clear preference to sustain mutations in one specific
tumor type. The novel driver candidates complement our current picture of the
emergence of these diseases. In summary, the catalog of driver genes and the
methodology presented here open new avenues to better understand the mechanisms
of tumorigenesis.
DOI: 10.1038/srep02650
PMCID: PMC3788361
PMID: 24084849 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20577028
|
1. Gen Physiol Biophys. 2010 Jun;29(2):160-74.
Mouse and human mitochondrial nucleoid--detailed structure in relation to
function.
Prachar J(1).
Author information:
(1)Laboratory of Electron Microscopy, Cancer Research Institute, Slovak Academy
of Sciences, Vlárska 7, 833 91 Bratislava, Slovakia. jarmil.prachar@savba.sk
The independent mitochondrial genetic information is organized in so-called
mitochondrial nucleoids that, in vertebrates, typically contain 5-7 genetic
units. The total number of nucleoids per cell is several hundred in cultured
cells. Mitochondrial nucleoids, similarly to the whole mitochondrial network,
have recently been successfully and extensively visualized using fluorescent and
confocal microscopy. In the present work, we show high-resolution micrographs of
mouse and human mitochondrial nucleoids obtained by transmission electron
microscopy. Position in the mitochondria, size, general appearance and other
properties of the human nucleoids appear the same as those of mouse nucleoids,
and all observations are also in full agreement with the results obtained in
different laboratories using different approaches. Most of nucleoids are located
inside mitochondrial tubes. However, we show directly that certain part of the
nucleoids close to inner membrane is bound to the complex of molecules that
crosscut both, the inner and the outer mitochondrial membranes. Nucleoids in
cells starving for serum are mostly more dense than those in dividing cells. We
discuss the position, appearance and other properties of the nucleoids in
relation to functional stage. Other electron-dense structures inside
mitochondria that could be erroneously considered to be mitochondrial nucleoids
are also described.
PMID: 20577028 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23220174
|
1. Int J Biochem Cell Biol. 2013 Mar;45(3):593-603. doi:
10.1016/j.biocel.2012.11.019. Epub 2012 Dec 7.
Distribution of mitochondrial nucleoids upon mitochondrial network fragmentation
and network reintegration in HEPG2 cells.
Tauber J(1), Dlasková A, Šantorová J, Smolková K, Alán L, Špaček T,
Plecitá-Hlavatá L, Jabůrek M, Ježek P.
Author information:
(1)Department of Membrane Transport Biophysics, No. 75, Institute of Physiology,
Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Mitochondrial DNA (mtDNA) is organized in nucleoids in complex with accessory
proteins, proteins of mtDNA replication and gene expression machinery. A robust
mtDNA genome is represented by hundreds to thousands of nucleoids in cell
mitochondrion. Detailed information is lacking about the dynamics of nucleoid
distribution within the mitochondrial network upon physiological and
pathological events. Therefore, we used confocal microscopy to study
mitochondrial nucleoid redistribution upon mitochondrial fission and following
reintegration of the mitochondrial network. Fission was induced by oxidative
stress at respiration inhibition by rotenone or upon elimination of the
protonmotive force by uncoupling or upon canceling its electrical component,
ΔΨ(m), by valinomycin; and by silencing of mitofusin MFN2. Agent withdrawal
resulted in concomitant mitochondrial network reintegration. We found two major
principal morphological states: (i) a tubular state of the mitochondrial network
with equidistant nucleoid spacing, 1.10±0.2 nucleoids per μm, and (ii) a
fragmented state of solitary spheroid objects in which several nucleoids were
clustered. We rarely observed singular mitochondrial fragments with a single
nucleoid inside and very seldom we observed empty fragments. Reintegration of
fragments into the mitochondrial network re-established the tubular state with
equidistant nucleoid spacing. The two major morphological states coexisted at
intermediate stages. These observations suggest that both mitochondrial network
fission and reconnection of the disintegrated network are nucleoid-centric,
i.e., fission and new mitochondrial tubule formation are initiated around
nucleoids. Analyses of combinations of these morphological icons thus provide a
basis for a future mitochondrial morphology diagnostics.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.biocel.2012.11.019
PMID: 23220174 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18421194
|
1. Intern Med. 2008;47(8):757-62. doi: 10.2169/internalmedicine.47.0843. Epub
2008 Apr 16.
Differential diagnosis and appropriate treatment of four thyrotoxic patients
with Graves' disease required to take amiodarone due to life-threatening
arrhythmia.
Sato K(1), Omi Y, Kodama H, Obara T, Yamazaki K, Yamada E, Seki T, Takano K,
Shiga T, Kasanuki H.
Author information:
(1)Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's
Medical University, Tokyo. satokan@attglobal.net
We report the treatment of four thyrotoxic patients. Two were cases of type I
amiodarone-induced thyrotoxicosis (AIT) treated with methimazole. The third
Graves' disease patient, who became hypothyroid 25 years after subtotal
thyroidectomy, developed type II AIT. Furthermore, one case with heart failure
and ventricular tachycardia, who developed an adverse reaction to antithyroid
agents and was prescribed amiodarone, underwent total thyroidectomy. The
clinical course was uneventful, and the patient is doing well. Since amiodarone
contains a large amount of iodine, it is frequently difficult to make a
differential diagnosis. Surgical treatment of Graves' disease patients is
recommended when immediate control of hyperthyroidism and heart failure is
required.
DOI: 10.2169/internalmedicine.47.0843
PMID: 18421194 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12869229
|
1. Int J STD AIDS. 2003 Jul;14(7):478-81. doi: 10.1258/095646203322025795.
Comparison of symptoms of influenza A with abacavir-associated hypersensitivity
reaction.
Keiser P(1), Nassar N, Skiest D, Andrews C, Yazdani B, White A, Hetherington S.
Author information:
(1)University of Texas Southwestern Medical Center at Dallas, Texas 75235, USA.
Philip.Keiser@email.swmed.edu
Differentiation between abacavir hypersensitivity and viral respiratory
infections is problematic. Fifteen cases of abacavir hypersensitivity were
matched to 30 controls with culture proven influenza A with no abacavir
exposure. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P =
0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P
= 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal
symptoms was also predictive of hypersensitivity reaction (P < 0.001).
Respiratory symptoms (cough, sore throat, or dyspnoea) were not associated with
abacavir hypersensitivity (OR = 0.08, P = 0.001). Multivariate analysis
confirmed the following associations for abacavir hypersensitivity: the number
of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P =
0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly
associated with gastrointestinal (GI) symptoms. Cough without GI symptoms is
associated with influenza.
DOI: 10.1258/095646203322025795
PMID: 12869229 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23721879
|
1. Trends Cell Biol. 2013 Sep;23(9):457-63. doi: 10.1016/j.tcb.2013.04.009. Epub
2013 May 27.
mtDNA makes a U-turn for the mitochondrial nucleoid.
Kukat C(1), Larsson NG.
Author information:
(1)Department of Mitochondrial Biology, Max Planck Institute for Biology of
Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.
Mitochondria contain mtDNA derived from the ancestral endosymbiont genome.
Important subunits of the oxidative phosphorylation system, which supplies cells
with the energy currency ATP, are encoded by mtDNA. A naked mtDNA molecule is
longer than a typical mitochondrion and is therefore compacted in vivo to form a
nucleoprotein complex, denoted the mitochondrial nucleoid. Mitochondrial
transcription factor A (TFAM) is the main factor packaging mtDNA into nucleoids
and is also essential for mtDNA transcription initiation. The crystal structure
of TFAM shows that it bends mtDNA in a sharp U-turn, which likely provides the
structural basis for its dual functions. Super-resolution imaging studies have
revealed that the nucleoid has an average diameter of ∼100nm and frequently
contains a single copy of mtDNA. In this review the structure of the
mitochondrial nucleoid and its possible regulatory roles in mtDNA expression
will be discussed.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tcb.2013.04.009
PMID: 23721879 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22865896
|
1. J Clin Endocrinol Metab. 2012 Oct;97(10):3515-21. doi: 10.1210/jc.2012-1797.
Epub 2012 Aug 3.
Total thyroidectomy in patients with amiodarone-induced thyrotoxicosis and
severe left ventricular systolic dysfunction.
Tomisti L(1), Materazzi G, Bartalena L, Rossi G, Marchello A, Moretti M, De
Napoli L, Mariotti R, Miccoli P, Martino E, Bogazzi F.
Author information:
(1)Department of Endocrinology and Metabolism, University of Pisa, Ospedale
Cisanello, Via Paradisa, 2, 56124 Pisa, Italy.
CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and left
ventricular (LV) systolic dysfunction have a high mortality rate. Usually,
medical therapy is the first choice for AIT patients, whereas the role of the
thyroidectomy is unsettled.
OBJECTIVE: The objective of the study was to evaluate the effect of a total
thyroidectomy on cardiac function and survival of AIT patients with severe LV
systolic dysfunction.
DESIGN: This was a retrospective cohort study.
SETTINGS: The study was conducted at a tertiary university center.
PATIENTS: All AIT patients (n=24; nine patients with type 1 AIT, 15 patients
with type 2 AIT) referred to the Department of Endocrinology and submitted to a
total thyroidectomy at the Department of Surgery, both at the University of
Pisa, during the years 1997-2010.
INTERVENTION: The intervention was a total thyroidectomy.
MAIN OUTCOME MEASURE: LV ejection fraction (EF) after the thyroidectomy and
survival in December 2011 were measured.
RESULTS: All enrolled patients had previously undergone to medical treatment for
AIT, as appropriate, without achieving euthyroidism. Patients with moderate to
severe LV systolic dysfunction (EF<40%, group 1, n=9) or with mild systolic
dysfunction (40%≤EF≤50%, group 2, n=5) were compared with patients with normal
systolic function (EF>50%, group 3, n=10). Two months after thyroidectomy, under
levothyroxine replacement therapy, LVEF improved in patients with LV systolic
dysfunction, particularly in those of group 1, in whom it increased from
28.2±7.2 to 38.3±6% (P=0.007). On the contrary, LVEF did not significantly
change in group 3 (from 57.1±3.0 to 59.8±6.6%, P=0.242). The mean follow-up was
67±42 months. No death occurred during and 2 months after surgery. One death
occurred in one patient of group 1, 30 months after the thyroidectomy, due to
acute myocardial infarction. No patient had relevant complications of
thyroidectomy.
CONCLUSIONS: Total thyroidectomy, by rapidly restoring euthyroidism, may improve
cardiac function and reduce the risk of mortality in AIT patients with severe LV
dysfunction.
DOI: 10.1210/jc.2012-1797
PMID: 22865896 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18595575
|
1. J Natl Med Assoc. 2008 Jun;100(6):716-9. doi: 10.1016/s0027-9684(15)31348-1.
Radioactive iodine in the treatment of type-2 amiodarone-induced thyrotoxicosis.
Gursoy A(1), Tutuncu NB, Gencoglu A, Anil C, Demirer AN, Demirag NG.
Author information:
(1)Department of Endocrinology and Metabolism, Baskent University Faculty of
Medicine, Ankara, Turkey. alptekingursoy@hotmail.com
OBJECTIVE: Amiodarone-induced thyrotoxicosis (AIT) is usually classified into
two types: type 1, in which a high iodine content triggers the autonomous
production of thyroid hormone; and type 2, in which destructive thyroiditis
causes the release of preformed thyroid hormone. AIT is a difficult management
problem that sometimes requires ablative thyroid therapy. The use of radioactive
iodine (RAI) therapy in patients with type-1 AIT who had a 24-hour radioactive
iodine uptake (RAIU) value of >10% has been previously reported. Despite its
documented efficacy at usual doses (10-30 mCi) in patients with type-1 AIT, the
efficacy of RAI in those with type-2 AIT has never been questioned, because
type-2 patients usually have low RAIU. We thought that high adjusted-dose RAI
might be an attractive alternative to thyroid gland ablation in patients with
type-2 AIT.
PATIENTS AND METHODS: Four patients with type-2 AIT who required thyroid
ablation were included in the study. These individuals were either poor
candidates for surgery or had refused surgery. The size of the thyroid gland in
all subjects was within normal limits, and each thyroid was characterized by a
homogenous echotexture on ultrasonography, the absence of vascularity on Doppler
sonography, a low (<4%) 24-hour RAIU value and the absence of thyroid
autoantibodies-all of which are characteristic of type-2 AIT.
RESULTS: The patients were initially treated with thionamides and
glucocorticoids. All patients except one achieved euthyroidism before RAI
therapy. All four patients received one dose of RAI (range 29-80 mCi) and
followed up for 12 months. No exacerbation of thyrotoxicosis was noted after RAI
therapy. Hypothyroidism (in three patients) or euthyroidism (in one patient) was
achieved in first six months.
CONCLUSIONS: In patients with type-2 AIT, RAI treatment may be the therapy of
choice for thyroid gland ablation.
DOI: 10.1016/s0027-9684(15)31348-1
PMID: 18595575 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22130792
|
1. J Clin Endocrinol Metab. 2012 Feb;97(2):499-506. doi: 10.1210/jc.2011-2390.
Epub 2011 Nov 30.
Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical
trial.
Eskes SA(1), Endert E, Fliers E, Geskus RB, Dullaart RP, Links TP, Wiersinga WM.
Author information:
(1)Department of Endocrinology and Metabolism, Academic Medical Center,
University of Amsterdam, Amsterdam 1105AZ, The Netherlands. s.eskes@sfg.nl
CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) type 2 is self-limiting in
nature, but most physicians are reluctant to continue amiodarone. When
prednisone fails to restore euthyroidism, possibly due to mixed cases of AIT
type 1 and 2, perchlorate (ClO(4)) might be useful because ClO(4) reduces the
cytotoxic effect of amiodarone on thyrocytes.
OBJECTIVES: Our objectives were to demonstrate the feasibility of continuation
of amiodarone in AIT type 2 and to evaluate the usefulness of ClO(4) (given
alone or in combination with prednisone) in AIT type 2.
DESIGN AND SETTING: A randomized multicenter study was conducted in 10 Dutch
hospitals.
METHODS: Patients with AIT type 2 were randomized to receive prednisone 30 mg/d
(group A, n = 12), sodium perchlorate 500 mg twice daily (group B, n = 14), or
prednisone plus perchlorate (group C, n = 10); all patients continued amiodarone
and were also treated with methimazole 30 mg/d. Follow-up was 2 yr.
MAIN OUTCOME MEASURES: Treatment efficacy (defined as TSH values ≥ 0.4 mU/liter
under continuation of amiodarone) and recurrent thyrotoxicosis were evaluated.
RESULTS: Initial therapy was efficacious in 100, 71, and 100% of groups A, B,
and C, respectively (P = 0.03). The 29% failures in group B became euthyroid
after addition of prednisone. Neither the time to reach TSH of 0.4 mU/liter or
higher [8 wk (4-20), 14 wk (4-32), and 12 wk (4-28) in groups A, B, and C
respectively] nor the time to reach free T(4) of 25 pmol/liter or below [4 wk
(4-20), 12 wk (4-20), and 8 wk (4-20) in groups A, B, and C) were significantly
different between groups (values as median with range). Recurrent thyrotoxicosis
occurred in 8.3%.
CONCLUSION: Euthyroidism was reached despite continuation of amiodarone in all
patients. Prednisone remains the preferred treatment modality of AIT type 2,
because perchlorate given alone or in combination with prednisone had no better
outcomes.
DOI: 10.1210/jc.2011-2390
PMID: 22130792 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24009526
|
1. PLoS Genet. 2013 Aug;9(8):e1003734. doi: 10.1371/journal.pgen.1003734. Epub
2013 Aug 29.
Comparative oncogenomic analysis of copy number alterations in human and
zebrafish tumors enables cancer driver discovery.
Zhang G(1), Hoersch S, Amsterdam A, Whittaker CA, Beert E, Catchen JM,
Farrington S, Postlethwait JH, Legius E, Hopkins N, Lees JA.
Author information:
(1)David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge,
Massachusetts, United States of America.
Comment in
Cross-species Array Comparative Genomic Hybridization Identifies Novel
Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma.
The identification of cancer drivers is a major goal of current cancer research.
Finding driver genes within large chromosomal events is especially challenging
because such alterations encompass many genes. Previously, we demonstrated that
zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly
aneuploid, much like human tumors. In this study, we examined 147 zebrafish
MPNSTs by massively parallel sequencing and identified both large and focal copy
number alterations (CNAs). Given the low degree of conserved synteny between
fish and mammals, we reasoned that comparative analyses of CNAs from fish versus
human MPNSTs would enable elimination of a large proportion of passenger
mutations, especially on large CNAs. We established a list of orthologous genes
between human and zebrafish, which includes approximately two-thirds of human
protein-coding genes. For the subset of these genes found in human MPNST CNAs,
only one quarter of their orthologues were co-gained or co-lost in zebrafish,
dramatically narrowing the list of candidate cancer drivers for both focal and
large CNAs. We conclude that zebrafish-human comparative analysis represents a
powerful, and broadly applicable, tool to enrich for evolutionarily conserved
cancer drivers.
DOI: 10.1371/journal.pgen.1003734
PMCID: PMC3757083
PMID: 24009526 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/22851646
|
1. Genetics. 2012 Oct;192(2):385-96. doi: 10.1534/genetics.112.142802. Epub 2012
Jul 30.
Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast
cancer driver.
Wallace MD(1), Pfefferle AD, Shen L, McNairn AJ, Cerami EG, Fallon BL, Rinaldi
VD, Southard TL, Perou CM, Schimenti JC.
Author information:
(1)Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA.
Identifying genomic alterations driving breast cancer is complicated by tumor
diversity and genetic heterogeneity. Relevant mouse models are powerful for
untangling this problem because such heterogeneity can be controlled. Inbred
Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors
that have tumor gene expression profiles closely resembling mature human mammary
luminal cell signatures. We genomically characterized mammary adenocarcinomas
from these mice to identify cancer-causing genomic events that overlap common
alterations in human breast cancer. Chaos3 tumors underwent recurrent copy
number alterations (CNAs), particularly deletion of the RAS inhibitor
Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs
including NF1, which is deleted or mutated in 27.7% of all breast carcinomas.
Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity
to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can
drive breast cancer. This should be informative for treatment of the significant
fraction of patients whose tumors bear NF1 mutations.
DOI: 10.1534/genetics.112.142802
PMCID: PMC3454871
PMID: 22851646 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24214964
|
1. Nucleic Acids Res. 2014 Jan;42(Database issue):D1048-54. doi:
10.1093/nar/gkt1025. Epub 2013 Nov 7.
DriverDB: an exome sequencing database for cancer driver gene identification.
Cheng WC(1), Chung IF, Chen CY, Sun HJ, Fen JJ, Tang WC, Chang TY, Wong TT, Wang
HW.
Author information:
(1)Pediatric Neurosurgery, Department of Surgery, Cheng Hsin General Hospital,
Taipei 11220, Taiwan, VGH-YM Genomic Research Center, National Yang-Ming
University, Taipei 11221, Taiwan, Institute of Biomedical Informatics, National
Yang-Ming University, Taipei 11221, Taiwan, Information Technology Office,
Taipei Veterans General Hospital, Taipei 11217, Taiwan, Institute of
Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan
and Department of Education and Research, Taipei City Hospital, Taipei 10341,
Taiwan.
Exome sequencing (exome-seq) has aided in the discovery of a huge amount of
mutations in cancers, yet challenges remain in converting oncogenomics data into
information that is interpretable and accessible for clinical care. We
constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which
incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP,
1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to
driver gene/mutation identification. We provide two points of view, 'Cancer' and
'Gene', to help researchers to visualize the relationships between cancers and
driver genes/mutations. The 'Cancer' section summarizes the calculated results
of driver genes by eight computational methods for a specific cancer
type/dataset and provides three levels of biological interpretation for
realization of the relationships between driver genes. The 'Gene' section is
designed to visualize the mutation information of a driver gene in five
different aspects. Moreover, a 'Meta-Analysis' function is provided so
researchers may identify driver genes in customer-defined samples. The novel
driver genes/mutations identified hold potential for both basic research and
biotech applications.
DOI: 10.1093/nar/gkt1025
PMCID: PMC3965046
PMID: 24214964 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11577024
|
1. Circ Res. 2001 Sep 28;89(7):591-8. doi: 10.1161/hh1901.096706.
Regulation of thyroid hormone receptor isoforms in physiological and
pathological cardiac hypertrophy.
Kinugawa K(1), Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, Camacho SA,
Bristow MR, Long CS, Simpson PC.
Author information:
(1)Division of Cardiology, University of Colorado Health Sciences Center,
Denver, CO, USA.
Physiological and pathological cardiac hypertrophy have directionally opposite
changes in transcription of thyroid hormone (TH)-responsive genes, including
alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum
Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional
abnormalities in pathological hypertrophy, such as pressure overload. These
findings suggest relative hypothyroidism in pathological hypertrophy, but serum
levels of TH are usually normal. We studied the regulation of TH receptors (TRs)
beta1, alpha1, and alpha2 in pathological and physiological rat cardiac
hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH
target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were
downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype,
phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was
upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine,
T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or
excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and
promoters. In addition, TR cotransfection and treatment with the
TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR
isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and
TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude
that TR isoforms have distinct regulation and function in rat cardiac myocytes.
Changes in myocyte TR levels can explain in part the characteristic molecular
phenotypes in physiological and pathological cardiac hypertrophy.
DOI: 10.1161/hh1901.096706
PMID: 11577024 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22833515
|
1. Eur Heart J. 2013 Sep;34(36):2839-49. doi: 10.1093/eurheartj/ehs218. Epub 2012
Jul 24.
Heart rate reduction by If-inhibition improves vascular stiffness and left
ventricular systolic and diastolic function in a mouse model of heart failure
with preserved ejection fraction.
Reil JC(1), Hohl M, Reil GH, Granzier HL, Kratz MT, Kazakov A, Fries P, Müller
A, Lenski M, Custodis F, Gräber S, Fröhlig G, Steendijk P, Neuberger HR, Böhm M.
Author information:
(1)Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische
Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Straße D 66421,
Homburg/Saar, Germany.
AIMS: In diabetes mellitus, heart failure with preserved ejection fraction
(HFPEF) is a significant comorbidity. No therapy is available that improves
cardiovascular outcomes. The aim of this study was to characterize myocardial
function and ventricular-arterial coupling in a mouse model of diabetes and to
analyse the effect of selective heart rate (HR) reduction by If-inhibition in
this HFPEF-model.
METHODS AND RESULTS: Control mice, diabetic mice (db/db), and db/db mice treated
for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic
distensibility was measured by magnetic resonance imaging. Left ventricular (LV)
pressure-volume analysis was performed in isolated working hearts, with
biochemical and histological characterization of the cardiac and aortic
phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced
compared with controls and were prevented by HR reduction in db/db-Iva. Left
ventricular end-systolic elastance (Ees) was increased in db/db compared with
controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other
contractility markers were reduced. Heart rate reduction in db/db-Iva lowered
Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility
parameters. In db/db active relaxation was prolonged and end-diastolic
capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01).
These parameters were ameliorated by HR reduction. Neither myocardial fibrosis
nor hypertrophy were detected in db/db, whereas titin N2B expression was
increased and phosphorylation of phospholamban was reduced both being prevented
by HR reduction in db/db-Iva.
CONCLUSION: In db/db, a model of HFPEF, selective HR reduction by If-inhibition
improved vascular stiffness, LV contractility, and diastolic function.
Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed
in humans.
DOI: 10.1093/eurheartj/ehs218
PMCID: PMC3858102
PMID: 22833515 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17245797
|
1. Pharmacoepidemiol Drug Saf. 2007 Mar;16(3):289-96. doi: 10.1002/pds.1337.
Identification of abacavir hypersensitivity reaction in health care claims data.
Nordstrom BL(1), Norman HS, Dube TJ, Wilcox MA, Walker AM.
Author information:
(1)i3 Drug Safety, Auburndale, MA, USA.
PURPOSE: Abacavir is associated with an infrequent but potentially serious
hypersensitivity reaction (HSR) that can include a wide range of signs and
symptoms. Identification of this reaction through medical insurance claims could
provide a simple and efficient means of monitoring the incidence of abacavir
hypersensitivity in large populations of patients.
METHODS: Using data from a safety study of 948 abacavir users with 22
hypersensitivity events identified from claims and validated through medical
record review, we used a recursive partitioning analysis to construct an
algorithm to differentiate between patients with and without validated adverse
events. Bootstrap resampling techniques provided validation for the analysis.
RESULTS: The analysis produced a classification tree with three decision nodes
that comprised the best indicators of HSRs. The predictors included any one of
several specific symptoms commonly found with this reaction, a claims diagnosis
of adverse effect of drug, anaphylactic shock or unspecified allergy, and a
discontinuation in abacavir prior to completing a 90-day course of therapy. The
algorithm demonstrated 95% sensitivity and 90% specificity when tested using a
bootstrap resampling approach with the current data.
CONCLUSIONS: A sensitive and specific algorithm for identifying abacavir
hypersensitivity from claims was created. This algorithm would permit efficient
identification of charts for medical review. Further testing of the algorithm
with additional medical claims data for abacavir users will be required to
ascertain its validity across databases.
(c) 2007 John Wiley & Sons, Ltd.
DOI: 10.1002/pds.1337
PMID: 17245797 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20005474
|
1. Trends Cardiovasc Med. 2009 Jul;19(5):152-7. doi: 10.1016/j.tcm.2009.09.002.
Heart rate reduction by I(f)-channel inhibition and its potential role in heart
failure with reduced and preserved ejection fraction.
Reil JC(1), Reil GH, Böhm M.
Author information:
(1)Klinik für Innere Medizin III, University of the Saarland, Homburg Saar,
Germany. reil@med-in.uni-saarland.de
Selective heart rate (HR) reduction by I(f)-channel inhibition is a recently
developed pharmacological principle in cardiovascular therapy. Among these newly
identified HR-lowering drugs, only ivabradine has now become approved for
clinical use. I(f)-channel inhibition mainly reduces HR, thereby improving
myocardial oxygen supply, energy balance, and cardiac function. Ivabradine was
well tolerated and revealed a good safety profile in the investigated study
populations. The guiding experimental and clinical results of I(f)-channel
inhibition were compared to those of beta-blockade as a HR reducing principle as
well as cornerstone of heart failure standard therapy. Beside its use in therapy
of coronary artery disease, I(f)-channel inhibition potentially exhibits
beneficial effects in systolic and diastolic heart failure as well. Therefore,
hemodynamic effects of ivabradine and its limitations in heart failure together
with the biological impact of HR reduction will be considered in this context.
Because no clinical data with specific heart-rate-reducing agents are available
in heart failure patients until now, the prospective significance of
I(f)-channel inhibition can only be speculated on. However, the presented
results and considerations are encouraging: ivabradine may play a therapeutic
role in the future protecting left ventricular function and structure from early
deterioration in heart failure with reduced and preserved ventricular ejection
fraction.
DOI: 10.1016/j.tcm.2009.09.002
PMID: 20005474 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22260378
|
1. Ren Fail. 2012;34(3):364-72. doi: 10.3109/0886022X.2011.647342. Epub 2012 Jan
20.
Serum T3 level can predict cardiovascular events and all-cause mortality rates
in CKD patients with proteinuria.
Yang JW(1), Han ST, Song SH, Kim MK, Kim JS, Choi SO, Han BG.
Author information:
(1)Department of Nephrology, Wonju College of Medicine, Yonsei University,
Wonju, Gangwon-do, South Korea.
BACKGROUND: Patients with proteinuria frequently show changes in thyroid hormone
levels. Serum T3 depression predicts a negative outcome in chronic kidney
disease (CKD) patients and may be associated with cardiovascular complications
or chronic inflammation. Few studies have explored the relationship between
thyroid hormone dysregulation and clinical outcome in patients with proteinuria.
METHODS: We reviewed thyroid function test results obtained from 211 patients
with 24 h urinary protein excretion greater than 150 mg/day and found a
correlation of thyroid hormone level with cardiovascular events and mortality.
RESULTS: T3 decreased with age (p = 0.001) and 24 h urine albumin (p = 0.028).
Free T4 decreased in accordance with 24 h urine protein and serum creatinine (p
= 0.034 and p = 0.033, respectively). In the Kaplan-Meier survival analysis,
lower cumulative survival, higher cardiovascular events, and mortality were
found in the low T3 group compared with the normal T3 group (p = 0.000, p =
0.013, and p = 0.001, respectively). In Cox regression analysis, we observed
that, with low T3, decreased sodium, and old age, the incidence of
cardiovascular complications (p = 0.000, p = 0.016, and p = 0.000,
respectively), cardiovascular mortality (p = 0.000, p = 0.048, and p = 0.001,
respectively), and all-cause mortality (p = 0.000, p = 0.017, and p = 0.000,
respectively) increased.
CONCLUSION: In CKD patients with proteinuria, low T3 concentration predicted
all-cause mortality and cardiovascular event independently of the severity of
proteinuria.
DOI: 10.3109/0886022X.2011.647342
PMID: 22260378 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8725589
|
1. Dermatol Clin. 1996 Apr;14(2):339-54. doi: 10.1016/s0733-8635(05)70361-2.
Burning mouth syndrome.
Lamey PJ(1).
Author information:
(1)Department of Oral Medicine, School of Clinical Dentistry, Queen's University
of Belfast, Northern Ireland.
Burning mouth syndrome is a common condition particularly affecting elderly
women. Numerous precipitating factors are recognized that lead to a burning
sensation in clinically normal mucosa. By taking each precipitating factor into
account, a favorable treatment outcome usually can be achieved. This article
highlights the significance of precipitating factors in burning mouth syndrome
and suggests a treatment protocol based on current scientific evidence.
DOI: 10.1016/s0733-8635(05)70361-2
PMID: 8725589 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18855539
|
1. Pharmacogenomics. 2008 Oct;9(10):1531-41. doi: 10.2217/14622416.9.10.1531.
Current trends in screening across ethnicities for hypersensitivity to abacavir.
Rodriguez-Nóvoa S(1), Soriano V.
Author information:
(1)Department of Pharmacokinetics and Pharmacogenomics, Hospital Carlos III,
Calle Sinesio Delgado 10, Madrid 28029, Spain. sonia_r_novoa@hotmail.com
Abacavir is a potent nucleoside analog reverse transcriptase inhibitor approved
for the treatment of HIV infection. Approximately 5-8% of Caucasian patients
receiving abacavir develop a hypersensitivity reaction, characterized by rash,
fever and, occasionally, multisystemic involvement. Rechallenge with the drug
can be fatal. The discovery of the mechanisms involved in this hypersensitivity
reaction and the identification of tools for its prediction are the subject of
this review. The most relevant finding is the recognition of a strong
association between one specific haplotype at the HLA complex type I,
HLA-B*5701, and the abacavir hypersensitivity reaction. The heterogeneity in the
prevalence of HLA-B*5701 across distinct ethnicities accounts for differences in
the risk of abacavir hypersensitivity reactions in distinct populations.
DOI: 10.2217/14622416.9.10.1531
PMID: 18855539 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14704232
|
1. Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1696-705. doi:
10.1152/ajpheart.00761.2003. Epub 2004 Jan 2.
Exercise training improves cardiac function-related gene levels through thyroid
hormone receptor signaling in aged rats.
Iemitsu M(1), Miyauchi T, Maeda S, Tanabe T, Takanashi M, Matsuda M, Yamaguchi
I.
Author information:
(1)Cardiovascular Division, Department of Internal Medicine, Institute of
Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Exercise training improves the aging-induced downregulation of myosin heavy
chain (MHC) and sarcoplasmic reticulum (SR) Ca(2+)-ATPase, which participate in
the regulation of cardiac contraction and relaxation. Thyroid hormone receptor
(TR), a transcriptional activator, affected the regulation of gene expression of
MHC and SR Ca(2+)-ATPase. We hypothesized that myocardial TR signaling
contributes to a molecular mechanism of exercise training-induced improvement of
MHC and SR Ca(2+)-ATPase genes with cardiac function in old age. We investigated
whether TR signaling and gene expression of MHC and SR Ca(2+)-ATPase in the aged
heart are affected by exercise training, using the hearts of sedentary young
rats (4 mo old), sedentary aged rats (23 mo old), and trained aged rats (23 mo
old, swimming training for 8 wk). Trained aged rats showed improvement in
cardiac function. Expression of TR-alpha1 and TR-beta1 proteins in the heart
were significantly lower in sedentary aged rats than in sedentary young rats and
were significantly higher in trained aged rats than in sedentary aged rats. The
activity of TR DNA binding to the transcriptional regulatory region in the
alpha-MHC and SR Ca(2+)-ATPase genes and the mRNA and protein expression of
alpha-MHC and SR Ca(2+)-ATPase in the heart and plasma 3,3'-triiodothyronine and
thyroxine levels were altered in association with changes in the myocardial TR
protein levels. These findings suggest that exercise training improves the
aging-induced downregulation of myocardial TR signaling-mediated transcription
of MHC and SR Ca(2+)-ATPase genes, thereby contributing to the improvement of
cardiac function in trained aged hearts.
DOI: 10.1152/ajpheart.00761.2003
PMID: 14704232 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18211669
|
1. BMC Endocr Disord. 2008 Jan 22;8:1. doi: 10.1186/1472-6823-8-1.
Relating circulating thyroid hormone concentrations to serum interleukins-6 and
-10 in association with non-thyroidal illnesses including chronic renal
insufficiency.
Abo-Zenah HA(1), Shoeb SA, Sabry AA, Ismail HA.
Author information:
(1)Department Of Internal Medicine, Faculty of Medicine, Menufiya University,
Egypt. abozenahamdy@hotmail.com
BACKGROUND: Because of the possible role of cytokines including interleukins
(IL) in systemic non-thyroidal illnesses' (NTI) pathogenesis and consequently
the frequently associated alterations in thyroid hormone (TH) concentrations
constituting the euthyroid sick syndrome (ESS), we aimed in this research to
elucidate the possible relation between IL-6 & IL-10 and any documented ESS in a
cohort of patients with NTI.
METHODS: Sixty patients and twenty healthy volunteers were recruited. The
patients were subdivided into three subgroups depending on their underlying NTI
and included 20 patients with chronic renal insufficiency (CRI), congestive
heart failure (CHF), and ICU patients with myocardial infarction (MI).
Determination of the circulating serum levels of IL-6 and IL-10, thyroid
stimulating hormone (TSH), as well as total T4 and T3 was carried out.
RESULTS: In the whole group of patients, we detected a significantly lower T3
and T4 levels compared to control subjects (0.938 +/- 0.477 vs 1.345 +/- 0.44
nmol/L, p = 0.001 and 47.9 +/- 28.41 vs 108 +/- 19.49 nmol/L, p < 0.0001
respectively) while the TSH level was normal (1.08+0.518 muIU/L). Further, IL-6
was substantially higher above controls' levels (105.18 +/- 72.01 vs 3.35 +/-
1.18 ng/L, p < 0.00001) and correlated negatively with both T3 and T4 (r =
-0.620, p < 0.0001 & -0.267, p < 0.001, respectively). Similarly was IL-10 level
(74.13 +/- 52.99 vs 2.64 +/- 0.92 ng/ml, p < 0.00001) that correlated negatively
with T3 (r = -0.512, p < 0.0001) but not T4. Interestingly, both interleukins
correlated positively (r = 0.770, p = <0.001). Moreover, IL-6 (R2 = 0.338, p =
0.001) and not IL-10 was a predictor of low T3 levels with only a borderline
significance for T4 (R2 = 0.082, p = 0.071).By subgroup analysis, the proportion
of patients with subnormal T3, T4, and TSH levels was highest in the MI patients
(70%, 70%, and 72%, respectively) who displayed the greatest IL-6 and IL-10
concentrations (192.5 +/- 45.1 ng/L & 122.95 +/- 46.1 ng/L, respectively)
compared with CHF (82.95 +/- 28.9 ng/L & 69.05 +/- 44.0 ng/L, respectively) and
CRI patients (40.05 +/- 28.9 ng/L & 30.4 +/- 10.6 ng/L, respectively).
Surprisingly, CRI patients showed the least disturbance in IL-6 and IL-10
despite the lower levels of T3, T4, and TSH in a higher proportion of them
compared to CHF patients (40%, 45%, & 26% vs 35%, 25%, & 18%, respectively).
CONCLUSION: the high prevalence of ESS we detected in NTI including CRI may be
linked to IL-6 and IL-10 alterations. Further, perturbation of IL-6 and not
IL-10 might be involved in ESS pathogenesis although it is not the only key
player as suggested by our findings in CRI.
DOI: 10.1186/1472-6823-8-1
PMCID: PMC2254394
PMID: 18211669
|
http://www.ncbi.nlm.nih.gov/pubmed/15055637
|
1. Gen Dent. 2003 Sep-Oct;51(5):458-61; quiz 462.
Burning mouth syndrome: a guide for the general practitioner.
Pinto A(1), Stoopler ET, DeRossi SS, Sollecito TP, Popovic R.
Author information:
(1)Department of Oral Medicine, University of Pennsylvania School of Dental
Medicine, Philadelphia, USA.
A commonly misdiagnosed condition, burning mouth syndrome (BMS) is characterized
by burning sensations of the oral cavity in the absence of physical
abnormalities of the oral mucosa. BMS affects middle-aged women predominantly.
This condition has a multifactorial etiology, although several conditions have
been associated with BMS, including depression/anxiety, hematinic deficiencies
(iron, folate, and vitamin B complex), oral habits such as tongue thrusting and
bruxism, and idiopathic BMS. Multiple approaches to treatment have been
described in the literature, although few controlled clinical trials have been
designed to determine their efficacy. This article examines BMS, its related
factors, and treatment options available to the general dentist.
PMID: 15055637 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/999108
|
1. Ann Intern Med. 1976 Dec;85(6):724-30. doi: 10.7326/0003-4819-85-6-724.
Thyroid function and metabolic state in chronic renal failure.
Spector DA, Davis PJ, Helderman JH, Bell B, Utiger RD.
Thirty-eight patients with chronic renal insufficiency who were in a dialysis
program underwent studies of thyroid function and metabolic status. Mean values
for serum total and free thyroxine (T4) concentrations and thyroxine-binding
globulin capacity were within normal limits. Although mean serum total
triiodothyronine (T3) concentration was normal, 43% of the group had low serum
T3 and 54% had low serum free T3 concentrations. Serum thyrotrophin (TSH)
concentrations were normal in all but four subjects who had very slight
elevations. Metabolic status was assessed by various metabolic tests; mean
values for each of these tests were normal, and the clinical index scores
indicated that all patients were euthyroid. Results of metabolic testing were
similar in patients with low and those with normal serum T3 concentrations. Low
serum T3 measurements did not accurately reflect metabolic state in patients
with chronic renal failure, whereas serum free T4 and TSH concentrations were
reliable indicators of thyroid state.
DOI: 10.7326/0003-4819-85-6-724
PMID: 999108 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19622616
|
1. J Clin Endocrinol Metab. 2009 Oct;94(10):3757-62. doi: 10.1210/jc.2009-0940.
Epub 2009 Jul 21.
Glucocorticoids are preferable to thionamides as first-line treatment for
amiodarone-induced thyrotoxicosis due to destructive thyroiditis: a matched
retrospective cohort study.
Bogazzi F(1), Tomisti L, Rossi G, Dell'Unto E, Pepe P, Bartalena L, Martino E.
Author information:
(1)Department of Endocrinology and Metabolism, University of Pisa, 56124 Pisa,
Italy. f.bogazzi@endoc.med.unipi.it
CONTEXT: Type 2 amiodarone-induced thyrotoxicosis (AIT) is a destructive
thyroiditis usually responsive to glucocorticoids; however, recent surveys
showed that many expert thyroidologists worldwide use thionamides for type 2 AIT
patients.
OBJECTIVE: The objective of the study was to compare the effectiveness of
methimazole (MMI) or prednisone (GLU) in type 2 AIT patients who had a short
cure time according to a published predictive model.
DESIGN: This was a matched retrospective cohort study.
SETTING: The study was conducted at a university center.
PATIENTS: Forty-two untreated type 2 AIT patients with a predicted cure time <
or = 40 d were divided into two groups (MMI and GLU groups). After matching for
the predicted cure time, patients in the GLU group were selected in a 1:1 ratio
to patients in the MMI group.
INTERVENTION: Patients were treated with GLU or MMI for 40 d. Patients still
thyrotoxic after 40 d continued glucocorticoids if in the GLU group or were
switched to prednisone (MMI-GLU group) if in the MMI group.
MAIN OUTCOME MEASURE: Time and rate of cure (healing) at 40 d were measured.
RESULTS: Patients still thyrotoxic after 40 d were 23.8 +/- 9.3% in the GLU
group and 85.7 +/- 7.6% in the MMI group (P = 0.000). The GLU and MMI-GLU groups
did not significantly differ in the nonhealing rate at 40 d (P = 0.730). When
patients in the MMI group were treated with glucocorticoids, 94.1% patients
achieved euthyroidism within 40 d. However, the global median cure time (MMI
period + prednisone period) was longer (60 d, 95% confidence interval 53.5-66.5
d) in the MMI-GLU group than the GLU group (21 d, 95% confidence interval
15.1-26.9 d).
CONCLUSIONS: Glucocorticoids are the first-line treatment in type 2 AIT, whereas
thionamides play no role in this destructive thyroiditis.
DOI: 10.1210/jc.2009-0940
PMID: 19622616 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10431669
|
1. Cutis. 1999 Jul;64(1):29-35.
A review of burning mouth syndrome.
Muzyka BC(1), De Rossi SS.
Author information:
(1)Louisiana State University Medical Center, School of Dentistry, New Orleans
70119, USA.
Burning mouth syndrome is a complicated, poorly understood, predominantly oral
condition that affects more than 1 million people in the United States. Women
are particularly affected by the condition; they are diagnosed with symptoms
seven times more frequently than males. Burning mouth syndrome is characterized
by a burning, painful sensation of the oral mucosa that most commonly involves
the anterior tongue. Many precipitating factors to burning mouth syndrome have
been proposed, and treatment addressing these factors has had limited success.
Patients with burning mouth syndrome are more likely to be evaluated by
physicians, and therefore it is advantageous for the physician to be familiar
with this oral condition. This paper reviews burning mouth syndrome, associated
causative factors, and treatment strategies for the physician.
PMID: 10431669 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16142094
|
1. Ann Otolaryngol Chir Cervicofac. 2005 Jun;122(3):146-9. doi:
10.1016/s0003-438x(05)82340-0.
[Cognitive-behavioral therapy in the burning mouth syndrome--a new approach].
[Article in French]
Bonfils P(1), Peignard P, Malinvaud D.
Author information:
(1)Formation Associée Claude Bernard et Unité CNRS UPRESSA 7060, Hôpital
Européen Georges Pompidou, Faculté Necker -- Enfants Malades, Université René
Descartes, 20 rue Leblanc, F-75015 Paris. pierre.bonfils@egp.ap-hop-paris.fr
OBJECTIVE: The aim of this study is to present a new approach of burning mouth
syndrome treatment by cognitive and behavioral therapy.
METHODS: Cognitive and behavioral therapy in a patient with severe and resistant
burning mouth syndrome.
RESULTS: Disappearing of the oral pain of the burning mouth syndrome.
CONCLUSION: After a review of the literature, we propose the treatment of
burning mouth syndrome by cognitive and behavioral therapy.
DOI: 10.1016/s0003-438x(05)82340-0
PMID: 16142094 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17439072
|
1. Recenti Prog Med. 2007 Feb;98(2):120-8.
[Burning mouth syndrome].
[Article in Italian]
Scardina GA(1), Pisano T, Messina P.
Author information:
(1)Dipartimento di Scienze Stomatologiche G. Messina, Sezione di
Odontostomatologia, Università, Palermo. scardina@odonto.unipa.it
Burning mouth syndrome (BMS) is characterized by burning sensations of the oral
cavity in the absence of abnormalities of the oral mucosa. BMS predominantly
affects middle-aged women. This condition has a multifactorial etiology.
Multiple approaches to treatment have been described. This article examines BMS,
its related factors, and treatment options.
PMID: 17439072 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18985004
|
1. Kulak Burun Bogaz Ihtis Derg. 2008 May-Jun;18(3):188-96.
Burning mouth syndrome.
Boy-Metin Z(1), Kayhan KB, Unür M.
Author information:
(1)Department of Oral Surgery and Medicine, Faculty of Dentistry, Istanbul
University, Istanbul, Turkey. zeynepboy@yahoo.com
Burning mouth syndrome (BMS) is characterized by oral burning or similar pain in
the absence of detectable oral mucosa changes. This condition is more common
among middle-aged and elderly women. Although various local, systemic, and
psychological factors are considered to be possible causes of BMS, it is still a
challenge in the field of oral medicine. The aim of this review was to discuss
several aspects of BMS, update current knowledge, and provide guidelines for
patient management.
PMID: 18985004 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22881233
|
1. Physiol Res. 2012;61(5):495-501. doi: 10.33549/physiolres.932321. Epub 2012
Aug 8.
Thyroid hormone abnormalities in hemodialyzed patients: low triiodothyronine as
well as high reverse triiodothyronine are associated with increased mortality.
Horáček J(1), Dusilová Sulková S, Kubišová M, Safránek R, Malířová E, Kalousová
M, Svilias I, Malý J, Sobotka L, Zák P.
Author information:
(1)Department of Internal Medicine IV, Faculty of Medicine and University
Hospital Hradec Králové, Charles University in Prague, Hradec Králové, Czech
Republic. horacek9@gmail.com
Numerous abnormalities of thyroid hormones in end-stage renal disease (ESRD)
have been described. Our aim was to analyze the impact of these abnormalities on
survival. In 167 hemodialyzed ESRD patients, TSH and thyroid hormone levels (T4,
fT4, T3, fT3, rT3) were determined. The patients were then prospectively
followed up for up to 5 years and the possible impact of any observed
abnormalities on their mortality was studied. Only 16.8 % patients had all six
tests within the reference range. The pattern of nonthyroidal illness syndrome
was found in 56.3 %. Low T3 was particularly common (44.3 %), and clearly
associated with increased 6- and 12-month mortality and decreased overall
survival (log rank test, P=0.007). Independent of T3 levels (Spearman
correlation, NS), increased rT3 was more frequently observed (9.9 %) than
expected from the literature, and was also related to increased mortality and
decreased survival (log rank test, P=0.021). Increased rT3 may be more common in
ESRD patients than previously described, and together with decreased T3 it may
serve as an indicator of poor prognosis in subsequent months.
DOI: 10.33549/physiolres.932321
PMID: 22881233 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19450321
|
1. BMJ Clin Evid. 2008 Mar 14;2008:1301.
Burning mouth syndrome.
Buchanan J(1), Zakrzewska J.
Author information:
(1)Barts and The London School of Medicine and Dentistry, Dental Institute,
Royal London Hospital, London, UK.
INTRODUCTION: Burning mouth syndrome mainly affects women, particularly after
the menopause, when its prevalence may be 18-33%.
METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the
following clinical question: What are the effects of treatments for burning
mouth syndrome? We searched: Medline, Embase, The Cochrane Library, and other
important databases up to February 2007 (Clinical Evidence reviews are updated
periodically, please check our website for the most up-to-date version of this
review). We included harms alerts from relevant organisations such as the US
Food and Drug Administration (FDA) and the UK Medicines and Healthcare products
Regulatory Agency (MHRA).
RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met
our inclusion criteria. We performed a GRADE evaluation of the quality of
evidence for interventions.
CONCLUSIONS: In this systematic review we present information relating to the
effectiveness and safety of the following interventions: anaesthetics (local),
antidepressants, benzodiazepines (topical clonazepam), benzydamine
hydrochloride, cognitive behavioural therapy (CBT), dietary supplements, and
hormone replacement therapy (HRT) in postmenopausal women.
PMCID: PMC2907957
PMID: 19450321 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17967714
|
1. J Diabetes Complications. 2007 Nov-Dec;21(6):397-402. doi:
10.1016/j.jdiacomp.2006.08.001.
Burning mouth syndrome and peripheral neuropathy in patients with type 1
diabetes mellitus.
Moore PA(1), Guggenheimer J, Orchard T.
Author information:
(1)Oral Health Science Institute, University of Pittsburgh School of Dental
Medicine, Pittsburgh, PA 15206, USA. pam7@pitt.edu
OBJECTIVE: Burning mouth syndrome (BMS) has been attributed secondarily to
diabetes, poor glycemic control, and diabetic neuropathy. The prevalence and
predictor factors of BMS were compared in type 1 diabetes mellitus (T1DM) and
nondiabetic subjects.
STUDY DESIGN: An assessment of 371 adult T1DM subjects and 261 control subjects
participating in a cross-sectional epidemiological study of oral health
complications of diabetes was performed. Subjects were participants of the
Pittsburgh Epidemiology of Diabetes Complications study. Prevalence of BMS was
determined by response to the following questions: "Do you now or in the last
month had any persistent uncomfortable sensations in your mouth or tongue? If
yes, would you describe the feeling as tingling, burning, sore, numb, or other?"
RESULTS: Burning mouth syndrome symptoms were reported by 28 T1DM and control
subjects (4.6%). Eleven had oral pathologies that might explain the BMS,
including atrophy of the tongue papillae, fissured tongue, denture stomatitis,
and candidiasis. The prevalence of BMS within the two groups with no pathologies
was similar; 12/371 (3.2%) vs. 5/233 (2.1%). Multivariate analyses of the 12
T1DM subjects with BMS found significant associations for female gender (P=.042)
and a diagnosis of diabetic peripheral neuropathy (P=.024).
CONCLUSIONS: In this T1DM population, BMS or related discomforts occurred
slightly more frequently than in the control group. Symptomatic T1DM subjects
were more likely to be female who had also developed peripheral neuropathy.
These findings and other similarities between BMS and diabetic peripheral
neuropathy suggest that a neuropathic process may be an underlying source of BMS
in some patients who have no apparent oral abnormality.
DOI: 10.1016/j.jdiacomp.2006.08.001
PMID: 17967714 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8170453
|
1. Minerva Stomatol. 1994 Jan-Feb;43(1-2):49-55.
[The burning mouth syndrome. A clinical study].
[Article in Italian]
Trombelli L(1), Zangari F, Calura G.
Author information:
(1)Istituto di Clinica Odontostomatologica, Università degli Studi di Ferrara.
Burning mouth syndrome (BMS) is a distinct clinical entity characterized by a
chief complaint of unremitting oral burning concomitant with no oral mucosal
clinically observable lesions. Numerous causes of this condition have been
suggested, including local factors, systemic factors, and psychogenic disorders.
A total of 36 consecutive subjects, 32 women and 4 men, complaining of BMS, who
had attended the Dental Clinic of the University of Ferrara during a period of 2
years, was studied. The method of assessment followed closely a strictly
co-ordinated management protocol based on conventional guidelines, namely
history, clinical examination and special investigations. A detailed history was
taken of duration of the condition, site affected, and pattern of burning. The
severity and the response to treatment were assessed with a Visual Linear
Analogue Scale (VLAS). A full medical history was taken, with regard to
xerostomia-inducing drug assumption. The presence and the severity of menopausal
symptoms were explored. Inquiries were made on use of mouthwashes. For the
denture-wearers, specific questioning was directed to the length of
denture-wearing experience, temporal association of the symptom with the wearing
of dentures, relationship to burning sensation of any relines or repairs,
denture cleaning technique, and use of fixatives. A complete routine intraoral
and extraoral examination was performed. The presence of parafunctional habits,
such as tongue thrusting, clenching, grinding, lip and cheek biting, was
investigated. If dentures were worn, their design and condition were examined.
In particular, the relation between the vertical and horizontal components of
the jaw and the denture base extension was assessed and the freeway space
measured.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 8170453 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11871678
|
1. Am Fam Physician. 2002 Feb 15;65(4):615-20.
Burning mouth syndrome.
Grushka M(1), Epstein JB, Gorsky M.
Author information:
(1)William Osler Health Center, Toronto, Ontario, Canada. mgrushka@yahoo.com
Burning mouth syndrome is characterized by a burning sensation in the tongue or
other oral sites, usually in the absence of clinical and laboratory findings.
Affected patients often present with multiple oral complaints, including
burning, dryness and taste alterations. Burning mouth complaints are reported
more often in women, especially after menopause. Typically, patients awaken
without pain but note increasing symptoms through the day and into the evening.
Conditions that have been reported in association with burning mouth syndrome
include chronic anxiety or depression, various nutritional deficiencies, type 2
diabetes (formerly known as non-insulin-dependent diabetes) and changes in
salivary function. However, these conditions have not been consistently linked
with the syndrome, and their treatment has had little impact on burning mouth
symptoms. Recent studies have pointed to dysfunction of several cranial nerves
associated with taste sensation as a possible cause of burning mouth syndrome.
Given in low dosages, benzodiazepines, tricyclic antidepressants or
anticonvulsants may be effective in patients with burning mouth syndrome.
Topical capsaicin has been used in some patients.
PMID: 11871678 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22612823
|
1. Gerodontology. 2012 Jun;29(2):84-9. doi: 10.1111/j.1741-2358.2010.00384.x.
Aetiology and therapeutics of burning mouth syndrome: an update.
Spanemberg JC(1), Cherubini K, de Figueiredo MA, Yurgel LS, Salum FG.
Author information:
(1)Stomatology and Bucomaxillofacial Cancer Prevent Division, São Lucas
Hospital, Pontifical Catholical University of Rio Grande do Sul (PUCRS), Porto
Alegre, Brazil.
OBJECTIVE: To provide a review on the aetiology and therapeutic options for the
management of patients with burning mouth syndrome (BMS).
BACKGROUND: BMS is a chronic disorder that frequently affects women and is
characterised by burning symptoms of the oral mucosa without clinical signs.
This syndrome has a complex and multifactorial characteristics, but its
aetiology remains unknown and this makes it difficult with regard to the
treatment and management of such patients. Despite not being accompanied by
evident organic changes and not presenting risks to health, BMS can
significantly reduce the quality of life for patients.
METHODS AND MATERIALS: The article reviews the literature regarding aetiologic
factors, clinical implications and treatment of BMS.
CONCLUSION: involvement of neurological, emotional and hormonal alterations is
proposed in BMS aetiology. However the mechanisms of its development are complex
and not completely understood. Tricyclic antidepressants, benzodiazepines and
antipsychotic drugs are the most accepted options in treatment and show variable
results. The correct diagnosis of BMS and the exclusion of possible local or
systemic factors that can be associated with the symptoms are fundamental. It is
also important to evaluate the quality of life for these patients to recognise
the potential impact of this condition on their lives.
© 2012 The Gerodontology Society and John Wiley & Sons A/S.
DOI: 10.1111/j.1741-2358.2010.00384.x
PMID: 22612823 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20440632
|
1. Clin Oral Investig. 2011 Aug;15(4):571-5. doi: 10.1007/s00784-010-0419-5. Epub
2010 May 4.
Risk factors in burning mouth syndrome: a case-control study based on patient
records.
Netto FO(1), Diniz IM, Grossmann SM, de Abreu MH, do Carmo MA, Aguiar MC.
Author information:
(1)Department of Oral Pathology and Maxillofacial Surgery, School of Dentistry,
Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627 Pampulha,
Cep. 31270901 Belo Horizonte, MG, Brazil.
Burning mouth syndrome (BMS) is a multifactorial condition which is still poorly
understood. The aim of this study was to evaluate a group of patients with BMS,
as compared to a control group, and to describe related local and systemic
factors. Records of patients referred to the Oral Pathology Service at the
School of Dentistry over a period of 7 years were considered for the study,
within which 32 patients with a diagnosis of BMS were found. A randomized group
matched for age and gender was also evaluated for the study. Data were analyzed
statistically using the SPSS 12.0 for Windows. Prevalence of BMS was 0.99% (32
BMS patients/3,243 records), considering that females were more commonly
affected than were males and that the majority of the individuals were in their
sixties. The univariate analysis performed comparing the two groups revealed
statistical differences concerning the presence of gastrointestinal diseases
(p = 0.003) and urogenital diseases (p = 0.012). The intake of H-2 receptor
antagonist and proton pump inhibitor drugs (p = 0.015) also proved to be
significant. Logistic regression analysis confirmed that gastrointestinal and
urogenital problems were indeed risk factors that were solely associated with
BMS. Although a diversity of related factors could be identified,
gastrointestinal problems were the most prevalent, suggesting that the
management of BMS patients requires attention and an appropriate approach to
such disorders.
DOI: 10.1007/s00784-010-0419-5
PMID: 20440632 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12017897
|
1. Harefuah. 2002 Apr;141(4):384-7, 407.
[Burning mouth syndrome].
[Article in Hebrew]
Elad S(1), Czerninski R, Eliay E.
Author information:
(1)Department of Mouth Medicine, University Hospital Hadassah, Jerusalem,
Israel.
Burning sensation of the tongue is a common complaint. In some patients this is
diagnosed as Burning Mouth Syndrome (BMS). The prevalence of BMS is 0.8-19% of
the general population. The typical complaint is localized to the anterior part
of the tongue and may be accompanied by dry mouth sensation or taste disorder.
The differential diagnosis of BMS is based on the specific details of the
complaint, the clinical findings and laboratory results. The patients population
consists of mainly post-menopausal women, even though it can appear in younger
patients of both genders. The pathogenesis is only partially identified. There
are different treatment approaches.
PMID: 12017897 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12618668
|
1. Med Oral. 2003 Mar-Apr;8(2):84-90.
Burning mouth syndrome in the Basque Country: a preliminary study of 30 cases.
[Article in English, Spanish]
Eguia Del Valle A(1), Aguirre-Urizar JM, Martinez-Conde R, Echebarria-Goikouria
MA, Sagasta-Pujana O.
Author information:
(1)Medicina Bucal, Departamento de Estomatología, Facultad de Medicina y
Odontología, Universidad del País Vasco/EHU. otpagurj@lg.ehu.es
OBJECTIVES: To know the most important clinical features of Burning Mouth
Syndrome (BMS) in our environment.
MATERIAL AND METHODS: A prospective study of 30 BMS patients, 29 female and 1
male, with a mean age of 60.2 years (range 37-89), was made. A previously
designed clinical protocol, including blood counts, levadure culture, oral pH
measurement and non-stimulated salivary flow rate, was completed by all
patients. Comparative and descriptive statistical analysis was performed. The
Chi-square test was applied (p< 0.05).
RESULTS: Moreover of a burning sensation, 60 % of patients presented oral
dryness and 60 % dysgeusia. The tongue was the most frequent site affected of
burning sensation (66.7 %). Type II of BMS was the most common (53.3%). In
women, 82.9 % were postmenopausal. A 13.3 % of patients suffered type II
Diabetes, 6.7 % vitamin deficiency and 56.6 % used xerostomy-inducer medication.
The 56.6 % of patients showed chronic anxiety and/or depression. The 46.7 % had
a deficient oral hygiene level and 44.4 % wore inadequate dentures. Salivary
flow rate was decreased in 50 % of patients. Significant levadure growth was not
detected in any case.
CONCLUSIONS: BMS patients in our environment are principally postmenopausal
women, with tongue burning, xerostomy, dysgeusia and chronic anxiety and/or
depression.
PMID: 12618668 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8469539
|
1. Oral Surg Oral Med Oral Pathol. 1993 Mar;75(3):303-7. doi:
10.1016/0030-4220(93)90141-p.
Burning mouth syndrome. Evaluation of multiple variables among 85 patients.
Maresky LS(1), van der Bijl P, Gird I.
Author information:
(1)Department of Oral Medicine and Periodontics, Faculty of Dentistry,
University of Stellenbosch, Tygerberg, South Africa.
The relationship between burning mouth syndrome and 48 variables was
investigated in 241 patients, 45 years old and older, who had attended the Oral
Medicine Clinic of the Faculty of Dentistry, University of Stellenbosch during a
period of 4 years. A total of 85 cases of burning mouth syndrome were diagnosed
in 65 women and 20 men. Statistically significant relationships (p < 0.05) were
found with self-medication, xerostomia, and other salivary disturbances in both
men and women with burning mouth syndrome when compared with their respective
controls. Among the women with BMS, significant relationships were also found
with anemia, inadequate diet, chronic infection, hormone therapy,
ulcerative/erosive lesions, and atrophy. In contrast men with BMS showed
statistically significant relationships between taking prescribed medication,
central nervous system disturbances, gingivitis, and denture-related problems.
In addition, significant associations were related to variables such as
psychogenic factors, regurgitation, flatulence, and periodontitis.
DOI: 10.1016/0030-4220(93)90141-p
PMID: 8469539 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9237148
|
1. J Prosthet Dent. 1997 Jul;78(1):93-7. doi: 10.1016/s0022-3913(97)70089-1.
Burning mouth syndrome: a review of etiologies.
Cibirka RM(1), Nelson SK, Lefebvre CA.
Author information:
(1)Department of Oral Rehabilitation, School of Dentistry, Medical College of
Georgia, Augusta, USA.
STATEMENT OF PROBLEM: Dental practitioners occasionally have patients present
clinically with a history of chief complaint of burning and painful sensations
in the oral cavity. Often the patient demonstrates clinically normal mucosa,
which can make formulating a diagnosis challenging. This scenario, has been
referred to as burning mouth syndrome, a multifactorial syndrome.
PURPOSE: The purpose of this article is to present a review of etiologic factors
and clinical implications related to the condition of burning mouth syndrome.
DOI: 10.1016/s0022-3913(97)70089-1
PMID: 9237148 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23201368
|
1. Oral Maxillofac Surg Clin North Am. 2013 Feb;25(1):67-76, vi. doi:
10.1016/j.coms.2012.11.001. Epub 2012 Nov 30.
Burning mouth syndrome.
Crow HC(1), Gonzalez Y.
Author information:
(1)Department of Oral Diagnostic Sciences, University at Buffalo, 355 Squire
Hall, 3435 Main Street, Buffalo, NY 14214, USA. hccrow@buffalo.edu
Pain in the tongue or oral tissues described as "burning" has been referred to
by many terms including burning mouth syndrome. When a burning sensation in the
mouth is caused by local or systemic factors, it is called secondary burning
mouth syndrome and when these factors are treated the pain will resolve. When
burning mouth syndrome occurs in the absence of identified risk indicators, the
term primary burning mouth syndrome is utilized. This article focuses on
descriptions, etiologic theories, and management of primary burning mouth
syndrome, a condition for which underlying causative agents have been ruled out.
Copyright © 2013. Published by Elsevier Inc.
DOI: 10.1016/j.coms.2012.11.001
PMID: 23201368 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23050296
|
1. Int J Pharm Compd. 2012 May-Jun;16(3):196-205.
Burning mouth syndrome: a discussion of a complex pathology.
Zur E(1).
Author information:
(1)Super-Pharm, Petach-Tikvah, Israel. eyalz@super-pharm.co.il
Burning mouth syndrome is a complex pathology for which there is very little
information about the etiology and pathogenesis. This lack of knowledge leaves
patients with suboptimal treatments. This article discusses the existing
scientific evidence about this disease. Since topical oral use of clonazepam
have been shown to be effective and safe to treat some patients suffering with
burning mouth syndrome, formulations including clonazepam are included with this
article. Compounding topical preparations of clonazepam offers opportunities for
compounding pharmacists to be more involved in improving the quality of life of
burning mouth syndrome patients.
PMID: 23050296 [Indexed for MEDLINE]
|
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